Physiological parameter monitoring device and preparation method therefor, and physiological parameter monitoring system

Abstract

A physiological parameter monitoring device and a preparation method therefor, and a physiological parameter monitoring system. The physiological parameter monitoring device comprises: a first flexible layer; a first sensing layer, comprising one or more physiological parameter sensors and an electrically conductive wiring; and a second flexible layer. In a region where the first flexible layer and the second flexible layer are in direct contact, one or more implantation through holes are formed, each implantation through hole penetrating through the first flexible layer and the second flexible layer in the thickness direction of the physiological parameter monitoring device.

Description

Physiological parameter monitoring device, its preparation method, and physiological parameter monitoring system

[0001] Cross-references to related applications

[0002] This application is based on and claims priority to Chinese Patent Application No. 202411060924.0, filed on August 2, 2024, the disclosure of which is incorporated herein by reference in its entirety. Technical Field

[0003] This disclosure relates to the field of sensing technology, and more specifically, to a physiological parameter monitoring device, its preparation method, and a physiological parameter monitoring system. Background Technology

[0004] In fields such as biology and medicine, it is often necessary to monitor various physiological parameters to understand the health and disease status of the monitored subjects, or to develop appropriate health care and treatment plans. However, to accurately monitor certain physiological parameters, it may be necessary to place corresponding sensors inside the monitored body tissues, which often requires surgery, resulting in problems such as large incisions, high risk of infection, and difficulty in real-time monitoring. Therefore, improvements are needed in the monitoring of physiological parameters. Summary of the Invention

[0005] One of the purposes of this disclosure is to provide a physiological parameter monitoring device, its preparation method, and a physiological parameter monitoring system.

[0006] According to a first aspect of this disclosure, a physiological parameter monitoring device is provided, comprising:

[0007] The first flexible layer is formed of a flexible material;

[0008] A first sensing layer is disposed on one side of the first flexible layer, wherein the first sensing layer includes one or more physiological parameter sensors and conductive wiring. Each physiological parameter sensor is configured to monitor a corresponding physiological parameter and generate a corresponding sensing signal. The conductive wiring is electrically connected to at least one physiological parameter sensor and configured to transmit the sensing signal from the at least one physiological parameter sensor and / or transmit an excitation signal to the at least one physiological parameter sensor; and

[0009] The second flexible layer is formed of a flexible material, wherein the second flexible layer and the first flexible layer enclose at least a portion of the non-sensing area of ​​the first sensing layer therebetween;

[0010] In this device, one or more implantation vias are formed in the area where the first flexible layer and the second flexible layer are in direct contact, and each implantation via penetrates the first flexible layer and the second flexible layer in the thickness direction of the physiological parameter monitoring device.

[0011] In some embodiments, the physiological parameter monitoring device further includes:

[0012] A second sensing layer is disposed on the side of the second flexible layer opposite to the first sensing layer, wherein the second sensing layer includes one or more physiological parameter sensors and conductive wiring; and

[0013] The third flexible layer is formed of a flexible material, wherein the third flexible layer and the second flexible layer enclose at least a portion of the non-sensing area of ​​the second sensing layer therebetween;

[0014] The one or more implantation vias are also formed in the area where the second flexible layer and the third flexible layer are in direct contact, and each implantation via penetrates the third flexible layer in the thickness direction.

[0015] In some embodiments, the flexible material includes a biocompatible material; and / or

[0016] The absolute value of the difference between the Young's modulus of the flexible material and the Young's modulus of the biological tissue monitored by the physiological parameter monitoring device is less than or equal to a preset threshold.

[0017] In some embodiments, the flexible material includes at least one of polymethyl methacrylate, polyimide, polydimethylsiloxane, parylene, hydrogenated styrene-butadiene-styrene block copolymer, Ecoflex, SU-8 photoresist, polyethylene terephthalate, polyethylene, polyvinyl chloride, cumene-terminated polystyrene-maleic anhydride copolymer, polysilyl ether, polyvinylpyrrolidone, polylactic acid-glycolic acid copolymer, polyvinyl alcohol, polyglycerol sebacate, silk protein, linezolid, collagen, chitosan, polyoctamethylene maleate (anhydride) citrate, polylactic acid (L-) and polycaprolactone.

[0018] In some embodiments, at least two flexible layers are formed of the same flexible material; or

[0019] Different flexible layers are formed from different flexible materials.

[0020] In some embodiments, the physiological parameter sensor includes a flexible sensor.

[0021] In some embodiments, the physiological parameter sensor includes at least one of a pressure sensor, an oxygen partial pressure sensor, a glucose concentration sensor, a temperature sensor, a neuronal electrical signal sensor, an electrolyte concentration sensor, and a neurobiomarker sensor.

[0022] In some embodiments, the conductive wiring is formed of a biocompatible and flexible conductive material; and / or

[0023] At least a portion of the outer surface of the conductive wiring is also covered with insulating material.

[0024] In some embodiments, the conductive wiring includes at least one of silver, gold, magnesium, molybdenum, copper, platinum, aluminum, titanium, chromium, nickel, carbon nanotubes, polyaniline, poly(3,4-ethylenedioxythiophene)-poly(styrenesulfonic acid), and carbon black; and / or

[0025] At least a portion of the outer surface of the conductive wiring is also coated with at least one of polyethylene terephthalate and nylon.

[0026] In some embodiments, at least one implantation via is disposed on the side of at least one physiological parameter sensor that is not directly connected to the conductive wiring.

[0027] In some embodiments, the lateral feature size of the implanted via in the layer of the physiological parameter monitoring device is 1 to 8 times the longitudinal feature size of the implanted via in the thickness direction.

[0028] According to a second aspect of this disclosure, a physiological parameter monitoring system is provided, including the physiological parameter monitoring device as described above; and the physiological parameter monitoring system further includes at least one of the following:

[0029] A data processing unit, electrically connected to the conductive wiring of the physiological parameter monitoring device, wherein the data processing unit is configured to process sensing signals from the physiological parameter monitoring device; and

[0030] An implantation tool configured to be removably inserted into a corresponding implantation port of the physiological parameter monitoring device.

[0031] In some embodiments, the implantation tool includes a body portion and a tip portion disposed at one end of the body portion, wherein the tip portion is thinner than the body portion, the tip portion is configured to pass through a corresponding implantation port of the physiological parameter monitoring device, and the body portion is configured to be attached to the physiological parameter monitoring device along a layer of the physiological parameter monitoring device when the tip portion passes through the implantation port.

[0032] In some embodiments, the lateral feature size of the implanted through-hole in the physiological parameter monitoring device is greater than the feature size of the cross-section of the tip portion of the implantation tool, but smaller than the feature size of the cross-section of the body portion of the implantation tool.

[0033] According to a third aspect of this disclosure, a method for preparing a physiological parameter monitoring device is provided, comprising:

[0034] A first flexible layer is provided, wherein the first flexible layer is formed of a flexible material;

[0035] A first sensing layer is formed on one side of the first flexible layer, wherein the first sensing layer includes one or more physiological parameter sensors and conductive wiring, each physiological parameter sensor is configured to monitor a corresponding physiological parameter and generate a corresponding sensing signal, and the conductive wiring is electrically connected to at least one physiological parameter sensor and is configured to transmit the sensing signal from the at least one physiological parameter sensor and / or transmit an excitation signal to the at least one physiological parameter sensor.

[0036] A second flexible layer is formed on the first sensing layer, wherein the second flexible layer is formed of a flexible material, and the second flexible layer and the first flexible layer enclose at least a portion of the non-sensing area of ​​the first sensing layer therebetween; and

[0037] One or more implantation vias are formed, wherein the one or more implantation vias are formed in the region where the first flexible layer and the second flexible layer are in direct contact, and each implantation via penetrates the first flexible layer and the second flexible layer in the thickness direction of the physiological parameter monitoring device.

[0038] In some embodiments, the method further includes:

[0039] A second sensing layer is formed on the side of the second flexible layer opposite to the first sensing layer, wherein the second sensing layer includes one or more physiological parameter sensors and conductive wiring; and

[0040] A third flexible layer is formed on the second sensing layer, wherein the third flexible layer is formed of a flexible material, and the third flexible layer and the second flexible layer enclose at least a portion of the non-sensing area of ​​the second sensing layer therebetween;

[0041] The one or more implantation vias are also formed in the area where the second flexible layer and the third flexible layer are in direct contact, and each implantation via penetrates the third flexible layer in the thickness direction.

