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

Abstract

The present disclosure provides a physiological parameter monitoring apparatus, a preparation method therefor, and a physiological parameter monitoring system. The physiological parameter monitoring apparatus comprises: a first flexible layer, wherein one or more implantation cavities are formed in the first flexible layer, and an opening of each of the implantation cavities is arranged on a first side of the first flexible layer; a first sensing layer, comprising one or more physiological parameter sensors and electrically conductive wiring, wherein each of the physiological parameter sensors is configured to monitor a corresponding physiological parameter and generate a corresponding sensing signal, and the electrically 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; and a second flexible layer, wherein the second flexible layer and the first flexible layer enclose at least part of a non-sensing area of the first sensing layer.

Description

Physiological parameter monitoring device, method of manufacturing the same and physiological parameter monitoring system

[0001] Cross-reference to related applications

[0002] This application is based on and claims priority to Chinese Patent Application No. 202411061241.7, filed on August 2, 2024, the disclosure of which is incorporated herein in its entirety. TECHNICAL FIELD

[0003] The present disclosure relates to the field of sensing technology, and more particularly, to a physiological parameter monitoring device, a method of manufacturing the same and a physiological parameter monitoring system. BACKGROUND

[0004] In the fields of biology, medicine, etc., it is often necessary to monitor various physiological parameters in order to understand the health and disease status of the monitoring object, or to develop appropriate health care, treatment plans, etc. for the monitoring object. However, in order to accurately monitor certain physiological parameters, it can be necessary to set the corresponding sensor inside the monitored body tissue, which often needs to be achieved through surgery, resulting in problems such as large incision, easy infection, and difficulty in real-time monitoring. Therefore, it is necessary to improve the monitoring of physiological parameters. SUMMARY

[0005] It is one of the objectives of the present disclosure to provide a physiological parameter monitoring device, a method of manufacturing the same and a physiological parameter monitoring system.

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

[0007] a first flexible layer formed of a flexible material, wherein one or more implant cavities are formed in the first flexible layer, and an opening of each implant cavity is disposed on a first side of the first flexible layer;

[0008] a first sensing layer disposed on a second side of the first flexible layer opposite to the first side, wherein the first sensing layer comprises 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 with 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; and

[0009] a second flexible layer formed of a flexible material, wherein the second flexible layer and the first flexible layer enclose at least part of a non-sensing area of the first sensing layer therebetween.

[0010] In some embodiments, the physiological parameter monitoring device further comprises:

[0011] a second sensing layer disposed on a side of the second flexible layer opposite the first sensing layer, wherein the second sensing layer comprises one or more physiological parameter sensors and conductive wiring; and

[0012] a third flexible layer formed of a flexible material, wherein the third flexible layer and the second flexible layer enclose at least a portion of a non-sensing area of the second sensing layer therebetween.

[0013] In some embodiments, one or more implant cavities are formed in the third flexible layer, and an opening of each implant cavity is disposed on a side of the third flexible layer opposite the second sensing layer.

[0014] In some embodiments, the flexible material comprises a biocompatible material; and / or

[0015] a difference between a Young's modulus of the flexible material and a Young's modulus of a biological tissue monitored by the physiological parameter monitoring device is less than or equal to a preset modulus threshold.

[0016] In some embodiments, the flexible material comprises 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, polysiloxane ether, polyvinylpyrrolidone, polylactic-glycolic acid copolymer, polyvinyl alcohol, polyglycerol sebacate, silk protein, linezolid, collagen, chitosan, poly (maleic acid octamethylene (anhydride) citrate), poly-L-lactic acid, and polycaprolactone.

[0017] In some embodiments, the same flexible layer is formed of one or more flexible materials; or

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

[0019] different flexible layers are formed of different flexible materials, respectively.

[0020] In some embodiments, at least one implant cavity comprises:

[0021] a main cavity portion located inside the flexible layer in which the implant cavity is located; and

[0022] a guide cavity portion communicating between the main cavity portion and an opening of the implant cavity;

[0023] wherein a corner exists in a region where the main cavity portion and the guide cavity portion meet each other.

[0024] In some embodiments, the lateral characteristic dimension of the subject lumen portion in the plane of the physiological parameter monitoring device is greater than the lateral characteristic dimension of the guide lumen portion in the plane of the physiological parameter monitoring device.

[0025] In some embodiments, the overlap area between the projection of the at least one implant lumen in the plane of the physiological parameter monitoring device and the projections of all physiological parameter sensors and all conductive wirings in the physiological parameter monitoring device in the plane of the physiological parameter monitoring device is less than or equal to a preset area threshold.

[0026] In some embodiments, the thickness of the flexible material between the implant lumen and the sensing layer nearest to the implant lumen is greater than or equal to a preset distance threshold.

[0027] In some embodiments, the physiological parameter sensor comprises a flexible sensor.

[0028] In some embodiments, the physiological parameter sensor comprises 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 neural biomarker sensor.

[0029] In some embodiments, the conductive wiring is formed of a biocompatible and flexible conductive material; and / or

[0030] The conductive wiring is further coated on at least a portion of the outer surface thereof with an insulating material.

[0031] In some embodiments, the conductive wiring comprises at least one of silver, gold, magnesium, molybdenum, copper, platinum, aluminum, titanium, chromium, nickel, carbon nanotube, polyaniline, poly(3,4-ethylenedioxythiophene)-poly(styrenesulfonic acid), and carbon black; and / or

[0032] The conductive wiring is further coated on at least a portion of the outer surface thereof with at least one of polyethylene terephthalate and nylon.

[0033] According to a second aspect of the present disclosure, there is provided a physiological parameter monitoring system, comprising a physiological parameter monitoring device as described above; and the physiological parameter monitoring system further comprises at least one of:

[0034] a data processing unit electrically connected to the conductive wirings of the physiological parameter monitoring device, wherein the data processing unit is configured to process the sensing signals from the physiological parameter monitoring device; and

[0035] an implant tool configured to be removably disposed in the respective implant lumen of the physiological parameter monitoring device.

