Tissue Expander For Breast Reconstruction Being Capable of Real-Time Monitoring and Treatment of Capsular Contracture Based on Matrix Metalloproteinase Sensor and Patients Information System Associated Therewith

Abstract

The present invention relates to a breast reconstruction tissue expander capable of real-time monitoring and treatment of capsular contracture including an MMP sensor, and a patient information system associated therewith. According to the present invention, patients or medical staff can easily check and evaluate in real-time, even from outside the human body, the presence of capsular contracture that may occur when wearing the breast reconstruction tissue expander, as well as the resulting inflammation or side effects. Consequently, effective treatment and response become possible before or when capsular contracture occurs.

Description

Technology Field

[0001] This specification relates to a breast reconstruction tissue expander capable of real-time spherical structure monitoring and treatment based on an implantable MMP sensor, and a patient information system associated therewith. Background Technology

[0002] Recently, as life expectancy following treatment for breast-related diseases such as breast cancer has increased and cosmetic aspects have become more emphasized, various methods for breast reconstruction after mastectomy are being widely used.

[0003] As an example of the breast reconstruction method described above, a breast reconstruction surgery is used in which a tissue expander is first inserted to expand the soft tissue to a level where an implant can be inserted, and then the tissue expander is replaced with a permanent implant.

[0004] When performing breast reconstruction, tissue expanders or implants are foreign substances that can enter the chest area and cause capsular contracture. For reference, capsular contracture is a condition in which a thick capsule forms around the inserted tissue expander or implant, causing it to gradually become hard to the touch, and is accompanied by inflammation. In cases where such side effects, including inflammation, occur, treatment is typically limited to subsequently surgically removing the tissue expander or implant.

[0005] Accordingly, the inventors have arrived at the present invention by diligently researching a method to monitor and treat capsular contracture and the resulting inflammation in real time as much as possible during breast reconstruction surgery. Prior art literature

[0006] U.S. Patent Application Publication No. 2011-0152913 The problem to be solved

[0007] In one aspect, the objective of the present invention is to provide a device that allows a patient or medical staff to easily check or evaluate side effects, such as the occurrence of capsular contracture and subsequent inflammation, in real time from outside the human body when wearing a tissue expander for breast reconstruction.

[0008] In another aspect, the object of the present invention is to provide a system that stores information transmitted from the tissue expander in real-time and cumulatively and allows medical staff and patients to share it. means of solving the problem

[0009] In one aspect, the present invention provides a tissue expander for breast reconstruction, wherein the tissue expander comprises an MMP sensor portion attached to the tissue expander, and the MMP sensor portion comprises a biosensor that detects MMP (Matrix metalloproteinase), which is a collagenase of surrounding tissue adjacent to the tissue expander.

[0010] In one example, the MMP sensor may be a biosensor comprising an MMP-specific peptide that induces a change in current upon cleavage by MMP. Additionally, it may be an MMP-specific redox reporter-peptide biosensor further comprising a redox reporter substance.

[0011] The above tissue expander can detect spherical contracture depending on whether collagenase is detected.

[0012] In another aspect, the present invention provides a patient information system that wirelessly transmits to the aforementioned tissue expander, receives tunneling current signal information according to the MMP from the tissue expander, and provides information regarding whether a spherical structure is established.

[0013] In another aspect, the present invention provides a user terminal that wirelessly transmits to the aforementioned tissue expander, receives tunneling current signal information according to the MMP from the tissue expander, and provides information regarding whether a spherical structure is established. Effects of the invention

[0014] According to the present invention, side effects such as capsular contracture and subsequent inflammation that may occur when wearing a tissue expander for breast reconstruction can be easily identified and evaluated in real time by the patient or medical staff even from outside the human body, thereby enabling effective treatment and response before or when capsular contracture occurs.