[0042] In some embodiments, where the provided first flexible layer is disposed on a support substrate, after forming the one or more implantation vias, the method further includes:

[0043] Separate the first flexible layer and the supporting substrate.

[0044] In some embodiments, having the second flexible layer and the first flexible layer enclose at least a portion of the non-sensing region of the first sensing layer includes:

[0045] A patterned sensing mask layer is formed on one of the first flexible layer and the second flexible layer, wherein the sensing mask layer covers an area corresponding to at least a portion of the non-sensing area of ​​the first sensing layer; and

[0046] Etching is performed to remove flexible material from the area of ​​one of the first and second flexible layers that is not covered by the sensing mask layer.

[0047] In some embodiments, forming one or more implantation vias includes:

[0048] A patterned via mask layer is formed on the outermost flexible layer of the physiological parameter monitoring device, wherein the via mask layer exposes the area in the flexible layer where the one or more implantation vias will be located;

[0049] Etching is performed to remove flexible material from areas of all flexible layers of the physiological parameter monitoring device that are not covered by the via mask layer.

[0050] Other features and advantages of this disclosure will become clearer from the following detailed description of exemplary embodiments with reference to the accompanying drawings. Attached Figure Description

[0051] The accompanying drawings, which form part of this specification, illustrate embodiments of this disclosure and, together with the specification, serve to explain the principles of this disclosure.

[0052] This disclosure will become clearer with reference to the accompanying drawings and the following detailed description, wherein:

[0053] Figure 1 shows a top view of a physiological parameter monitoring device according to an exemplary embodiment of the present disclosure;

[0054] Figure 2 shows a top view of the physiological parameter monitoring device according to another exemplary embodiment of the present disclosure;

[0055] Figure 3 shows a side view of a physiological parameter monitoring device according to an exemplary embodiment of the present disclosure;

[0056] Figure 4 shows a side view of a physiological parameter monitoring device according to yet another exemplary embodiment of the present disclosure;

[0057] Figure 5 shows a block diagram of a physiological parameter monitoring system according to an exemplary embodiment of the present disclosure;

[0058] Figure 6 shows a schematic diagram of the structure of an implantation tool according to an exemplary embodiment of the present disclosure;

[0059] Figure 7 shows a flowchart of a method for preparing a physiological parameter monitoring device according to an exemplary embodiment of the present disclosure;

[0060] Figure 8 shows a flowchart of a method for preparing a physiological parameter monitoring device according to another exemplary embodiment of the present disclosure.

[0061] Note that in the embodiments described below, the same reference numerals are sometimes used across different figures to denote the same parts or parts having the same function, and repeated descriptions are omitted. In this specification, similar reference numerals and letters are used to denote similar items; therefore, once an item is defined in one figure, it does not need to be discussed further in subsequent figures.

[0062] For ease of understanding, the positions, dimensions, and extents of the structures shown in the accompanying drawings and other materials may not represent actual positions, dimensions, and extents. Therefore, the disclosed invention is not limited to the positions, dimensions, and extents disclosed in the accompanying drawings and other materials. Furthermore, the drawings are not necessarily drawn to scale, and some features may be enlarged to show details of specific components. Detailed Implementation

[0063] Various exemplary embodiments of the present disclosure will now be described in detail with reference to the accompanying drawings. It should be noted that, unless otherwise specifically stated, the relative arrangement, numerical expressions, and values ​​of the components and steps set forth in these embodiments do not limit the scope of the present disclosure.

[0064] The following description of at least one exemplary embodiment is merely illustrative and is in no way intended to limit this disclosure or its application or use. Those skilled in the art will understand that they merely illustrate exemplary ways that can be used to implement this disclosure, and are not exhaustive.

[0065] Techniques, methods, and equipment known to those skilled in the art may not be discussed in detail, but where appropriate, such techniques, methods, and equipment should be considered part of the specification.

[0066] To better understand the health and disease status of living organisms, one or more physiological parameters of various bodily tissues can be monitored. This document will use the monitoring of physiological parameters of the human brain tissue as an example to elaborate on the technical solutions of this disclosure. However, those skilled in the art will understand that, as needed, the physiological parameter monitoring device and the physiological parameter monitoring system included herein can also monitor one or more physiological parameters of other relevant tissues in the human or animal body, provided that a corresponding physiological parameter sensor is installed in the physiological parameter monitoring device and the device is implanted at a suitable location in the tissue to be monitored; no limitation is imposed here. Furthermore, the physiological parameter monitoring device and the physiological parameter monitoring system included herein can be used for therapeutic purposes or for non-therapeutic purposes.

[0067] Traumatic brain injury (TBI) is a head injury that causes temporary or permanent changes in brain function. It is one of the major health problems worldwide, with approximately 27 million cases annually, primarily caused by traffic accidents and accidental falls. Epidemiological surveys show a rapid increase in the incidence of severe TBI in my country, reaching 1.0‰–1.5‰ annually, with a mortality rate exceeding 20% ​​and a severe disability rate exceeding 50%. Furthermore, international data shows that for patients with severe TBI and a Glasgow Coma Scale (GCS) score of 8 or lower, the mortality rate is as high as 35%–45%. Therefore, accurately identifying the clinical status of patients with TBI (especially severe TBI) is crucial for subsequent medical treatment and reducing secondary damage following the initial injury.

[0068] To identify the clinical status of patients with TBI, multimodal monitoring of physiological parameters related to the brain is becoming increasingly widespread. In clinical and research work, a focus on developing management protocols based on personalized precision medicine will help improve individual patient outcomes. For example, in 2022, Geert Meyfroidt provided recommended values ​​for neuromonitoring in his article "Management of moderate to severe traumatic brain injury: an update for the intensivist," as shown in Table 1 below:

[0069] Table 1

[0070] Table 1 clearly outlines the target values ​​for intracranial pressure (ICP), partial pressure of brain tissue oxygen (PbtO2), brain glucose concentration, and intracranial temperature (ICT). For treatment teams relying solely on clinical presentations and radiological findings, this information helps them monitor changes in the patient's condition promptly and implement appropriate and effective interventions. Furthermore, real-time monitoring of other intracranial physiological parameters is possible, including but not limited to monitoring neuronal electrical signals, intracranial electrolyte concentrations, neurobiological markers, lactate, pyruvate, glycerol, and glutamate, to facilitate early detection of secondary brain injury and quantify the extent of brain damage.

[0071] In some examples, the following physiological parameters within the brain can be monitored using a unimodal or bimodal approach. These physiological parameters may specifically include:

[0072] (I) Intracranial Pressure (ICP): Intracranial pressure can be monitored to reflect changes in intracranial pressure in real time, dynamically, and accurately, thereby guiding treatment decisions. In acute TBI patients, intracranial hypertension (i.e., an intracranial pressure consistently greater than 15 mmHg (1 mmHg = 0.133 kPa) caused by intracranial hemorrhage, cerebral contusion, cerebral edema, and cerebral swelling is a major cause of poor prognosis. Currently, the main clinical methods for monitoring intracranial pressure are invasive ICP monitoring and non-invasive ICP monitoring. Invasive dynamic intracranial pressure monitoring, as an important mechanism in the treatment of moderate to severe traumatic brain injury, allows for real-time understanding and monitoring of changes in intracranial pressure, enabling timely and effective judgment and treatment measures based on the patient's condition. Among these, intraventricular (IVC) monitoring is the most widely used. By placing a pressure or fiber optic sensor inside the skull to measure the pressure at a specific point, continuous monitoring can be achieved. This method provides data with high stability and accuracy, and is currently the gold standard for ICP monitoring in clinical practice. However, this method may cause operation-related complications such as infection and bleeding, and is expensive. Furthermore, it may experience zero-point drift, which significantly limits its clinical application. Non-invasive intracranial pressure monitoring mainly includes transcranial Doppler (TCD) ultrasound monitoring of cerebral blood flow, flash visual evoked potential (FVEP), two-depth transorbital Doppler (TDTD) ultrasound, optic nerve sheath diameter (ONSD) measurement, tympanic membrane displacement (TMD) technology, otoacoustic emission (OAE) technology, near-infrared spectroscopy (NIRS) technology, and optical coherence tomography (OCT) technology. However, many interfering factors exist during non-invasive intracranial pressure monitoring, which may lead to significant measurement errors.