[0036] According to a third aspect of the present disclosure, there is provided a method for preparing a physiological parameter monitoring device, comprising:

[0037] providing a carrier substrate;

[0038] forming a first flexible substrate layer over the carrier substrate, wherein the first flexible substrate layer is formed of a flexible material;

[0039] forming a patterned first filler layer, wherein the first filler layer is formed of a filler material, and the first filler layer comprises a patterned first filler portion over the first flexible substrate layer;

[0040] forming a first flexible structure layer, wherein the first flexible structure layer is formed of a flexible material, the first flexible structure layer covers exposed top surfaces of the first flexible substrate layer and the first filler layer, and the first flexible substrate layer and the first flexible structure layer collectively form a first flexible layer;

[0041] forming a first sensing layer over the first flexible layer, wherein the first sensing layer comprises one or more physiological parameter sensors and conductive wiring, each physiological parameter sensor is configured to monitor a respective physiological parameter and generate a respective sensing signal, and the conductive wiring is electrically connected with at least one physiological parameter sensor and is configured to transmit a sensing signal from the at least one physiological parameter sensor and / or transmit an excitation signal to the at least one physiological parameter sensor;

[0042] forming a second flexible layer over 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 a non-sensing area of the first sensing layer therebetween; and

[0043] removing the filler material and the carrier substrate.

[0044] In some embodiments, the carrier substrate is a rigid substrate.

[0045] In some embodiments, the filler material comprises at least one of gold, silver, copper, platinum, aluminum, titanium, chromium, and nickel.

[0046] In some embodiments, removing the filler material comprises:

[0047] forming a patterned cavity mask layer on a side of the carrier substrate opposite to the first flexible substrate layer;

[0048] performing etching to remove portions of the carrier substrate and the first flexible substrate layer that are not covered by the cavity mask layer; and

[0049] performing a wet etch to remove the fill material of the first fill layer to form one or more implant cavities in the first flexible layer.

[0050] In some embodiments, the first flexible base layer is patterned, and the first fill layer further comprises a second fill portion filling spaces of the first flexible base layer not filled by the flexible material;

[0051] removing the fill material comprises:

[0052] forming a patterned cavity mask layer on a side of the carrier substrate opposite the first flexible base layer, wherein the cavity mask layer does not cover over at least a portion of the second fill portion;

[0053] performing an etch to remove portions of the carrier substrate not covered by the cavity mask layer to expose the at least a portion of the second fill portion; and

[0054] performing a wet etch to remove the fill material of the first fill layer to form one or more implant cavities in the first flexible layer.

[0055] In some embodiments, the carrier substrate comprises a sacrificial layer formed of a sacrificial material in direct contact with the first flexible base layer, removing the carrier substrate comprises:

[0056] performing a wet etch to remove the sacrificial material of the sacrificial layer to detach the carrier substrate from the first flexible base layer.

[0057] In some embodiments, the sacrificial material comprises at least one of silver, copper, platinum, aluminum, titanium, chromium, and nickel.

[0058] In some embodiments, the first flexible base layer is patterned, and the first fill layer further comprises a second fill portion filling spaces of the first flexible base layer not filled by the flexible material, the carrier substrate comprises an electrically conductive layer formed of an electrically conductive material and a sacrificial layer formed of a sacrificial material on the electrically conductive layer, and the sacrificial material and the fill material are electrolytic materials;

[0059] removing the fill material and the carrier substrate comprises:

[0060] electrically connecting the carrier substrate to a positive pole of a power source, and a negative pole of the power source to an inert material, removing the electrolytic material through an electrolytic reaction occurring in an electrolyte solution to form one or more implant cavities in the first flexible layer, and detach the carrier substrate from the first flexible base layer.

[0061] In some embodiments, the electrolytic material comprises at least one of magnesium, aluminum, zinc, chromium, iron, nickel, copper, and silver.

[0062] In some embodiments, enclosing, with the second flexible layer and the first flexible layer, at least a portion of a non-sensing region of the first sensing layer therebetween comprises:

[0063] forming a patterned sensing mask layer 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 a non-sensing region of the first sensing layer; and

[0064] performing etching to remove flexible material in an area of the one of the first flexible layer and the second flexible layer that is not covered by the sensing mask layer.

[0065] In some embodiments, the method further comprises:

[0066] forming a second sensing layer on a side of the second flexible layer opposite the first sensing layer, wherein the second sensing layer comprises one or more physiological parameter sensors and conductive wiring; and

[0067] forming a third flexible layer 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 a non-sensing region of the second sensing layer therebetween.

[0068] According to a fourth aspect of the present disclosure, there is provided a method for preparing a physiological parameter monitoring device, comprising:

[0069] providing a pre-fabricated assembly, wherein the pre-fabricated assembly comprises a fourth flexible layer formed of a flexible material and a third sensing layer disposed above the fourth flexible layer, wherein the third sensing layer comprises one or more physiological parameter sensors and conductive wiring, each physiological parameter sensor being configured to monitor a respective physiological parameter and to generate a respective sensing signal, and the conductive wiring being electrically connected with at least one physiological parameter sensor and being configured to transmit a sensing signal from the at least one physiological parameter sensor and / or to transmit an excitation signal to the at least one physiological parameter sensor;

[0070] forming a patterned fifth flexible base layer above the pre-fabricated assembly, wherein the fifth flexible base layer is formed of a flexible material;

[0071] forming a patterned second filling layer, wherein the second filling layer is formed of a filling material, and the second filling layer comprises a third filling portion filling a space of the fifth flexible base layer that is not filled by the flexible material and a patterned fourth filling portion located above the fifth flexible base layer;

[0072] forming a fifth flexible structural layer, wherein the fifth flexible structural layer is formed of a flexible material, the fifth flexible structural layer is disposed on an exposed top surface of the fifth flexible base layer, and the fifth flexible base layer and the fifth flexible structural layer collectively form a fifth flexible layer; and

[0073] removing the fill material.

[0074] In some embodiments, the fill material includes at least one of gold, silver, copper, platinum, aluminum, titanium, chromium, and nickel.

[0075] In some embodiments, the fill material is removed by wet etching to form one or more implant cavities in the fifth flexible layer.

[0076] In some embodiments, the fill material is an electrolytic material;

[0077] removing the fill material includes:

[0078] electrically connecting the fill material to a positive pole of a power source, and a negative pole of the power source is connected to an inert material, the electrolytic material is removed by an electrolysis reaction occurring in an electrolyte solution to form one or more implant cavities in the fifth flexible layer.

[0079] In some embodiments, the electrolytic material includes at least one of magnesium, aluminum, zinc, chromium, iron, nickel, copper, and silver.

[0080] In some embodiments, the method further includes enclosing at least a portion of the non-sensing region of the third sensing layer between the fifth flexible layer and the fourth flexible layer, including:

[0081] forming a patterned sensing mask layer on one of the fourth flexible layer and the fifth flexible layer, wherein the sensing mask layer covers an area corresponding to at least a portion of the non-sensing region of the third sensing layer; and

[0082] performing etching to remove flexible material in an area of the one of the fourth flexible layer and the fifth flexible layer that is not covered by the sensing mask layer.