[0015] In addition, information transmitted from the tissue expander is stored in real-time and cumulatively on the hospital system and / or on the user terminals of medical staff or patients, and can assist in establishing medical and treatment plans as it is shared between medical staff and patients. Brief explanation of the drawing

[0016] Figure 1 is a schematic diagram showing the principle of spherical construction. FIG. 2 is a schematic diagram showing a tissue expander for breast reconstruction according to one embodiment of the present invention. Figure 3a shows an enlarged view of the MMP sensor section in Figure 2. Figures 3b and 3c are enlarged schematic diagrams of the MMP sensor structure. FIGS. 4a and 4b are schematic diagrams showing a tissue expander additionally equipped with a drug port according to another embodiment of the present invention. FIG. 5 schematically illustrates a user terminal and a patient information management system associated with a tissue expander according to one embodiment of the present invention. Specific details for implementing the invention

[0017] In this specification, terms such as “part,” “module,” “device,” “terminal,” “sensor,” and “system” may refer to a combination of hardware as well as software driven by said hardware. For example, the hardware may be a data processing device including a CPU or other processor. Additionally, the software driven by the hardware may be a program such as an executing process, object, executable, thread of execution, or computational program.

[0018] In this specification, the MMP sensor is not limited to any biosensor capable of detecting MMP, and may include known biosensors capable of detecting MMP. For example, as described below, the biosensor may be a current change measuring biosensor, i.e., an MMP-specific peptide biosensor, which includes a peptide capable of being cleaved by MMP and a redox reporter (tunneling state) that causes a change in electron transfer (redox reaction) depending on the distance from the electrode.

[0019] The present invention will be described in detail below with reference to the attached drawings.

[0020] The tissue expander for breast reconstruction of exemplary embodiments of the present invention includes an MMP sensor unit attached to the tissue expander. The MMP sensor unit includes a biosensor that detects MMP (Matrix metalloproteinase), which is a collagenase of surrounding tissue adjacent to the tissue expander, and since spherical contracture can be detected depending on whether the collagenase is detected, real-time monitoring of spherical contracture is possible.

[0021] Figure 1 is a schematic diagram showing the principle of spherical construction.

[0022] As illustrated in Fig. 1, the actual reason for the occurrence of capsular contracture is that collagen fibers formed along the surface of silicone breast implants or tissue expanders are cleaved by collagenase, and the remaining fragments are reconnected through cross-linking, resulting in a shortening of the collagen fibers surrounding the implant, thereby inducing capsular contracture. In other words, since collagenase plays the most decisive role in capsular contracture, capsular contracture can be detected by detecting this collagenase.

[0023] Accordingly, in exemplary embodiments of the present invention, a sensor that detects collagenase, i.e., Matrix metalloproteinase (MMP), is mounted on a tissue expander.

[0024] In one example, the biosensor detecting the MMP may use a known sensor.

[0025] For example, the biosensor that detects the above MMP is a biosensor comprising an MMP-specific peptide and an oxidation-reduction reporter substance, such as methylene blue, in which electron transfer changes upon cleavage by MMP (i.e., an MMP-specific oxidation-reduction reporter-peptide).

[0026] That is, MMP can be detected by sensing the electron transfer between the electrode and the methylene blue (MB) that occurs as the Methylene blue connected to the peptide end moves away from the electrode upon cleavage by MMP, i.e., the tunneling current (hereinafter referred to as the tunneling current due to MMP). Consequently, contracture can be detected. This MMP-specific redox reporter-peptide biosensor is advantageous for application to the breast reconstruction tissue expanders of the embodiments of the present invention in that it can relatively easily detect spherical contracture according to changes in current.

[0027] In one example, concentric electrodes are used to integrate this biosensor with a COMS circuit, thereby enabling quantitative detection of MMP through the difference in current according to MMP concentration and / or time.

[0028] In one example, it is preferable that the MMP sensor is a sensor that detects MMP2 or MMP9 in particular.