[0073] (II) Intracranial Oxygen Partial Pressure: Brain hypoxia after TBI is a crucial factor affecting patient prognosis. When intracranial pressure is significantly elevated, the local brain tissue oxygen partial pressure is inversely proportional to intracranial pressure. Therefore, monitoring PbtO2 can guide clinical treatment strategies. Currently, commonly used PbtO2 monitoring techniques are based on continuous invasive probes. The consensus of the International Society of Critical Care Medicine and the European Society of Critical Care Medicine recommends PbtO2 or jugular venous oxygen saturation monitoring, TCD or transcranial color Doppler cerebral blood flow monitoring, and continuous electroencephalogram (cEEG) monitoring for neurocritical patients to effectively and comprehensively assess their brain function. Although jugular venous oxygen saturation monitoring is a mature method, merely intermittently monitoring the oxygen concentration of venous blood returning from the brain can only indirectly indicate the brain's oxygen utilization. The normal reference range for jugular venous oxygen saturation is 55%–75%, and its monitoring results are related to various factors; both excessively high and low levels indicate impaired oxygen uptake by brain tissue. Furthermore, non-invasive brain oxygenation monitoring methods have long attracted considerable attention, among which near-infrared spectroscopy (NIRS) obtains information on brain oxygen supply by measuring the concentrations of oxygenated and deoxygenated hemoglobin in brain tissue. However, current research suggests that the clinical value of NIRS remains highly controversial and cannot yet replace current invasive monitoring techniques.

[0074] (III) Glucose Concentration: Intracranial glucose concentration is primarily detected using cerebral microdialysis (CMD). This technique is a continuous monitoring method for brain metabolism, capable of crossing the blood-brain barrier and providing information on energy metabolism at the subcellular level. Because CMD can only detect the microenvironment within a few cubic millimeters of the probe, the placement of the probe significantly impacts the results. Multiple CMD studies have found different prognoses for patients with varying glucose levels; specifically, patients with TBI who maintain stable, normal glucose levels within 50 hours post-injury have a better prognosis. Furthermore, several CMD studies suggest that interleukin-related factors are associated with prognosis 6 months post-injury after TBI. Other common CMD metabolic analysis indicators include lactate, pyruvate, glycerol, and glutamate. However, due to the limitations of CMD, most reports are still in the research stage.

[0075] (iv) Intracranial Temperature: TBI can cause a series of pathological and physiological changes in the brain parenchyma, resulting in a rise or fall in brain temperature. After TBI, brain parenchymal temperature is generally 0.39–2.50°C higher than the body's core temperature (e.g., rectal temperature), which may be related to the high metabolism of brain tissue. Furthermore, a brain temperature lower than the body's core temperature may be a sign of impending death. Currently, implantable temperature sensors are commonly used to measure cortical temperature by implanting them into the cerebral cortex. Intracranial temperature sensors can also be integrated with intracranial pressure or intracranial oxygen partial pressure sensors for dual-modal monitoring. However, this detection method involves larger incisions and shorter measurement times.

[0076] (V) Neuronal Electrical Signals: In moderate to severe TBI patients, 22%–33% experience seizures. In comatose patients, the incidence of nonconvulsive epilepsy and nonconvulsive status epilepticus is as high as 5%–48%, and is closely related to patient prognosis. The European Society of Intensive Care Medicine recommends the use of cEEG to monitor treatment-resistant status epilepticus and suggests its application in the diagnosis and management of status epilepticus and unexplained persistent disturbances of consciousness. The American Society for Clinical Neurophysiology recommends the use of cEEG to monitor nonconvulsive seizures and status epilepticus. Currently, cEEG mainly includes two categories: electrocorticography (ECG) and stereotactic electroencephalography (SEEG). ECG places electrodes on the cerebral cortex, while SEEG places electrodes in deep brain tissue. To monitor stereotactic electroencephalography (EEG), silicon-based or stainless steel neural probes can be used as deep-implanted electrodes in the cerebral cortex. These probes can be implanted inside the cerebral cortex to measure brain nerve signals, thereby reflecting the patient's brain function information in real time and dynamically, and providing early indications of the patient's neurological function status. This has unparalleled advantages over neuroimaging examinations such as CT scans.

[0077] (vi) Intracranial electrolyte concentration: Various types of electrolyte disturbances often occur after acute TBI, which can cause cerebral edema, acid-base imbalance, and impaired neuronal electrical conduction, further aggravating brain damage. Therefore, clarifying the changes in electrolyte levels after acute TBI is of great significance for the treatment of TBI patients.

[0078] (vii) Neurobiological biomarkers: Following total intracytoplasmic brain injury (TBI), specific proteins are released into the blood or cerebrospinal fluid. Their expression can be objectively detected and can reflect the patient's condition and prognosis. In 2018, the U.S. Food and Drug Administration approved the expression levels of glial fibrillary acidic protein (GFAP) and UCH-L1 within 12 hours after injury as biomarkers for the clinical assessment of mild TBI. Related studies have shown that elevated serum GFAP and UCH-L1 levels within 12 hours have a sensitivity of 97.6% and a negative predictive value of 99.6% for diagnosing TBI, which is superior to the diagnostic effect of CT.

[0079] Clinically, one or more of the aforementioned monitoring methods can be used for TBI patients. However, due to the characteristics of the various physiological parameters described above, surgery is often required to implant the corresponding monitoring device in order to achieve better monitoring results. This leads to problems such as large wound areas, susceptibility to infection, and difficulty in real-time monitoring. To address these issues, this disclosure proposes a flexible physiological parameter monitoring device and a physiological parameter monitoring system incorporating it. The device can be implanted into the body tissue using a minimally invasive approach. By placing appropriate physiological parameter sensors within the device, real-time monitoring of one or more physiological parameters can be achieved. This is of great significance for many aspects of clinical diagnosis, injury assessment, surgical indications, treatment plans, evaluation of treatment effects, and prognosis in patients with traumatic brain injury.

[0080] In an exemplary embodiment of this disclosure, as shown in Figures 1 to 3, the physiological parameter monitoring device 100 may include a first flexible layer 110 formed of a flexible material, a first sensing layer disposed on one side of the first flexible layer 110, and a second flexible layer 130 formed of a flexible material.

[0081] In some embodiments, the flexible material may include a biocompatible material. Furthermore, the absolute value of the difference between the Young's modulus of the flexible material and the Young's modulus of the biological tissue monitored by the physiological parameter monitoring device 100 may be less than or equal to a preset threshold; in other words, the Young's modulus of the flexible material may be substantially equal to the Young's modulus of the biological tissue monitored by the physiological parameter monitoring device 100. By employing a flexible material with the above characteristics, the mechanical mismatch between the implanted physiological parameter monitoring device 100 and the biological tissue can be minimized, thereby reducing adverse effects caused by neuroinflammation, etc. In some specific examples, flexible materials may include polymethyl methacrylate (PMMA), polyimide (PI), polydimethylsiloxane (PDMS), parylene, styrene-butylene-styrene block copolymer (SEBS), Ecoflex, SU-8 photoresist, polyethylene terephthalate (PET), polyethylene (PEE), polyvinyl chloride (PVC), cumene-terminated polystyrene-co-maleic anhydride (Cumene-PSMA), polymethysilane ether (PSE), polyvinylpyrrolidone (PVP), etc. Alternatively, flexible materials may include other biocompatible and biodegradable materials such as rubber or resins, including polylactic acid hydroxyacetic acid copolymer (PLGA), polyvinyl alcohol (PVA), polyglyceryl sebacate (PGS), silk fibroin, linezolid (Zyvox), collagen, chitosan, poly(octamethylene maleate (anhydride) citrate) (POMaC), poly(L-lactic acid) (PLLA), and polycaprolactone (PCL). One or more of the substances listed above may be used as needed when forming each flexible layer, and there are no limitations herein.

[0082] In some embodiments, the first flexible layer 110 and the second flexible layer 130 may be formed of the same flexible material. Alternatively, in other embodiments, different flexible materials may be used to form the first flexible layer 110 and the second flexible layer 130 as needed, without limitation.