[0083] In some embodiments, the pre-fabricated assembly further includes:

[0084] a sixth flexible layer disposed above the third sensing layer, wherein the sixth flexible layer is formed of a flexible material; and

[0085] a fourth sensing layer disposed above the sixth flexible layer, wherein the fourth sensing layer comprises one or more physiological parameter sensors and conductive wiring, and the sixth flexible layer and the fourth flexible layer enclose at least a portion of a non-sensing area of the fourth sensing layer therebetween.

[0086] Other features of the present disclosure, and their advantages, will become more apparent in the light of the following detailed description of exemplary embodiments of the present disclosure. BRIEF DESCRIPTION OF DRAWINGS

[0087] The accompanying drawings, which constitute a part of this specification, illustrate embodiments of the present disclosure and serve to explain the principles of the present disclosure.

[0088] The present disclosure can be understood moreappreciably with the following detailed description when taken in conjunction with the accompanying drawings, in which:

[0089] FIG. 1 shows a top view structural schematic diagram of a physiological parameter monitoring device according to a first embodiment of the present disclosure;

[0090] FIG. 2 shows a top view structural schematic diagram of a physiological parameter monitoring device according to a second embodiment of the present disclosure;

[0091] FIG. 3 shows a top view structural schematic diagram of a physiological parameter monitoring device according to a third embodiment of the present disclosure;

[0092] FIG. 4 shows a side view structural schematic diagram of a physiological parameter monitoring device according to a fourth embodiment of the present disclosure;

[0093] FIG. 5 shows a side view structural schematic diagram of a physiological parameter monitoring device according to a fifth embodiment of the present disclosure;

[0094] FIG. 6 shows a side view structural schematic diagram of a physiological parameter monitoring device according to a sixth embodiment of the present disclosure;

[0095] FIG. 7 shows a side view structural schematic diagram of a physiological parameter monitoring device according to a seventh embodiment of the present disclosure;

[0096] FIG. 8 shows a block diagram of a physiological parameter monitoring system according to an exemplary embodiment of the present disclosure;

[0097] FIG. 9 shows a structural schematic diagram of an implantation tool according to an exemplary embodiment of the present disclosure;

[0098] FIG. 10 shows a flow schematic diagram of a method for preparing a physiological parameter monitoring device according to an exemplary embodiment of the present disclosure;

[0099] FIGS. 11(a) to 11(h) show process schematic diagrams of preparing a physiological parameter monitoring device according to a specific embodiment of the present disclosure;

[0100] FIGS. 12(a) to 12(f) illustrate a partial process of manufacturing a physiological parameter monitoring device according to another embodiment of the present disclosure;

[0101] FIG. 13 illustrates a schematic diagram of an electrolysis reaction device according to an embodiment of the present disclosure;

[0102] FIG. 14 illustrates a flow diagram of a method for manufacturing a physiological parameter monitoring device according to another exemplary embodiment of the present disclosure.

[0103] Note that, in the following embodiments, the same reference numerals are sometimes used across different drawings to represent the same or similar parts or parts having the same function, and repeated description thereof is omitted. In the present specification, like numbers and letters indicate like items throughout the drawings, and thus, once an item is defined in one drawing, it is not necessary to discuss it further in subsequent drawings.

[0104] For ease of understanding, the position, size, range, and the like of each structure shown in the drawings and the like are sometimes not actual position, size, range, and the like. Therefore, the disclosed application is not limited to the position, size, range, and the like disclosed in the drawings and the like. In addition, the drawings are not necessarily drawn to scale, and some features can be exaggerated to show details of specific components. DETAILED DESCRIPTION

[0105] Various exemplary embodiments of the present disclosure will now be described in detail with reference to the accompanying drawings. It should be noted that the relative arrangement, numerical expressions, and numerical values of the components and steps set forth in these embodiments do not limit the scope of the present disclosure unless otherwise specifically stated.

[0106] The following description of at least one exemplary embodiment is merely illustrative in nature and is in no way limiting to the scope of the disclosure and its applications or uses. Any procedural steps, processes, and techniques described herein are structural means for achieving the exemplary embodiments of the present disclosure, and are not exhaustive.

[0107] Techniques, methods, and equipment known to those of ordinary skill in the relevant art can not be discussed in detail, but should be considered part of the specification where appropriate.

[0108] In order to better understand the health and disease conditions of a living body, one or more physiological parameters of various body tissues of the living body can be monitored. In this paper, the monitoring of physiological parameters of cranial brain tissue in the human body will be taken as an example to elaborate the technical solutions of the present disclosure in detail. However, those skilled in the art can understand that, according to the needs, the physiological parameter monitoring device and the physiological parameter monitoring system containing the same provided in this paper can also monitor one or more physiological parameters of other related tissues in the human or animal body, as long as corresponding physiological parameter sensors are arranged in the physiological parameter monitoring device and the physiological parameter monitoring device is implanted into a suitable position in the body tissue to be monitored, which is not limited herein. In addition, the physiological parameter monitoring device and the physiological parameter monitoring system containing the same provided in this paper can be used for therapeutic purposes or can also be used for non-therapeutic purposes.

[0109] 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 about 27 million cases per year, mainly caused by traffic accidents and accidental falls, etc. Related epidemiological surveys show that the incidence of severe craniocerebral injury in China has increased sharply, reaching 1.0‰-1.5‰ per year, with a mortality rate of more than 20% and a severe disability rate of more than 50%. In addition, foreign data shows that for patients with severe craniocerebral injury with a Glasgow Coma Scale (GCS) score of less than or equal to 8, the mortality rate is as high as 35%-45%. Therefore, correctly identifying the clinical status of patients with TBI (especially severe TBI) is crucial for subsequent medical treatment and reducing secondary injury after the initial injury.

[0110] In order to identify the clinical status of TBI patients, multi-modal monitoring of physiological parameters related to the patient's cranium and brain has become increasingly widespread. In clinical and research work, focusing on the development of management protocols based on personalized precision medicine will help improve individual patient outcomes. For example, in 2022, Geert Meyfroidt gave the recommended values of neurological monitoring in the article "Management of moderate to severe traumatic brain injury: an update for the intensivist", as shown in Table 1 below:

[0111] Table 1

[0112] In Table 1, the relevant monitoring target values of intracranial pressure (ICP), partial pressure of brain tissue oxygen (PbtO2), glucose concentration (Brain glucose), and intracranial temperature (ICT) are explicitly given. For the treatment team who can only rely on clinical manifestations and radiological results, this helps them to monitor the condition changes in time and make reasonable and effective intervention on the condition. In addition, other physiological parameters in the intracranial can also be monitored in real time, including but not limited to monitoring neuron electrical signals, intracranial electrolyte concentration, neural biomarkers, lactic acid, pyruvic acid, glycerol and glutamate, etc., so as to early judge the occurrence of secondary brain injury, and quantify the degree of brain injury at the same time.