[0029] Specifically, in embodiments of the present invention, by mounting a biosensor comprising an MB (Methylene blue, MB)-peptide, which is a peptide specifically cleaved by MMP2 or MMP9, on a tissue expander, MMP2 or MMP9 expressed during globular formation can be quantitatively detected, thereby allowing the degree of globular formation to be quantitatively detected in real time.

[0030] FIG. 2 is a schematic diagram showing a tissue expander for breast reconstruction according to one embodiment of the present invention.

[0031] As shown in FIG. 2, in one example, the tissue expander includes a body in which a protrusion (10) is formed in one part and a perimeter (20) is formed integrally with the protrusion (10) and is inclined or curved outward. Additionally, the body may include one or more port portions (30) capable of injecting an expansion solution and / or therapeutic drug, etc., into the tissue expander.

[0032] In addition, one or more MMP sensor parts (100) may be formed in the tissue expander.

[0033] In one example, an MMP sensor part (100) may be positioned spaced apart from the surface of the tissue expander.

[0034] In this regard, a biosensor detects a signal generated by a target substance and a bioreceptor capable of selectively reacting with it. It is necessary to increase selectivity to specifically react with the desired target among countless chemical and biological substances. Therefore, it is desirable for the MMP sensor portion (100) to be formed at the part of the tissue expander most likely to come into contact with human tissue, as this can increase sensing efficiency. Accordingly, the MMP sensor portion (100) can be located on the surface of the tissue expander.

[0035] At this time, it is preferable that each MMP sensor part (100) be formed on at least the protrusion (10) and the periphery part (20). As an example, one MMP sensor part (100) may be formed on the protrusion (10), and one MMP sensor part (100) may be formed on each side of the periphery part (20), but is not limited thereto.

[0036] Figure 3a shows an enlarged view of the MMP sensor section in Figure 2.

[0037] As illustrated in FIG. 3a, the MMP sensor portion (100) of the tissue expander may include: a biocompatible silicon substrate formed on at least a portion of the surface of the tissue expander; one or more MMP sensors (150) attached to the silicon substrate and comprising a redox reporter [e.g., methylene blue (MB)]-peptide that is specifically cleaved by an MMP such as MMP2 or MMP9 to change the movement of electrons; a current detection module for detecting a current from the MMP sensor; and a transmission module for transmitting the detected current signal to the outside.

[0038] FIGS. 3b and 3c are enlarged schematic diagrams of the MMP sensor structure used in one embodiment of the present invention.

[0039] In order to attach a peptide synthesized with methylene blue, which is a redox reporter, to a plurality of electrodes [e.g., gold (Au) electrodes] deposited on a silicon oxide film formed on a solid substrate such as a silicon chip, a well-shaped PDMS can first be used to connect the Cys at the peptide terminals to the gold electrodes through a thiolate bond.

[0040] In one example, a peptide capable of being cleaved by MMP2 or MMP9 can be designed to contain methylene blue (MB), which acts as a redox reporter, i.e., a tunneling state.

[0041] Specifically, by using MB-Gly-Pro-Leu-Gly-Met-Trp-Ser-Arg-Lys-Cys (MB-GPLGMWSRKC), an MMP2 or MMP9-specific MB-peptide, the Gly and Met linkage can be cleaved by MMP2 or MMP9, thereby altering electron transfer and enabling the sensing of MMP2 or MMP9. Furthermore, the degree of electron transfer can correspond to the concentration of MMP2 or MMP9.

[0042] Meanwhile, the MMP sensor unit (100) may include a current measuring module that measures the tunneling current of electrons from the MMP sensor.

[0043] The current measurement module may use concentric electrodes as shown in FIG. 3a to integrate the biosensor with a CMOS circuit for signal processing.

[0044] The above concentric electrode structure is a two-electrode structure consisting of an island electrode that detects a tunneling current signal that captures the potential and an enclosing electrode that surrounds it. Since the area of ​​the island electrode and the enclosing electrode differs by more than 1000 times, the potential of the aqueous solution is fixed to the voltage of the enclosing electrode due to the difference in capacitance of the electrical double layer with respect to the aqueous solution, thereby having a self-gating effect, so that the current change caused by MMP can be detected even without a reference electrode.