[0083] In some embodiments, as shown in Figures 1 to 3, the first sensing layer may include one or more physiological parameter sensors 121 and conductive wiring 122. Each physiological parameter sensor 121 may be configured to monitor a corresponding physiological parameter and generate a corresponding sensing signal. Additionally, the conductive wiring 122 may be electrically connected to at least one physiological parameter sensor 121. Depending on the monitoring requirements, the conductive wiring 122 may be configured to transmit sensing signals from the at least one physiological parameter sensor 121 to which it is connected, or it may be configured to transmit excitation signals to the at least one physiological parameter sensor 121 to which it is connected. In most cases, the sensing signals generated by the physiological parameter sensors 121 are electrical signals; therefore, the conductive wiring 122 may be electrically connected to each physiological parameter sensor 121 respectively. Furthermore, a portion of the conductive wiring 122 may also be connected between two physiological parameter sensors 121 to achieve necessary signal transmission between them. Furthermore, considering that in some cases, depending on monitoring needs, it may not be necessary to use all the physiological parameter sensors 121 in the physiological parameter monitoring device 100, the conductive wiring 122 can be electrically connected only to the physiological parameter sensors 121 that will be used, thereby simplifying the circuitry and facilitating the implantation of the physiological parameter monitoring device 100. The other end of the conductive wiring 122 can be electrically connected to an external circuit outside the physiological parameter monitoring device 100, such as a data processing unit, which may include, but is not limited to, a circuit board (e.g., a PCB), a processor, a memory, a mobile terminal, a computer device, etc. The external circuit can be located outside the body or tissue to be monitored, without being implanted, and can be used to perform the desired processing of the sensed signals, etc.

[0084] In a specific example, as shown in Figures 1 and 2, the physiological parameter sensor 121 may include at least one of the following: a pressure sensor 121a for monitoring intracranial pressure, an oxygen partial pressure sensor 121b for monitoring the partial pressure of oxygen in local brain tissue, a glucose concentration sensor 121c for monitoring intracranial glucose concentration, a temperature sensor 121d for monitoring intracranial temperature, a neuronal electrical signal sensor 121e for monitoring neuronal electrical signals, an electrolyte concentration sensor 121f for monitoring intracranial electrolyte concentration, and a neurobiomarker sensor 121g for monitoring neurobiological biomarkers. The conductive wiring 122 can be electrically connected to each of the above-mentioned physiological parameter sensors 121 to output the sensing signals generated by these sensors. Furthermore, according to monitoring requirements, the conductive wiring 122 can also input excitation signals to the corresponding physiological parameter sensor 121 to provide the necessary excitation during the monitoring process. For example, the conductive wiring 122 can input excitation signals to electrodes, stimulators, etc., in the neuronal electrical signal sensor 121e to provide excitation signals to brain tissue, thereby completing the monitoring of neuronal electrical signals. It is understood that, depending on the specific monitoring needs, the physiological parameter sensor 121 may include other types of sensors, and there are no limitations on this.

[0085] In some embodiments, by providing multiple types of physiological parameter sensors 121 in the physiological parameter monitoring device 100, multimodal monitoring of multiple physiological parameters can be achieved. Further, in some embodiments, the positions of various types of physiological parameter sensors 121 can be arranged as needed to optimize the monitoring effect. In other embodiments, multiple physiological parameter sensors 121 of the same type can also be provided in the physiological parameter monitoring device 100, and these same-type physiological parameter sensors 121 can be arranged at different locations to help monitor the distribution of the same physiological parameter at multiple locations. For example, as mentioned above, the glucose concentration in the brain may vary significantly with location; therefore, multiple glucose concentration sensors 121c can be provided at different locations in the physiological parameter monitoring device 100 to more accurately reflect the distribution of glucose concentration and reduce measurement errors. In still other embodiments, the multiple physiological parameter sensors 121 in the physiological parameter monitoring device 100 may include both different types of physiological parameter sensors 121 and physiological parameter sensors of the same type; this is not limited here.

[0086] In some embodiments, the conductive wiring 122 may be formed of a biocompatible and flexible conductive material. For example, the conductive wiring 122 may include solid metal materials such as silver, gold, magnesium, molybdenum, copper, platinum, aluminum, titanium, chromium, and nickel. Alternatively, the conductive wiring 122 may include liquid conductive polymers such as carbon nanotubes, polyaniline, poly(3,4-ethylenedioxythiophene)-poly(styrene sulfonic acid) (PEDOT:PSS), and carbon black. In some embodiments, the conductive wiring 122 may be electrically isolated from each other by an insulating flexible material. Alternatively, in other embodiments, at least a portion of the outer surface of the conductive wiring 122 may be coated with an insulating material to prevent short circuits between adjacent conductive wires. For example, at least a portion of the outer surface of the conductive wiring 122 may be coated with at least one of polyethylene terephthalate and nylon to achieve electrical insulation between adjacent conductive wires. In some embodiments, the conductive wiring 122 in the physiological parameter monitoring device 100 can be formed by flexible printed circuit board cables, nylon filaments or other biocompatible flexible wires. Such conductive wiring 122 can achieve electrical connection between the physiological parameter monitoring device 100 and the external circuit through the skull hole or drill hole at the brain injury site, thereby realizing the monitoring of the corresponding physiological parameters.

[0087] In some embodiments, to enable the physiological parameter sensor 121 to accurately monitor the corresponding physiological parameters, depending on the specific type of the physiological parameter sensor 121, the sensing area of ​​the physiological parameter sensor 121 may be exposed to the body tissue to be monitored via the sensing window 180, or the sensing area of ​​the physiological parameter sensor 121 may be in direct contact with the body tissue to be monitored, avoiding being obscured by a flexible layer above or below it. Furthermore, in some embodiments, depending on the specific type of the physiological parameter sensor 121, the physiological parameter sensor 121 may also be completely covered by a flexible material, without being directly exposed to the body tissue to be monitored, while still achieving the monitoring of the corresponding physiological parameters. In other words, as shown in Figures 1 to 3, the second flexible layer 130 and the first flexible layer 110 can enclose at least a portion of the non-sensing area of ​​the first sensing layer (or, the first sensing layer can be disposed between the first flexible layer 110 and the second flexible layer 130, and at least one of the first flexible layer 110 and the second flexible layer 130 has at least a portion corresponding to the sensing area of ​​the first sensing layer removed), thereby exposing at least the sensing area of ​​the first sensing layer (or the corresponding physiological parameter sensor 121), or exposing the sensing area of ​​the first sensing layer (or the corresponding physiological parameter sensor 121) to the corresponding flexible layer. This can avoid interference with detection on the one hand, and protect the circuits and other structures in the first sensing layer from damage by the first flexible layer 110 and the second flexible layer 130, thus extending the service life of the physiological parameter monitoring device 100.

[0088] Furthermore, as shown in Figures 1 to 3, since the first sensing layer can be sandwiched between the first flexible layer 110 and the second flexible layer 130, the entire physiological parameter monitoring device 100 is also substantially flexible, thus adapting well to the sensing environment (e.g., the environment of the body tissue to be monitored). The physiological parameter monitoring device 100 can also be easily implanted into body tissues, thereby helping to monitor the corresponding physiological parameters more accurately and reducing or even avoiding damage to the tissues to be monitored. In some embodiments, to improve the flexibility of the entire physiological parameter monitoring device 100, the physiological parameter sensor 121 can be a flexible sensor. However, it is understood that in other embodiments, since the physiological parameter sensor 121 is typically very thin and has flexible layers on its upper and lower sides that provide some protection, the physiological parameter sensor 121 itself does not necessarily have to be flexible, and this is not a limitation.

[0089] Furthermore, as shown in Figures 1 to 3, an implantation via 190 can be formed in the area where the first flexible layer 110 and the second flexible layer 130 directly contact each other. This implantation via 190 can penetrate the first flexible layer 110 and the second flexible layer 130 in the thickness direction of the physiological parameter monitoring device 100 (i.e., the longitudinal direction shown in Figure 3). By providing such an implantation via 190, the physiological parameter monitoring device 100 can be implanted into the body tissue to be monitored via a minimally invasive method using the implantation tool described below. It is understood that this minimally invasive implantation method can effectively reduce the wound area, inhibit infection, and thus improve the patient's experience.

[0090] In some embodiments, as shown in FIG1, the physiological parameter monitoring device 100 may have only one implantation through-hole 190 to help reduce the size of the physiological parameter monitoring device 100, thereby facilitating minimally invasive implantation. Alternatively, in other embodiments, as shown in FIG2, the physiological parameter monitoring device 100 may have multiple implantation through-holes 190. By providing multiple implantation through-holes 190, one or more implantation through-holes 190 with appropriate positions can be selected as needed during the implantation process, thereby reducing the difficulty of implantation. In addition, by providing multiple implantation through-holes 190, redundant implantation through-holes 190 can be provided for implantation in case of accidents such as one implantation through-hole 190 being damaged by the implantation tool, thereby reducing the discard rate of the physiological parameter monitoring device 100.