[0113] In some examples, the following physiological parameters in the intracranial can be monitored based on a single or dual modal manner, which can specifically include:

[0114] (1) Intracranial pressure: Intracranial pressure can be monitored to reflect the changes in intracranial pressure in real time, dynamically and accurately, thereby guiding treatment decisions. Intracranial hypertension (i.e., a state in which intracranial pressure is greater than 15 mmHg (1 mmHg = 0.133 kPa) when the patient is lying flat) caused by intracranial hemorrhage, brain contusion and laceration, brain edema and brain swelling in patients with acute TBI is the main cause of poor prognosis. At present, the methods of intracranial pressure monitoring used in clinical practice are mainly divided into invasive ICP monitoring and non-invasive ICP monitoring. Invasive dynamic intracranial pressure monitoring, as an important mechanism in the treatment of moderate and severe craniocerebral injury, can understand and master the patient's condition at any time according to the changes in intracranial pressure, and make timely and effective judgments and treatment measures according to the patient's condition. Among them, the most widely used is intraventricular (IVC) monitoring. By placing a pressure or optical fiber sensor in the intracranial space, the pressure at a certain point in the intracranial space can be measured, allowing for continuous monitoring, and the stability and accuracy of the data obtained by this method are relatively high, making it the gold standard for monitoring ICP in clinical practice. However, this method may cause operation-related complications such as infection and bleeding, and is expensive, in addition, it may also cause zero drift, etc., which to a large extent limits its clinical application. Non-invasive intracranial pressure monitoring mainly includes transcranial Doppler (TCD) monitoring of cerebral blood flow, flash visual evoked potential (FVEP), two-depth transorbital Doppler (TDTD) technology, optic nerve sheath diameter (ONSD) measurement, tympanic membrane displacement (TMD) technology, otoacoustic emission (OAE) technology, near-infrared spectroscopy (NIRS) technology, optical coherence tomography (OCT) technology, etc. However, there are many interference factors in the process of non-invasive intracranial pressure monitoring, which may cause large measurement errors.

[0115] (II) Intracranial oxygen tension: Hypoxia in brain tissue after TBI is an important factor affecting the prognosis of patients. When intracranial pressure is significantly increased, the value of partial pressure of oxygen in local brain tissue is inversely proportional to intracranial pressure. Therefore, by monitoring PbtO2, the treatment strategy can be guided. At present, the commonly used PbtO2 monitoring is based on continuous invasive probe monitoring technology. The consensus of the International Intensive Care Society and the European Critical Care Association is to recommend PbtO2 or jugular venous oxygen saturation monitoring, TCD or transcranial color Doppler cerebral blood flow monitoring and continuous electroencephalogram (cEEG) for critically ill patients, so as to effectively and fully evaluate the brain function of patients. Although jugular venous oxygen saturation monitoring is a mature monitoring method, only intermittent monitoring of venous blood oxygen concentration returning from the brain can only indirectly indicate the brain's use of oxygen. The normal reference range of jugular venous oxygen saturation is 55% to 75%, and the monitoring results are related to many factors. Both too high and too low indicate that the brain tissue oxygen uptake is impaired. In addition, non-invasive brain tissue oxygen monitoring methods have been of great concern. Near-infrared spectroscopy (NIRS) obtains information on cerebral oxygen supply by measuring the concentration of oxygenated hemoglobin and deoxygenated hemoglobin in brain tissue. However, existing research results suggest that the clinical value of NIRS is still highly controversial and cannot replace the current invasive monitoring technology.

[0116] (III) Glucose concentration: Intracranial glucose concentration is mainly detected by cerebral microdialysis (CMD). This technique is a method for continuous monitoring of brain metabolism, which can penetrate the blood-brain barrier and provide energy metabolism at the subcellular level of the brain. Because CMD can only detect the microenvironment in a few cubic millimeters around the probe, the location of the probe has a great influence on the results. Many CMD detection studies have found that patients with different glucose levels have different prognoses. Specifically, TBI patients who maintain stable, normal glucose levels within 50 hours after injury have a good prognosis. In addition, the results of many CMD studies suggest that interleukin series factors after TBI are related to the prognosis 6 months after injury. In addition, common metabolic analysis indicators of CMD can also include lactate, pyruvate, glycerol and glutamate, etc. However, due to the limitations of CMD, most of the current reports are still in the research stage.

[0117] (IV) Intracranial temperature: TBI can cause a series of pathological and physiological changes in the brain parenchyma, and the brain temperature will rise or fall. After TBI, the temperature of the brain parenchyma is generally 0.39-2.50℃ higher than the core temperature of the human body (such as the anal temperature), which may be related to the high metabolism of brain tissue. In addition, the brain temperature lower than the core temperature of the human body may be a sign of pre-death. At present, the implanted temperature sensing probe is generally implanted into the cerebral cortex to measure the temperature of the cortex, and the intracranial temperature sensor can also be integrated with the intracranial pressure detection or intracranial oxygen partial pressure detection probe to perform dual-mode monitoring. However, this detection method causes a larger wound, and the measurement time is shorter.

[0118] (V) Neuronal electrical signals: In patients with moderate to severe TBI, 22%-33% of patients have seizures, and in coma patients, the incidence of non-convulsive seizures and non-convulsive status epilepticus is as high as 5%-48%, and is closely related to the prognosis of patients. The European Society of Intensive Care Medicine recommends using cEEG to monitor refractory status epilepticus, and suggests that it be applied to the diagnosis and management of status epilepticus and persistent disturbance of consciousness of unknown origin. The American Clinical Neurophysiology Association recommends using cEEG to monitor non-convulsive seizures and status epilepticus. At present, cEEG mainly includes two categories of electrocorticography and stereoelectroencephalography. The electrocorticography is to place the electrode on the cerebral cortex, while the stereoelectroencephalography is to place the electrode in the deep brain tissue. In order to monitor the stereoelectroencephalography, a silicon-based or stainless steel neural probe can be used as a brain cortex deep implantable electrode, which can be implanted into the brain cortex to measure brain neural signals, so as to reflect the brain function information of the patient in real time and dynamically, and early indicate the neurological status of the patient, which has incomparable advantages over CT and other neuroimaging examinations.