[0045] Meanwhile, in one example, the detected tunneling current signal, which changes according to the number of methylene blue fixed to the gold electrode, can be wirelessly transmitted to an external human user terminal and / or patient information system described later through the MedRadio (medical device radio communication service) frequency band.

[0046] For reference, after immobilizing MB-peptide on a gold electrode, current can be measured using cyclic voltammetry. The voltage is initially applied at -0.4V and then double-swept down to 0.2V, with a scan rate of 10 V / sec. In the equilibrium state without applied voltage, MB+ and LMB (Leucomethylene blue), a reducing agent of methylene blue, coexist in two states. However, when a voltage of -0.4V is continuously applied, electron tunneling occurs from the gold electrode to MB+, and consequently, the interface of the biosensor is entirely converted to LMB, after which current measurement can be performed.

[0047] Subsequently, when the current is measured while sweeping the voltage down to 0.2V, electron tunneling occurs from the LMB to the electrode; however, when the voltage is swept down to -0.4V after sweeping down to 0.2V, electron tunneling occurs from the electrode to MB+, contrary to when a positive voltage sweep is performed. Therefore, as the MB-peptide is cleaved by the MMP, the MB, which acts as the electron tunneling site, detaches along with the peptide, so it can be confirmed that the current gradually decreases over time.

[0048] Meanwhile, in one example, the MMP sensor unit (100) can be charged using known wireless power transfer (WPT) technology.

[0049] In addition, in one example, the sensor may be manufactured as a single chip by embedding a micro MMP sensor part (100) of, for example, 0.4 x 1.0 mm. For example, the MMP sensor part may be manufactured as a chip-type structure in which an antenna for wireless communication, a wireless charging coil, and a secondary battery are integrated together with the sensor. The wireless charging coil of the structure receives power from the outside and transfers power to the secondary battery. Additionally, an external base station for wireless power supply may be additionally provided.

[0050] Such an MMP sensor unit is capable of not only sensing spherical structures but also preventing or treating them.

[0051] That is, in one example, the MMP sensor may include an MMP-specific peptide, and an MMP inhibitor or inhibitory drug may be bound to the terminal of the peptide. For instance, a corticosteroid or doxycycline, which is an MMP2 or MMP9 inhibitory drug, may be bound to glycine at the terminal of the peptide so that the drug is released when the peptide is cleaved by MMP2 or MMP9. Accordingly, by inhibiting MMP2 or MMP9, globular formation can be prevented.

[0052] Meanwhile, in another example, when contracture is detected through the sensor, medical personnel inject a drug through a separate drug port so that the tissue expander can release the drug into the surrounding tissue.

[0053] FIGS. 4a and 4b are schematic diagrams showing a tissue expander additionally equipped with a drug port according to another embodiment of the present invention.

[0054] As illustrated in FIGS. 4a and 4b, for drug injection / release, the tissue expander body may additionally be provided with a drug port (30) along with an expansion port (40).

[0055] The above expansion port (40) includes an injection port (41) into which an expansion solution is injected and a storage portion (42) capable of storing the injected expansion solution.

[0056] A drug port (30) for drug injection / release is a port formed separately from an expansion port (40) and may include a soft injection port (34) and a hard separation wall (35). A drug injected through the injection port (34) may move through a hole (36) present on at least one surface of the separation wall (35), move through a drug transfer channel (33) to a drug release channel (31) at the end of the body, and be delivered into the body through a plurality of drug discharge ports (32). The drug release channel (31) may be provided with at least two protruding sutures (50) for fixation and support.

[0057] In this way, the aforementioned MMP current change signal collected from the sensor is transmitted to the patient information management system or user terminal described later, and if it is determined that a spherical structure has been detected based on the signal, a drug can be injected through the drug port (30) after a medical examination by a doctor, and the drug can be released into the human tissue accordingly.