[0091] In some embodiments, as shown in Figures 1 to 3, at least one implantation via 190 may be disposed on the side of at least one physiological parameter sensor 121 that is not directly connected to the conductive wiring 122. For example, the implantation via 190 may be disposed at the front end of the physiological parameter monitoring device 100 (i.e., the left side shown in Figure 3), while the conductive wiring 122 may be disposed at the rear end of the physiological parameter monitoring device 100 (i.e., the right side shown in Figure 3) and continue to extend rearward for electrical connection with external circuitry. By setting the implantation via 190 to maintain a certain distance from the physiological parameter sensor 121 and / or the conductive wiring 122, damage to the devices or circuits in the physiological parameter monitoring device 100 by implantation tools or the like inserted through the implantation via 190 during implantation can be avoided, thereby helping to improve the reliability of the physiological parameter monitoring device 100. Furthermore, by placing the implantation hole 190 at one end of the physiological parameter monitoring device 100, especially at the front end of the physiological parameter monitoring device 100 in the implantation direction, it can also help the main body of the physiological parameter monitoring device 100 to unfold against the implantation tool during the implantation process, thus avoiding the flexible physiological parameter monitoring device 100 from shrinking and affecting the subsequent monitoring effect, as will be explained in detail later.

[0092] In some embodiments, the lateral feature dimension Lh of the implantation via 190 in the layer of the physiological parameter monitoring device 100 can be 1 to 8 times the longitudinal feature dimension Lv of the implantation via 190 in the thickness direction, so that an implantation tool can be inserted through the implantation via 190 for implantation. As the ratio of the lateral feature dimension to the longitudinal feature dimension increases, the implantation tool can be inserted more evenly in the implantation via, or the angle between the implantation tool and the layer of the physiological parameter monitoring device can be smaller, for example, less than or equal to 45°, so as to improve the reliability and stability of implantation. In a specific example, when the implantation via 190 is cylindrical, its cross-sectional diameter can be about 1 to 8 times its height. For example, the cross-sectional diameter of the implantation via 190 can be about 10 to 20 micrometers, 20 to 50 micrometers, 50 to 60 micrometers, or 60 to 80 micrometers, while the depth of the implantation via 190 (or the thickness of the physiological parameter monitoring device 100) can be about 10 to 20 micrometers or 20 to 30 micrometers. Furthermore, the cross-section of the implantation port 190 can be of various shapes, including but not limited to circles, squares, rectangles, triangles, polygons, etc. In addition, the implantation port 190 can pass through the physiological parameter monitoring device 100 perpendicularly (as shown in Figure 3), or it can pass through the physiological parameter monitoring device 100 at an angle, without limitation.

[0093] In yet another exemplary embodiment of this disclosure, as shown in FIG4, the physiological parameter monitoring device 100 may further include a second sensing layer disposed on the side of the second flexible layer 130 opposite to the first sensing layer and a third flexible layer 150 formed of a flexible material.

[0094] Similar to the first sensing layer, the second sensing layer may include one or more physiological parameter sensors 141 and conductive wiring 142. The corresponding physiological parameter sensors 141 and conductive wiring 142 in the second sensing layer can be configured according to specific monitoring needs, which will not be elaborated here.

[0095] Furthermore, the third flexible layer 150 can be formed of the flexible material described above. In the physiological parameter monitoring device 100, depending on specific needs, at least two flexible layers can be formed of the same flexible material to simplify the manufacturing process of the physiological parameter monitoring device 100 and reduce its manufacturing cost; alternatively, different flexible layers can be formed of different flexible materials, without limitation.

[0096] As shown in Figure 4, similar to how the second flexible layer 130 and the first flexible layer 110 can enclose at least a portion of the non-sensing area of ​​the first sensing layer, the third flexible layer 150 and the second flexible layer 130 can enclose at least a portion of the non-sensing area of ​​the second sensing layer (or, in other words, the second sensing layer can be disposed between the second flexible layer 130 and the third flexible layer 150). To expose the sensing areas of the first and second sensing layers (or the corresponding physiological parameter sensors 121 and 141) to the body tissue to be monitored, portions corresponding to the sensing areas in one or two flexible layers can be removed as needed. In a specific example, at least a portion of the sensing area of ​​the physiological parameter sensor 121 in the first sensing layer can be exposed to the body tissue via the sensing window 180 in the first flexible layer 110, and at least a portion of the sensing area of ​​the physiological parameter sensor 141 in the second sensing layer can be exposed to the body tissue via the sensing window 180 in the third flexible layer 150, as shown in Figure 4. That is, both sides of the physiological parameter monitoring device 100 can be used to monitor corresponding physiological parameters. In another specific example, at least a portion of the sensing area of ​​the physiological parameter sensor 121 in the first sensing layer can be exposed to the first flexible layer 110, while at least a portion of the sensing area of ​​the physiological parameter sensor 141 in the second sensing layer can be exposed to both the second flexible layer 130 and the first flexible layer 110. Thus, at least the bottom side of the physiological parameter monitoring device 100 can be used to perform the monitoring of the corresponding physiological parameter. In yet another specific example, at least a portion of the sensing area of ​​the physiological parameter sensor 121 in the first sensing layer can be exposed to both the second flexible layer 130 and the third flexible layer 150, while at least a portion of the sensing area of ​​the physiological parameter sensor 141 in the second sensing layer can be exposed to the third flexible layer 150. Thus, at least the top side of the physiological parameter monitoring device 100 can be used to perform the monitoring of the corresponding physiological parameter.

[0097] Furthermore, as shown in Figure 4, one or more implantation vias 190 are also formed in the area where the second flexible layer 130 and the third flexible layer 150 are in direct contact, and each implantation via penetrates the third flexible layer 150 in the thickness direction. That is, the implantation via 190 can penetrate the entire physiological parameter monitoring device 100 in the thickness direction for subsequent implantation. Moreover, since the implantation via 190 avoids the areas where the physiological parameter sensors and conductive wiring are located, damage to the physiological parameter monitoring device 100 can be effectively avoided.

[0098] As can be understood from the above description, more sensing layers and corresponding flexible layers can be stacked in the physiological parameter monitoring device 100 as needed, without any limitation.

[0099] According to another aspect of this disclosure, a physiological parameter monitoring system is provided. As shown in FIG5, the physiological parameter monitoring system may include the physiological parameter monitoring device 100 as described above.

[0100] In addition, in some embodiments, the physiological parameter monitoring system may also include a data processing unit 200, which may be electrically connected to the conductive wiring 122 of the physiological parameter monitoring device 100 and configured to process the sensed signals from the physiological parameter monitoring device 100. For example, the data processing unit 200 may take the form of a circuit board, memory, processor, mobile terminal, or computer device, so as to further process the sensed signals as needed.

[0101] In some embodiments, as shown in FIG5, the physiological parameter monitoring system may further include an implantation tool 300, which may be configured to be removably inserted into a corresponding implantation port 190 of the physiological parameter monitoring device 100, thereby implanting the physiological parameter monitoring device 100 into the body tissue in a minimally invasive manner.