[0119] (VI) Intracranial electrolyte concentration: After acute TBI, various types of electrolyte disorders often occur, and electrolyte disorders can cause brain cell edema and acid-base imbalance, nerve electrical activity conduction disorders, etc., further aggravating brain injury. Therefore, it is of great significance to understand the change rule of electrolyte after acute TBI for the treatment of TBI patients.

[0120] (VII) Neurobiological markers: After TBI, specific proteins in the cytoplasm are released into the blood or cerebrospinal fluid, the expression of which 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 biological markers for clinical judgment of mild TBI. Related studies have shown that the increase of GFAP and UCH-L1 levels in serum within 12 hours has a sensitivity of 97.6% and a negative predictive value of 99.6% for diagnosing TBI, which is better than the effect of CT diagnosis.

[0121] In the clinic, one or more of the above monitoring can be performed for a TBI patient. However, in order to obtain better monitoring effect according to the characteristics of various physiological parameters as described above, it is often necessary to perform surgery to implant the corresponding monitoring device, which will result in problems such as large wound area, easy infection, and difficult real-time monitoring. In order to solve the above problems, the present disclosure provides a flexible physiological parameter monitoring device and a physiological parameter monitoring system comprising the same, which can be implanted into the body tissue in a minimally invasive manner, and through the setting of appropriate physiological parameter sensors therein, real-time monitoring of one or more physiological parameters can be achieved, which has great significance for many aspects such as clinical diagnosis, injury judgment, surgical indication, treatment scheme, treatment effect evaluation and prognosis judgment of patients with craniocerebral trauma.

[0122] In an exemplary embodiment of the present disclosure, as shown in FIGS. 1-7, the physiological parameter monitoring device 100 can include a first flexible layer 110 formed of a flexible material, a first sensing layer, and a second flexible layer 130 formed of a flexible material.

[0123] In some embodiments, the flexible material can include a biocompatible material. In addition, 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 can be less than or equal to a preset modulus threshold, or in other words, the Young's modulus of the flexible material can be substantially equal to the Young's modulus of the biological tissue monitored by the physiological parameter monitoring device 100. By using a flexible material with the above characteristics, mechanical mismatch between the implanted physiological parameter monitoring device 100 and the biological tissue can be reduced as much as possible, thereby reducing adverse effects caused by neuroinflammation, etc. In some specific examples, the flexible material can include Polymethyl Methacrylate (PMMA), Polyimide (PI), Polydimethylsiloxane (PDMS), Parylene, Styrene Ethylene Butylene Styrene (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, the flexible material can include other rubber or resin materials, etc. biocompatible and biodegradable materials with high biocompatibility, such as Polylactic acid hydroxyacetic acid copolymer (PLGA), Polyvinyl alcohol (PVA), Polyglyceryl sebacate (PGS), silk protein, Zyvox, collagen, chitosan, Poly(octamethylene maleate (anhydride) citrate) (POMaC), Poly(L-lactic acid) (PLLA), and Polycaprolactone (PCL), etc. In forming each flexible layer, one or more of the above-listed substances can be used as needed, without limitation.

[0124] In some embodiments, the same flexible layer can be formed of a single flexible material. Alternatively, in other embodiments, the same flexible layer can also be formed of multiple flexible materials, without limitation. In addition, in some embodiments, the first flexible layer 110 and the second flexible layer 130 can be formed of the same flexible material. Alternatively, in other embodiments, different flexible materials can be used to form the first flexible layer 110 and the second flexible layer 130, respectively, as needed, without limitation.

[0125] In some embodiments, as shown in FIGS. 1-7, the first sensing layer can include one or more physiological parameter sensors 121 and conductive wires 122. Each physiological parameter sensor 121 can be configured to monitor a corresponding physiological parameter and generate a corresponding sensing signal. In addition, the conductive wires 122 can be electrically connected to at least one physiological parameter sensor 121. According to the monitoring needs, the conductive wires 122 can be configured to transmit the sensing signal from the at least one physiological parameter sensor 121 to which they are connected, or can be configured to transmit an excitation signal to the at least one physiological parameter sensor 121 to which they are connected. In most cases, the sensing signal generated by the physiological parameter sensor 121 is an electrical signal, and thus the conductive wires 122 can be electrically connected to each physiological parameter sensor 121, respectively. In addition, some of the conductive wires 122 can also be connected between two physiological parameter sensors 121 to achieve the necessary signal transmission therebetween. In addition, considering that in some cases, according to the monitoring needs, not all of the physiological parameter sensors 121 in the physiological parameter monitoring device 100 can be used, in which case the conductive wires 122 can be electrically connected only to the physiological parameter sensors 121 to be used, thereby simplifying the circuit and facilitating the implantation of the physiological parameter monitoring device 100. The other end of the conductive wires 122 can be electrically connected to an external circuit outside the physiological parameter monitoring device 100, such as a data processing unit, including but not limited to a circuit board (e.g., a PCB board), a processor, a memory, a mobile terminal, a computer device, etc. The external circuit can be disposed outside the body or tissue to be monitored, without being implanted, and can be used to perform the desired processing of the sensing signal, etc.

[0126] In a specific example, as shown in FIGS. 1-3, the physiological parameter sensors 121 can include at least one of a pressure sensor 121a for monitoring intracranial pressure, a partial pressure of oxygen sensor 121b for monitoring partial pressure of oxygen in local brain tissue, a glucose concentration sensor 121c for monitoring glucose concentration in brain, a temperature sensor 121d for monitoring intracranial temperature, a neuron electrical signal sensor 121e for monitoring neuron electrical signal, an electrolyte concentration sensor 121f for monitoring intracranial electrolyte concentration, a neural biomarker sensor 121g for monitoring neural biomarker, etc. The conductive wires 122 can be electrically connected to each of the physiological parameter sensors 121 to output sensing signals generated by the physiological parameter sensors 121. In addition, the conductive wires 122 can also input excitation signals to the corresponding physiological parameter sensors 121 to provide excitation required in the monitoring process. For example, the conductive wires 122 can input excitation signals to electrodes, stimulators, etc. in the neuron electrical signal sensor 121e to provide excitation signals to brain tissue, thereby completing the monitoring of neuron electrical signal. It can be understood that the physiological parameter sensors 121 can include other types of sensors depending on specific monitoring requirements, which are not limited herein.

[0127] In some embodiments, by providing multiple types of physiological parameter sensors 121 in the physiological parameter monitoring device 100, multi-modal 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 required 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 physiological parameter sensors 121 of the same type can be arranged at different positions to help monitor the distribution of the same physiological parameter at multiple positions. For example, as described above, the glucose concentration in the brain can vary greatly with the position, and therefore multiple glucose concentration sensors 121c can be provided at different positions in the physiological parameter monitoring device 100 to better reflect the distribution of glucose concentration and reduce measurement errors. In yet other embodiments, the multiple physiological parameter sensors 121 of the physiological parameter monitoring device 100 can include both physiological parameter sensors 121 of different types and physiological parameter sensors 121 of the same type, which are not limited herein.