[0058] The drug injected into the drug port (30) may be a drug administered for the treatment of capsular contracture that may occur due to a tissue expander implanted in the body, and may include, for example, a fibrosis inhibitor, a proliferation inhibitor, an anti-ischemic complex, an anticoagulant, etc.

[0059] The above-mentioned fibrosis inhibitors specifically include pirfenidone, mitomycin, acetylsalicylic acid, genistein, selenocystine, or tranilast, but are not limited thereto.

[0060] The above proliferation inhibitors are specifically tamoxifen, holofuginone, vitamin C, asiaticoside, and cyclosporine

[0061] Examples include cyclosporine (A), homoharringtonine, vitamin A, D-penicillamine, or liposomes, but are not limited thereto.

[0062] The above anti-ischemic complex may specifically be Necrox-5 or Necrox-7, and the above anticoagulant may specifically be a tissue type plasminogen activator, urokinase (thrombolytic), heparin or suramin, but is not limited thereto.

[0063] Meanwhile, in other exemplary embodiments of the present invention, a patient information system is provided that wirelessly transmits to the tissue expander described above, receives MMP current change signal information from the tissue expander, and provides information regarding whether a spherical structure is formed.

[0064] In addition, in another exemplary embodiment of the present invention, a user terminal is provided that wirelessly transmits to the tissue expander described above, receives MMP current change signal information from the tissue expander, and provides information regarding whether or not to construct a spherical structure.

[0065] FIG. 4 schematically illustrates a user terminal and a patient information management system associated with a tissue expander according to one embodiment of the present invention.

[0066] In one example, when a signal indicating a change in MMP current exceeding a certain level is received from the sensor, the patient information system and / or user terminal may provide an alarm signal regarding spherical contracture. In this case, the appropriate concentration of MMP at a level suspected of spherical contracture can be predicted through in vitro / in vivo experiments.

[0067] As described above, real-time monitoring of capsular contracture is made possible by a tissue expander equipped with an MMP sensor, and the results can be provided in real-time and cumulatively to a hospital's patient information management system or to medical staff and / or patient user terminals. As a result, patients or medical staff can easily identify and evaluate side effects such as capsular contracture and subsequent inflammation in real-time from outside the human body, thereby enabling preemptive treatment and response before the occurrence of capsular contracture, and can also assist in establishing medical and treatment plans. Explanation of the symbols

[0068] 10: Protrusion 20: Circumference 30: Drug port 31: Drug release channel 32: Drug outlet 33: Drug transport channels 34: Drug port infusion port 35: Drug port separation wall 36: Hole 40: Expansion Port 41: Expansion port injection port 50: Protruding suture 100: Sensor section 150: Sensor 00: Tissue expander P: Port

Claims

Claim 1 A method for detecting breast capsular contracture, wherein the method detects breast capsular contracture using a biosensor that detects Matrix Metalloproteinase (MMP), a collagenase of surrounding tissue adjacent to a human implantable tissue expander, and wherein the biosensor is attached to the tissue expander. Claim 2 delete Claim 3 A method according to claim 1, wherein the biosensor is a biosensor that detects a change in current by MMP. Claim 4 The method according to claim 1, wherein the biosensor comprises an MMP-specific peptide that induces a current change upon cleavage by an MMP. Claim 5 The method according to claim 1, wherein the biosensor comprises a peptide that induces a current change upon cleavage by MMP and further comprises an MMP-specific redox reporter-peptide biosensor comprising a redox reporter substance. Claim 6 The method according to claim 1, wherein the biosensor is an MMP2 or MMP9 specific peptide biosensor. Claim 7 A method of providing information regarding whether a spherical structure is established, detected by any one of the methods of paragraphs 1, 3 through 6, to a patient or user through a user terminal and a patient information management system. Claim 8 delete Claim 9 delete

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