[0102] In a specific embodiment, as shown in FIG. 6, the implantation tool 300 may include a main body portion 310 and a tip portion 320 provided at one end of the main body portion 310. For example, by means of electrolysis or the like, one end of a commercially available hard metal needle (such as a tungsten needle, a stainless steel needle, etc.) can be corroded into a tapered shape, so that the corroded portion forms the tip portion 320, and the remaining portion serves as the main body portion 310. As can be seen from FIG. 6, the tip portion 320 is thinner than the main body portion 310, so the tip portion 320 can be more easily penetrated, and a technician or a manipulator can complete the implantation operation by clamping the main body portion 310. In addition, in some embodiments, the lateral characteristic dimension Lh of the implantation through hole 190 in the plane of the physiological parameter monitoring device 100 may be greater than the characteristic dimension d2 of the cross section of the tip portion 320 of the implantation tool 300 and less than the characteristic dimension d1 of the cross section of the main body portion 310 of the implantation tool 300, that is, d2 < Lh < d1. For example, when the implantation through hole 190, the tip portion 320 and the main body portion 310 of the implantation tool 300 are all cylindrical, the lateral diameter of the implantation through hole 190 may be greater than the diameter of the tip portion 320 of the implantation tool 300 and less than the diameter of the main body portion 310 of the implantation tool 300. In this way, the tip portion 320 can be configured to penetrate through the corresponding implantation through hole 190 of the physiological parameter monitoring device 100, and the main body portion 310 can be configured to be attached to the physiological parameter monitoring device 100 along the plane of the physiological parameter monitoring device 100 when the tip portion 320 penetrates through the implantation through hole 190. Especially when the characteristic dimension of the cross section of the main body portion 310 is greater than the lateral characteristic dimension of the implantation through hole 190, the main body portion 310 can be stuck at the edge of the implantation through hole 190, so that the implantation tool 300 can be stably assembled in the implantation through hole 190, realizing the implantation of the physiological parameter monitoring device 100. Specifically, after the tip portion 320 penetrates through the corresponding implantation through hole 190, a bio-soluble glue (such as polysaccharide) or a water-soluble glue (such as polyethylene glycol) can be used to paste the physiological parameter monitoring device 100 onto the side surface of the main body portion 310 of the implantation tool 300, so that the flexible physiological parameter monitoring device 100 is kept in an unfolded state. During the implantation process, the skull injury can be found on the skull, the opening diameter of which can be less than 5 mm, or an opening of a similar size can be drilled at a suitable position on the skull by using a skull drill or the like. Then, the implantation tool 300 with the physiological parameter monitoring device 100 is inserted into the intracranial cavity through the skull opening and longitudinally inserted into the cerebral cortex (that is, implanted perpendicular to or substantially perpendicular to the cortical surface). Then, for the bio-soluble glue agent, it can be waited for a period of time to dissolve, and for the water-soluble glue, it can be removed by rinsing with a phosphate buffer solution or the like.After the physiological parameter monitoring device 100 is separated from the implantation tool 300, the implantation tool 300 can be removed, leaving the physiological parameter monitoring device 100 extended within the cerebral cortex to begin real-time monitoring of relevant intracranial physiological parameters. The sensed signals are then transmitted to an external circuit via conductive wiring for further processing. In some embodiments, multiple physiological parameter sensors can be arranged according to the implantation direction to monitor various physiological parameters such as intracranial pressure, local brain tissue oxygen partial pressure, glucose concentration, intracranial temperature, neuronal electrical signals, intracranial electrolyte concentration, and neurobiological markers. Furthermore, excitation signals can be transmitted via conductive wiring to the stimulation electrodes in the physiological parameter monitoring device 100 to provide necessary electrical stimulation to the brain.

[0103] In some embodiments, for ease of implantation, the lateral feature dimension of the implantation via 190 (e.g., the diameter of the via) can be approximately 1.2 to 1.5 or 1.5 to 1.8 times the diameter of the tip portion 132 of the implantation tool. For example, in the case where the diameter of the implantation via 190 is 90 micrometers, an implantation tool having a tip portion 132 with a diameter of 50 micrometers can be used to perform minimally invasive implantation.

[0104] According to another aspect of this disclosure, a method for preparing a physiological parameter monitoring device is also provided. In an exemplary embodiment, as shown in FIG7, the method may include:

[0105] Step S910: Provide the first flexible layer.

[0106] The first flexible layer can be formed of a flexible material, including but not limited to the materials listed above. In some embodiments, the first flexible layer can be provided separately, for example, a film formed of a flexible material can be provided as the first flexible layer. In other embodiments, the first flexible layer can also be formed on a support substrate, for example, the support substrate can be a rigid substrate. In this way, in subsequent processes, the fabrication of related components of the physiological parameter monitoring device can continue on the support substrate, thereby reducing the fabrication difficulty and improving the fabrication quality. Then, after the fabrication of the physiological parameter monitoring device is completed or substantially completed, the support substrate can be removed to obtain a flexible physiological parameter monitoring device that can be easily implanted into body tissues. In some specific examples, the first flexible layer can be fabricated based on standard semiconductor processes. For example, a solution containing flexible material can be spin-coated onto the support substrate using a spin coating process, and then excess liquid in the solution can be removed by drying or other operations to form the first flexible layer. Alternatively, the first flexible layer can be formed on the support substrate using processing methods such as chemical vapor deposition, atomic layer deposition, spraying, inkjet printing, etc., without limitation.

[0107] Furthermore, as shown in Figure 7, the method for preparing a physiological parameter monitoring device may further include:

[0108] Step S920: A first sensing layer is formed on one side of the first flexible layer.

[0109] As described above, the first sensing layer may include one or more physiological parameter sensors and conductive wiring. Each physiological parameter sensor can be configured to monitor a corresponding physiological parameter and generate a corresponding sensing signal. The conductive wiring can be electrically connected to at least one physiological parameter sensor and configured to transmit the sensing signal from the at least one physiological parameter sensor and / or transmit an excitation signal to the at least one physiological parameter sensor. The type and number of physiological parameter sensors can be rationally configured according to monitoring needs. For example, one or more of the following can be configured: pressure sensor, oxygen partial pressure sensor, glucose concentration sensor, temperature sensor, neuronal electrical signal sensor, electrolyte concentration sensor, and neurobiomarker sensor, as described above. The number of each type of sensor can be one or more, without limitation. The required physiological parameter sensors and corresponding conductive wiring can be fabricated on one side of the first flexible layer based on standard semiconductor processes. This process may involve processes such as spin coating, exposure, development, sputtering or evaporation, stripping, and etching, thereby forming a desired patterned layer on the first flexible layer, and thus forming the corresponding structure of the physiological parameter sensor and / or conductive wiring. Furthermore, when using liquid conductive polymers or the like to form conductive wiring, the conductive liquid can be distributed in a suitable location based on processes such as shadow masking, screen printing, and liquid pipetting (e.g., transferring liquid to the desired location using a pipette), and then the conductive structure can be cured by removing excess liquid through heating.

[0110] Furthermore, as shown in Figure 7, the method for preparing a physiological parameter monitoring device may further include:

[0111] Step S930: A second flexible layer is formed on the first sensing layer.

[0112] As mentioned above, the second flexible layer can be formed of the same or different flexible material as the first flexible layer. Similarly, thin film deposition processes such as spin coating, chemical vapor deposition, atomic layer deposition, spraying, and inkjet printing can be used, or a liquid synthesis and curing method can be used to cover the second flexible layer on top of the first sensing layer. Here, the second flexible layer can serve as a protective layer, wrapping and protecting the physiological parameter sensor and conductive wiring to isolate them from the external environment. On the one hand, it can prevent external factors such as oxygen and water vapor from corroding the devices or wires in the first sensing layer; on the other hand, it can also serve as an insulating layer to prevent body tissue (e.g., brain tissue) from directly contacting the physiological parameter sensor and conductive wiring.

[0113] Furthermore, as mentioned above, in order for a physiological parameter sensor to accurately monitor the corresponding physiological parameters, it may be necessary to expose its sensing area (e.g., an electrical signal recording site or a stimulation site) within the tissue to be monitored. Accordingly, having the second flexible layer and the first flexible layer enclose at least a portion of the non-sensing area of ​​the first sensing layer may include: forming a patterned sensing mask layer on one of the first and second flexible layers, wherein the sensing mask layer covers the area corresponding to at least a portion of the non-sensing area of ​​the first sensing layer; and performing etching to remove flexible material from the area of ​​the first and second flexible layers not covered by the sensing mask layer. In a specific example, a patterned sensing mask layer may be formed over the second flexible layer, and then a dry or wet etching process may be used to remove the flexible material from the area not covered by the sensing mask layer. Finally, the residual sensing mask layer (e.g., photoresist) may be removed, thereby forming a sensing window in the second mask layer that exposes the sensing area to ensure monitoring effectiveness.

[0114] Finally, as shown in Figure 7, the method for preparing a physiological parameter monitoring device may further include:

[0115] Step S940: Form one or more implantation vias.

[0116] As described above, one or more implantable vias can be formed in the area where the first and second flexible layers directly contact each other to avoid interference with the circuitry in the first sensing layer. Furthermore, each implantable via penetrates both the first and second flexible layers in the thickness direction of the physiological parameter monitoring device, allowing the implantation tool to pass through it during minimally invasive implantation. In some embodiments, forming one or more implantable vias may include: forming a patterned via mask layer on the outermost flexible layer of the physiological parameter monitoring device, wherein the via mask layer exposes the area in the flexible layer where one or more implantable vias will be located; and performing etching to remove flexible material from all flexible layers of the physiological parameter monitoring device not covered by the via mask layer. In a specific example, the patterned via mask layer can be formed over the second flexible layer based on photolithography processes (including spin coating, exposure, development, evaporation or sputtering, stripping, etc.), and the material of the via mask layer may be a metal or photoresist, depending on the subsequent etching process. Then, dry etching, such as reactive ion etching, can be used to completely etch away the flexible material (including a portion of the first flexible layer and a portion of the second flexible layer) in the area not covered by the via mask layer, thereby forming an implantable via. Alternatively, in another specific example, especially when the first flexible layer is disposed on a support substrate, a suitable etching solution can be used based on a wet etching process to remove the flexible material in the area not covered by the via mask layer, thereby forming an implantable via.