[0128] In some embodiments, the conductive wires 122 can be formed of biocompatible and flexible conductive materials. For example, the conductive wires 122 can include solid metallic materials such as silver, gold, magnesium, molybdenum, copper, platinum, aluminum, titanium, chromium, nickel, etc. Alternatively, the conductive wires 122 can include liquid conductive polymers such as carbon nanotubes, polyaniline, poly(3,4-ethylenedioxythiophene)-poly(styrenesulfonic acid) (PEDOT:PSS), carbon black, etc. In some embodiments, the conductive wires 122 can be electrically isolated from each other by insulating flexible materials. Alternatively, in other embodiments, the conductive wires 122 can be further coated with insulating materials on at least part of their outer surfaces to avoid short circuiting between adjacent conductive wires. For example, the conductive wires 122 can be further coated with at least one of polyethylene terephthalate and nylon on at least part of their outer surfaces to achieve electrical isolation between adjacent conductive wires. In some embodiments, the conductive wires 122 in the physiological parameter monitoring device 100 can be formed of flexible printed circuit board wires, nylon wires, or other biocompatible flexible wires, etc. Such conductive wires 122 can achieve electrical connection between the physiological parameter monitoring device 100 and external circuits via a skull hole or a burr hole at a brain injury site, etc., to achieve monitoring of corresponding physiological parameters.

[0129] In some embodiments, in order to enable the physiological parameter sensor 121 to accurately monitor the corresponding physiological parameter, depending on the specific type of the physiological parameter sensor 121, the sensing region of the physiological parameter sensor 121 can be exposed to the body tissue to be monitored via the sensing window, or in other words, the sensing region of the physiological parameter sensor 121 can be directly in contact with the body tissue to be monitored, without being shielded by the flexible layers above or below. In other words, as shown in FIGS. 1-4 and 7, the second flexible layer 130 and the first flexible layer 110 can enclose at least a portion of the non-sensing region of the first sensing layer therebetween (or in other words, the first sensing layer can be disposed between the first flexible layer 110 and the second flexible layer 130, and at least a portion of at least one of the first flexible layer 110 and the second flexible layer 130 corresponding to the sensing region of the first sensing layer is removed to form the sensing window 180), so as to at least expose the sensing region of the first sensing layer (or the corresponding physiological parameter sensor 121), or in other words, expose the sensing region of the first sensing layer (or the corresponding physiological parameter sensor 121) to the corresponding flexible layer, so as to on the one hand avoid interference with detection, and on the other hand protect the circuit and other structures in the first sensing layer from damage by substances in the body tissue, thereby prolonging the service life of the physiological parameter monitoring device 100. In addition, in some embodiments, depending on the specific type of the physiological parameter sensor 121, the physiological parameter sensor 121 can also be completely covered by the flexible material without being directly exposed to the body tissue to be monitored, and the monitoring of the corresponding physiological parameter can also be achieved, as shown in FIGS. 5 and 6.

[0130] In addition, as shown in FIGS. 1-7, 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 basically flexible, so as to be well adapted to the sensing environment (for example, adapted to the body tissue environment to be monitored, etc.), and the physiological parameter monitoring device 100 can be conveniently implanted into the body tissue, thereby helping to more accurately monitor the corresponding physiological parameter and reducing or even avoiding damage to the tissue to be monitored, etc. In some embodiments, in order to make the entire physiological parameter monitoring device 100 have better flexibility, the physiological parameter sensor 121 therein can be a flexible sensor. However, it can be understood that in other embodiments, since the physiological parameter sensor 121 is usually very thin in thickness, and the upper and lower sides thereof are provided with flexible layers capable of providing a certain protection, the physiological parameter sensor 121 itself does not necessarily have to be flexible, which is not limited herein.

[0131] Further, as shown in FIGS. 1-7, an implant cavity 190 can be formed in the first flexible layer 110. If the side of the first flexible layer 110 where the opening of the implant cavity 190 is located is considered as the first side of the first flexible layer 110, then the first sensing layer can be disposed on the second side of the first flexible layer 110 opposite to the first side so as to avoid the interference of the implant cavity 190 with the physiological parameter sensor 121 and the conductive wiring 122. By providing such an implant cavity 190, the physiological parameter monitoring device 100 can be implanted into the body tissue to be monitored by a minimally invasive way with the help of an implant tool as described later. It can be understood that such a minimally invasive implantation can effectively reduce the wound area and inhibit infection, thereby improving the experience of the patient. It should be noted that in FIGS. 1-3, the implant cavity 190 and the opening 193 thereof are located below the second flexible layer 130, and thus the outlines thereof are represented by dashed lines. In a specific example, as shown in FIGS. 4, 6 and 7, the first flexible layer 110 can be located at the bottom of the physiological parameter monitoring device 100, and accordingly, the implant cavity 190 is also disposed at the bottom of the physiological parameter monitoring device 100. Alternatively, in another specific example, as shown in FIG. 5, the first flexible layer 110 can be located at the top of the physiological parameter monitoring device 100, and accordingly, the implant cavity 190 is also disposed at the top of the physiological parameter monitoring device 100, without limitation. In addition, the implant cavities can be disposed in the flexible layer located at the bottom and / or the flexible layer located at the top in different ways, as will be described in detail later.

[0132] In some embodiments, as shown in FIGS. 1, 2, 4, 5 and 6, only one implant cavity 190 can be provided in the physiological parameter monitoring device 100 to help reduce the size of the physiological parameter monitoring device 100, thereby facilitating the minimally invasive implantation. Alternatively, in other embodiments, as shown in FIGS. 3 and 7, a plurality of implant cavities 190 can be provided in the physiological parameter monitoring device 100. By providing a plurality of implant cavities 190, the implant cavity 190 with a suitable position can be selected as needed during implantation to achieve the implantation of the physiological parameter monitoring device 100, thereby reducing the difficulty of implantation. In addition, by providing a plurality of implant cavities 190, in the event of an accident such as the implant cavity 190 being poked by the implant tool, a redundant implant cavity 190 can be provided for implantation, thereby reducing the discard rate of the physiological parameter monitoring device 100.