[0117] In another exemplary embodiment of this disclosure, in order to form the physiological parameter monitoring device shown in FIG4, as shown in FIG8, after step S930, the method for preparing the physiological parameter monitoring device may further include:

[0118] Step S950: A second sensing layer is formed on the side of the second flexible layer opposite to the first sensing layer.

[0119] As described above, the second sensing layer may include one or more physiological parameter sensors and conductive wiring. Similarly, the desired physiological parameter sensors and corresponding conductive wiring can be fabricated on one side of the second flexible layer using standard semiconductor processes. This process may involve spin coating, exposure, development, sputtering or evaporation, stripping, etching, etc., to form a desired patterned layer on the second flexible layer, thereby forming the corresponding structure of the physiological parameter sensors and / or conductive wiring. Furthermore, when using liquid conductive polymers or the like to form the conductive wiring, the conductive liquid can be distributed at appropriate locations using processes such as shadow masking, screen printing, and pipetting (e.g., transferring liquid to the desired location using a pipette), and then the conductive structure can be cured by removing excess liquid through heating.

[0120] Furthermore, the method for preparing a physiological parameter monitoring device may also include:

[0121] In step S960, a third flexible layer is formed on the second sensing layer.

[0122] As mentioned above, the third flexible layer can be formed of the same or different flexible material as the first or second flexible layer. Similarly, thin film deposition processes such as spin coating, chemical vapor deposition, atomic layer deposition, spraying, and inkjet printing can be used, or a liquid synthesis and curing method can be used to cover the third flexible layer on top of the second sensing layer. Here, the third flexible layer can serve as a protective layer, wrapping and protecting the physiological parameter sensor and conductive wiring to isolate them from the external environment. On the one hand, it can prevent external factors such as oxygen and water vapor from corroding the devices or wires in the second sensing layer; on the other hand, it can also serve as an insulating layer to prevent body tissue (e.g., brain tissue) from directly contacting the physiological parameter sensor and conductive wiring.

[0123] Furthermore, as mentioned above, in order for physiological parameter sensors to accurately monitor the corresponding physiological parameters, it may be necessary to expose the sensing area (e.g., electrical signal recording sites or stimulation sites) within the tissue to be monitored. For example, a third flexible layer and a second flexible layer can enclose at least a portion of the non-sensing area of ​​the second sensing layer. In a specific example, a patterned sensing mask layer can be formed below the first flexible layer or above the third flexible layer. Then, a dry or wet etching process is used to remove the flexible material in the area not covered by the sensing mask layer. Finally, the residual sensing mask layer (e.g., photoresist) is removed, thereby forming a sensing window in one or more flexible layers that exposes the sensing area to ensure monitoring effectiveness.

[0124] In addition, in order to enable the implantation tool to be inserted into the implantation via, one or more implantation vias are also formed in the area where the second and third flexible layers are in direct contact, and each implantation via penetrates the third flexible layer in the thickness direction.

[0125] In the physiological parameter monitoring device disclosed herein, additional sensing layers and corresponding flexible layers can be provided. Accordingly, after the fabrication of all flexible layers is completed, sensing windows can be opened at appropriate locations on the physiological parameter monitoring device as needed to expose the sensing area of ​​the physiological parameter sensor. Furthermore, after the fabrication of all flexible layers is completed, one or more implantation vias can be formed at appropriate locations using an etching process.

[0126] In some embodiments, when the provided first flexible layer is disposed on a carrier substrate, the first flexible layer and the carrier substrate can be separated after the fabrication of the physiological parameter monitoring device is completed or substantially completed, for example, after the formation of one or more implantation vias. In some embodiments, the carrier substrate may include a hard layer formed of a conductive or non-conductive hard material such as silicon, silicon oxide, glass, low-resistivity silicon, or indium tin oxide glass. Furthermore, in other embodiments, the carrier substrate may also include a sacrificial layer formed of a sacrificial material located on one side of the hard layer for subsequent separation of the carrier substrate from the physiological parameter monitoring device. Depending on the specific separation method, a suitable sacrificial material may be used. For example, when using wet etching to remove the sacrificial material to separate the carrier substrate and the physiological parameter monitoring device, the sacrificial material may include at least one of silver, copper, platinum, aluminum, titanium, chromium, and nickel. In some embodiments, the sacrificial layer may be unpatterned and can be coated on the hard layer using methods such as evaporation (e.g., electron beam evaporation), sputtering (e.g., magnetron sputtering), or atomic layer deposition in semiconductor processes.

[0127] This disclosure provides a flexible, biocompatible physiological parameter monitoring device and a physiological parameter monitoring system incorporating the same. Depending on the needs, various types of physiological parameter sensors can be incorporated into the physiological parameter monitoring device, thereby achieving highly integrated multimodal, real-time monitoring of physiological parameters. For example, it can quantify changes in indicators such as brain electrophysiological activity after secondary brain trauma. The physiological parameter monitoring device of this disclosure can be easily and conveniently implanted into body tissues using minimally invasive implantation techniques, effectively reducing mechanical mismatch with body tissues after implantation. Furthermore, the physiological parameter monitoring device of this disclosure can be fabricated using semiconductor processes, which are simple, low-cost, and enable wide application.

[0128] The terms “left,” “right,” “front,” “back,” “top,” “bottom,” “upper,” “lower,” “high,” “lower,” etc., used in the specification and claims, if present, are for descriptive purposes and not necessarily for describing unchanging relative positions. It should be understood that such terms are interchangeable where appropriate, enabling embodiments of this disclosure described herein to operate, for example, in orientations different from those shown or otherwise described herein. For example, when the device in the drawings is reversed, a feature previously described as “above” other features may now be described as “below” other features. The device may also be oriented in other ways (rotated 90 degrees or in other orientations), in which case the relative spatial relationships will be interpreted accordingly.

[0129] In the specification and claims, when an element is described as being "on top of," "attached to," "connected to," "coupled to," or "in contact with" another element, the element may be directly located on top of, directly attached to, directly connected to, directly coupled to, or directly in contact with the other element, or one or more intermediate elements may be present. Conversely, when an element is described as being "directly" located on top of, directly attached to, directly connected to, directly coupled to, or directly in contact with another element, no intermediate elements are present. In the specification and claims, when a feature is arranged "adjacent" to another feature, it may mean that a feature has a portion overlapping with the adjacent feature or a portion located above or below the adjacent feature.

[0130] As used herein, the term “exemplary” means “serving as an example, instance, or illustration” and not as a “model” to be precisely copied. Any implementation described herein by example is not necessarily to be construed as preferred or advantageous over other implementations. Moreover, this disclosure is not limited to any theory expressed or implied as given in the field of art, background art, summary of invention, or detailed description.

[0131] As used herein, the term "substantially" means any minor variation resulting from design or manufacturing defects, device or component tolerances, environmental influences, and / or other factors. The term "substantially" also allows for differences from the perfect or ideal situation due to parasitic effects, noise, and other practical considerations that may exist in the actual implementation.

[0132] Furthermore, terms such as “first,” “second,” etc., may be used in this document for reference purposes only and are not intended to be limiting. For example, unless the context clearly indicates otherwise, the words “first,” “second,” and other such numerical terms relating to structures or elements do not imply order or sequence.

[0133] It should also be understood that when the term “including / contains” is used herein, it indicates the presence of the indicated feature, whole, step, operation, unit and / or component, but does not preclude the presence or addition of one or more other features, wholes, steps, operations, units and / or components and / or combinations thereof.

[0134] In this disclosure, the term “provide” is used broadly to cover all ways of obtaining an object, and therefore “provide an object” includes, but is not limited to, “purchasing,” “preparing / manufacturing,” “arranging / setting up,” “installing / assembling,” and / or “ordering” an object.

[0135] As used herein, the term “and / or” includes any and all combinations of one or more of the listed items in association. The terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting of this disclosure. As used herein, the singular forms “a,” “an,” and “the” are also intended to include the plural forms unless the context clearly indicates otherwise.

[0136] Those skilled in the art will recognize that the boundaries between the above operations are merely illustrative. Multiple operations may be combined into a single operation, a single operation may be distributed among additional operations, and operations may be performed with at least partial overlap in time. Moreover, alternative embodiments may include multiple instances of a particular operation, and the order of operations may be changed in various other embodiments. However, other modifications, variations, and substitutions are equally possible. Aspects and elements of all the embodiments disclosed above may be combined in any way and / or in combination with aspects or elements of other embodiments to provide multiple additional embodiments. Therefore, this specification and the accompanying drawings should be considered illustrative rather than restrictive.

[0137] While specific embodiments of this disclosure have been described in detail by way of example, those skilled in the art should understand that the examples are for illustrative purposes only and not intended to limit the scope of this disclosure. The various embodiments disclosed herein can be combined in any way without departing from the spirit and scope of this disclosure. Those skilled in the art should also understand that various modifications can be made to the embodiments without departing from the scope and spirit of this disclosure. The scope of this disclosure is defined by the appended claims.

Claims

1. A physiological parameter monitoring device, comprising: The first flexible layer is formed of a flexible material; A first sensing layer is disposed on one side of the first flexible layer, wherein the first sensing layer includes one or more physiological parameter sensors and conductive wiring. Each physiological parameter sensor is configured to monitor a corresponding physiological parameter and generate a corresponding sensing signal. The conductive wiring is electrically connected to at least one physiological parameter sensor and configured to transmit the sensing signal from the at least one physiological parameter sensor and / or transmit an excitation signal to the at least one physiological parameter sensor; and The second flexible layer is formed of a flexible material, wherein the second flexible layer and the first flexible layer enclose at least a portion of the non-sensing area of ​​the first sensing layer therebetween; In this device, one or more implantation vias are formed in the area where the first flexible layer and the second flexible layer are in direct contact, and each implantation via penetrates the first flexible layer and the second flexible layer in the thickness direction of the physiological parameter monitoring device.

2. The physiological parameter monitoring device according to claim 1 further includes: A second sensing layer is disposed on the side of the second flexible layer opposite to the first sensing layer, wherein the second sensing layer includes one or more physiological parameter sensors and conductive wiring; and The third flexible layer is formed of a flexible material, wherein the third flexible layer and the second flexible layer enclose at least a portion of the non-sensing area of ​​the second sensing layer therebetween; The one or more implantation vias are also formed in the area where the second flexible layer and the third flexible layer are in direct contact, and each implantation via penetrates the third flexible layer in the thickness direction.

3. The physiological parameter monitoring device according to claim 1 or 2, wherein, Flexible materials include biocompatible materials; and / or The absolute value of the difference between the Young's modulus of the flexible material and the Young's modulus of the biological tissue monitored by the physiological parameter monitoring device is less than or equal to a preset threshold.

4. The physiological parameter monitoring device according to claim 1 or 2, wherein, Flexible materials include at least one of polymethyl methacrylate, polyimide, polydimethylsiloxane, parylene, hydrogenated styrene-butadiene-styrene block copolymer, Ecoflex, SU-8 photoresist, polyethylene terephthalate, polyethylene, polyvinyl chloride, cumene-terminated polystyrene-maleic anhydride copolymer, polysilyl ether, polyvinylpyrrolidone, polylactic acid-glycolic acid copolymer, polyvinyl alcohol, polyglycerol sebacate, silk protein, linezolid, collagen, chitosan, polyoctamethylene maleate (anhydride) citrate, polylactic acid (L-) and polycaprolactone.

5. The physiological parameter monitoring device according to claim 1 or 2, wherein, At least two flexible layers are formed of the same flexible material; or Different flexible layers are formed from different flexible materials.

6. The physiological parameter monitoring device according to claim 1 or 2, wherein, Physiological parameter sensors include flexible sensors.

7. The physiological parameter monitoring device according to claim 1 or 2, wherein, Physiological parameter sensors include at least one of pressure sensors, oxygen partial pressure sensors, glucose concentration sensors, temperature sensors, neuronal electrical signal sensors, electrolyte concentration sensors, and neurobiomarker sensors.

8. The physiological parameter monitoring device according to claim 1 or 2, wherein, The conductive wiring is formed of a biocompatible and flexible conductive material; and / or At least a portion of the outer surface of the conductive wiring is also covered with insulating material.

9. The physiological parameter monitoring device according to claim 1 or 2, wherein, Conductive wiring includes at least one of silver, gold, magnesium, molybdenum, copper, platinum, aluminum, titanium, chromium, nickel, carbon nanotubes, polyaniline, poly(3,4-ethylenedioxythiophene)-poly(styrenesulfonic acid), and carbon black; and / or At least a portion of the outer surface of the conductive wiring is also coated with at least one of polyethylene terephthalate and nylon.

10. The physiological parameter monitoring device according to claim 1 or 2, wherein, At least one implantation via is located on the side of at least one physiological parameter sensor that is not directly connected to the conductive wiring.

11. The physiological parameter monitoring device according to claim 1 or 2, wherein, The transverse feature size of the implanted via in the layer of the physiological parameter monitoring device is 1 to 8 times the longitudinal feature size of the implanted via in the thickness direction.

12. A physiological parameter monitoring system, comprising a physiological parameter monitoring device according to any one of claims 1 to 11; and the physiological parameter monitoring system further comprising at least one of the following: The data processing unit is electrically connected to the conductive wiring of the physiological parameter monitoring device, wherein, The data processing unit is configured to process sensing signals from the physiological parameter monitoring device; and An implantation tool configured to be removably inserted into a corresponding implantation port of the physiological parameter monitoring device.

13. The physiological parameter monitoring system according to claim 12, wherein, The implantation tool includes a main body and a tip portion disposed at one end of the main body, wherein the tip portion is thinner than the main body, the tip portion is configured to pass through a corresponding implantation port of the physiological parameter monitoring device, and the main body is configured to be attached to the physiological parameter monitoring device along the surface of the physiological parameter monitoring device when the tip portion passes through the implantation port.

14. The physiological parameter monitoring system according to claim 13, wherein, The lateral feature size of the implanted through-hole in the physiological parameter monitoring device is greater than the feature size of the cross-section of the tip portion of the implantation tool, but smaller than the feature size of the cross-section of the body portion of the implantation tool.

15. A method for preparing a physiological parameter monitoring device, comprising: A first flexible layer is provided, wherein the first flexible layer is formed of a flexible material; A first sensing layer is formed on one side of the first flexible layer, wherein the first sensing layer includes one or more physiological parameter sensors and conductive wiring, each physiological parameter sensor is configured to monitor a corresponding physiological parameter and generate a corresponding sensing signal, and the conductive wiring is electrically connected to at least one physiological parameter sensor and is configured to transmit the sensing signal from the at least one physiological parameter sensor and / or transmit an excitation signal to the at least one physiological parameter sensor. A second flexible layer is formed on the first sensing layer, wherein the second flexible layer is formed of a flexible material, and the second flexible layer and the first flexible layer enclose at least a portion of the non-sensing area of ​​the first sensing layer therebetween; and One or more implantation vias are formed, wherein the one or more implantation vias are formed in the region where the first flexible layer and the second flexible layer are in direct contact, and each implantation via penetrates the first flexible layer and the second flexible layer in the thickness direction of the physiological parameter monitoring device.

16. The method of claim 15, further comprising: A second sensing layer is formed on the side of the second flexible layer opposite to the first sensing layer, wherein the second sensing layer includes one or more physiological parameter sensors and conductive wiring; and A third flexible layer is formed on the second sensing layer, wherein the third flexible layer is formed of a flexible material, and the third flexible layer and the second flexible layer enclose at least a portion of the non-sensing area of ​​the second sensing layer therebetween; The one or more implantation vias are also formed in the area where the second flexible layer and the third flexible layer are in direct contact, and each implantation via penetrates the third flexible layer in the thickness direction.

17. The method according to claim 15 or 16, wherein, When the provided first flexible layer is disposed on a supporting substrate, after forming the one or more implantation vias, the method further includes: Separate the first flexible layer and the supporting substrate.

18. The method according to claim 15 or 16, wherein, Enclosing at least a portion of the non-sensing area of ​​the first sensing layer between the second flexible layer and the first flexible layer includes: A patterned sensing mask layer is formed on one of the first flexible layer and the second flexible layer, wherein the sensing mask layer covers an area corresponding to at least a portion of the non-sensing area of ​​the first sensing layer; and Etching is performed to remove flexible material from the area of ​​one of the first and second flexible layers that is not covered by the sensing mask layer.

19. The method according to claim 15 or 16, wherein, Forming one or more implantation vias includes: A patterned via mask layer is formed on the outermost flexible layer of the physiological parameter monitoring device, wherein the via mask layer exposes the area in the flexible layer where the one or more implantation vias will be located; Etching is performed to remove flexible material from areas of all flexible layers of the physiological parameter monitoring device that are not covered by the via mask layer.

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