[0133] In some embodiments, as shown in FIGS. 4-7, the implant cavity 190 can include a main cavity portion 191 and a guide cavity portion 192. For example, the implant cavity 190 as a whole can be in a finger cot shape, such that an implant tool as described later can be sleeved in the implant cavity 190 for implantation operation. Herein, the main cavity portion 191 can be located inside the flexible layer where the implant cavity 190 is located, or in other words, the main cavity portion 191 can be substantially enclosed by the flexible material. The guide cavity portion 192 can be communicated between the main cavity portion 191 and an opening 193 of the implant cavity 190, and the size of the guide cavity portion 192 can be designed such that the implant tool can enter the implant cavity 190 from the opening 193, and during implantation, most of the implant tool can be located in the main cavity portion 191, so that the physiological parameter monitoring device 100 can be substantially stably sleeved outside the implant tool and placed at a suitable position in the body tissue under the guidance of the implant tool. In some embodiments, the lateral characteristic dimension L1 of the main cavity portion 191 in the layer of the physiological parameter monitoring device 100 can be greater than the lateral characteristic dimension L2 of the guide cavity portion 192 in the layer of the physiological parameter monitoring device 100. In addition, L1 can be smaller than the length of the implant tool, so that a part of the implant tool can be sleeved in the implant cavity 190, and another part of the implant tool outside the implant cavity 190 can be retained for clamping, so as to achieve implantation; and the size of L2 can be determined according to the diameter of the implant tool, so that the implant tool can be fitted in the implant cavity 190 through the guide cavity portion 192. For example, in the case that the implant tool is a needle and its diameter is 200 microns, the lateral characteristic dimension L2 of the guide cavity portion 192 in any direction of the layer of the physiological parameter monitoring device 100 can be about 300-400 microns, so that the implant tool can be smoothly arranged in the implant cavity 190. In some embodiments, the arrangement of the guide cavity portion 192 relative to the main cavity portion 191 in the lateral direction can be determined according to the direction of implantation. For example, as shown in FIGS. 4-7, if one end of the conductive wire 122 for connecting to the physiological parameter sensor 121 is defined as the front end, and the other end for connecting to the external circuit is defined as the rear end, the guide cavity portion 192 of the implant cavity 190 can be arranged at the rear or rear end of the main cavity portion 191, so that the implant tool can be sleeved at the relatively front part of the physiological parameter monitoring device 100 to move forward with the physiological parameter monitoring device 100 to achieve implantation, avoiding the physiological parameter monitoring device 100 from being wrinkled or the like during implantation. In addition, the opening 193 of the guide cavity portion 192 communicated with the external environment can be various shapes, including but not limited to circular, oval, square, rectangular (as shown in FIGS. 1-3), triangular, polygonal, and the like.

[0134] Further, as shown in FIGS. 4-7, there can be a corner in the area where the main cavity portion 191 and the guide cavity portion 192 meet each other, for example, in the specific example shown in FIGS. 4-7, a substantially right-angled corner can be formed at the location where the main cavity portion 191 and the guide cavity portion 192 meet each other, so that the implant tool can be more stably clamped in the implant cavity 190 by means of the corner, avoiding the occurrence of undesirable falling off and the like during implantation.

[0135] It can be understood that in some other embodiments, depending on the specific shape of the implant tool and the like, the cavity of the implant cavity 190 can also have other shapes, which are not limited herein.

[0136] In some embodiments, as shown in FIGS. 2-7, the implant cavity 190 can be arranged to be staggered with the physiological parameter sensors 121 and / or the conductive wires 122 in the sensing layer in the lateral direction. For example, the implant cavity 190 can be arranged in the middle region of the physiological parameter monitoring device 100 to enable convenient implantation of the physiological parameter monitoring device 100 with the implant tool; while the physiological parameter sensors 121 and / or the conductive wires 122 can be arranged in the peripheral region of the physiological parameter monitoring device 100, as far as possible staggered with the implant cavity 190, to avoid damage to the physiological parameter sensors 121 and / or the conductive wires 122 during implantation, while also facilitating the connection of the physiological parameter sensors 121 and / or the conductive wires 122 to the external circuit. In other words, the overlapping area between the projection of the at least one implant cavity 190 in the layer of the physiological parameter monitoring device 100 and the projections of all physiological parameter sensors and all conductive wires in the layer of the physiological parameter monitoring device 100 can be less than or equal to a preset area threshold, or even the projection of the implant cavity 190 in the layer can not overlap with the projection of any physiological parameter sensor and conductive wire (as specifically shown in FIG. 2), which on the one hand can avoid the implant tool puncturing the flexible material around the implant cavity 190 during implantation and causing damage to the devices or circuits in the sensing layer, and on the other hand, since at least part of the physiological parameter sensors 122 need to be exposed to the flexible material to be in direct contact with the body tissue, such arrangement can also effectively avoid interference between the implant cavity 190 and the sensing window 180. However, it can be understood that in the case of limited area of the physiological parameter monitoring device 100, as shown in FIG. 1, the implant cavity 190 can also be arranged to overlap with the physiological parameter sensors and / or the conductive portion, which is not limited herein. In a specific example, the preset area threshold can be set to 50 square microns, or other preset area thresholds can also be set as needed.

[0137] In some embodiments, as shown in FIGS. 4 and 5, in order to avoid damaging the devices or circuits in the sensing layer by the implantation tool, the thickness D of the flexible material between the implantation cavity 190 and the sensing layer closest to the implantation cavity 190 can be greater than or equal to a preset distance threshold. Specifically, the thickness of the flexible material between the implantation cavity and the physiological parameter sensor closest to each other can be greater than or equal to the preset distance threshold. Similarly, the thickness of the flexible material between the implantation cavity and the conductive wiring closest to each other can be greater than or equal to the preset distance threshold. In a specific example, the preset distance threshold can be set to 5 microns, or other preset distance thresholds can also be set as needed.

[0138] In some other specific embodiments of the present disclosure, as shown in FIGS. 6 and 7, the physiological parameter monitoring device 100 can further include a second sensing layer on the side of the second flexible layer 130 opposite to the first sensing layer, and a third flexible layer 150 formed by a flexible material.

[0139] Similar to the first sensing layer, the second sensing layer can include one or more physiological parameter sensors 141 and conductive wirings 142. The corresponding physiological parameter sensors 141 and conductive wirings 142 in the second sensing layer can be set according to specific monitoring needs, which will not be repeated here.

[0140] In addition, the third flexible layer 150 can be formed by a flexible material as described above. Similarly, the third flexible layer 150 can be formed by one flexible material, or can also be formed by multiple flexible materials, which is not limited here. In addition, in the physiological parameter monitoring device 100, depending on specific needs, at least two flexible layers can be formed by the same flexible material, so as to simplify the manufacturing process of the physiological parameter monitoring device 100 and reduce its manufacturing cost; or different flexible layers can also be formed by different flexible materials respectively, which is not limited here.

[0141] As shown in FIGS. 6 and 7, similar to the second flexible layer 130 and the first flexible layer 110 can enclose at least part of the non-sensing area of the first sensing layer therebetween, the third flexible layer 150 and the second flexible layer 130 can enclose at least part of the non-sensing area of the second sensing layer therebetween (or in other words, the second sensing layer can be disposed between the second flexible layer 130 and the third flexible layer 150). In order to expose the sensing area of the first sensing layer and the second sensing layer (or the corresponding physiological parameter sensors 121 and 141) to the body tissue to be monitored, the part of the flexible layer corresponding to the sensing area can be removed as needed to form a sensing window 180. In a specific example, as shown in FIG. 7, the sensing area of at least part of the physiological parameter sensor 121 in the first sensing layer can be exposed to the first flexible layer 110, and the sensing area of at least part of the physiological parameter sensor 141 in the second sensing layer can be exposed to the third flexible layer 150, i.e., both sides of the physiological parameter monitoring device 100 can be used for monitoring the corresponding physiological parameters. In another specific example, the sensing area of at least part of the physiological parameter sensor 121 in the first sensing layer can be exposed to the first flexible layer 110, and the sensing area of at least part of the physiological parameter sensor 141 in the second sensing layer can be exposed to the second flexible layer 130 and the first flexible layer 110, so that at least the bottom side of the physiological parameter monitoring device 100 can be used to perform monitoring of the corresponding physiological parameters. In yet another specific example, the sensing area of at least part of the physiological parameter sensor 121 in the first sensing layer can be exposed to the second flexible layer 130 and the third flexible layer 150, and the sensing area of at least part of the physiological parameter sensor 141 in the second sensing layer can be exposed to the third flexible layer 150, so that at least the top side of the physiological parameter monitoring device 100 can be used to perform monitoring of the corresponding physiological parameters.

[0142] In some embodiments, as shown in FIG. 6, the implant cavity 190 can be provided only in the first flexible layer 110. Alternatively, in other embodiments, as shown in FIG. 7, one or more implant cavities 190 can also be formed in the third flexible layer 150, and the opening of the implant cavity 190 can be provided on the side of the third flexible layer 150 opposite to the second sensing layer. According to the need for implantation, implantation of the physiological parameter monitoring device 100 can be performed using only the implant cavity at a suitable position in one flexible layer. Alternatively, in other embodiments, implantation can also be performed using two or more implant cavities located at the top and bottom respectively, to improve the stability and reliability of implantation. It can be understood that the implant cavities located at the top and bottom of the physiological parameter monitoring device 100 can be aligned with each other in the thickness direction (i.e., the longitudinal direction perpendicular to the layer plane of the physiological parameter monitoring device), or can also be staggered with each other (as specifically shown in FIG. 7), without limitation.

[0143] Further, more sensing layers and corresponding flexible layers can also be stacked in the physiological parameter monitoring device 100 according to requirements, which is not limited herein. In addition, one or more implant cavities can be provided in the outermost flexible layers (e.g., the top and bottom flexible layers) of the physiological parameter monitoring device 100, so as to implant the physiological parameter monitoring device 100 into the body tissue at a suitable position.

[0144] According to another aspect of the present disclosure, a physiological parameter monitoring system is provided. As shown in FIG. 8, the physiological parameter monitoring system can include the physiological parameter monitoring device 100 as described above.

[0145] In addition, in some embodiments, the physiological parameter monitoring system can further include a data processing unit 200, which can be electrically connected to the conductive wiring 122 of the physiological parameter monitoring device 100 and configured to process the sensing signals from the physiological parameter monitoring device 100. For example, the data processing unit 200 can be in the form of a circuit board (e.g., a PCB board), a memory, a processor, a mobile terminal, a computer device, etc., so as to further process the sensing signals according to requirements.

[0146] In some embodiments, as shown in FIGS. 8 and 9, the physiological parameter monitoring system can further include an implantation tool 300, which can be configured to be removably disposed in the corresponding implantation cavity 190 of the physiological parameter monitoring device 100, so as to implant the physiological parameter monitoring device 100 into the body tissue in a minimally invasive manner. In a specific example, the implantation tool can be a commercially available hard metal needle (e.g., a tungsten needle, a stainless steel needle, etc.), which can be sleeved into the implantation cavity 190 via the opening 193 of the implantation cavity 190, so as to complete the assembly of the implantation tool and the physiological parameter monitoring device. Further, a technician or a mechanical hand, etc. can complete the implantation operation of the physiological parameter monitoring device 100 by clamping and moving the implantation tool 300. Since the implantation tool 300 can be sleeved in the implantation cavity 190, this arrangement has good stability and reliability, so that the implantation tool and the physiological parameter monitoring device can not need to be stuck together using glue or the like during the implantation process, which helps to simplify the implantation process, reduce the implantation difficulty, and can effectively avoid the pollution or adverse reactions that may be caused by the glue or the like. During the implantation process, the skull injury site can be found on the skull, and the opening diameter thereof can be less than 5 mm, or a skull drill or the like can be used to drill an opening of a similar size at a suitable position of the skull. Then, the implantation tool 300 with the physiological parameter monitoring device 100 is inserted into the intracranial cavity through the skull opening and is longitudinally inserted into the cerebral cortex, i.e., implanted in a direction perpendicular or substantially perpendicular to the surface of the cortex. Then, the implantation tool 300 can be removed, and the physiological parameter monitoring device 100 is kept stretched inside the cerebral cortex, so as to start the real-time monitoring of the related physiological parameters in the cranium and brain, and transmit the sensing signals to the external circuit through the conductive wiring for further processing. In some embodiments, the corresponding multiple physiological parameter sensors can be arranged according to the implantation direction, so as to monitor multiple physiological parameters such as intracranial pressure, partial pressure of oxygen in local brain tissue, glucose concentration, intracranial temperature, neuron electrical signal, intracranial electrolyte concentration, neural biomarker, etc. In addition, excitation signals can be transmitted to the stimulation electrodes in the physiological parameter monitoring device 100 through the conductive wiring, so as to perform the required electrical stimulation on the brain.

[0147] According to yet another aspect of the present disclosure, a method for manufacturing a physiological parameter monitoring device is also provided. In an exemplary embodiment, as shown in FIGS. 10 and 11(a), the method can include:

[0148] In step S911, a carrier substrate 400 is provided.

[0149] In some embodiments, the carrier substrate 400 can be a rigid substrate to facilitate subsequent processes. For example, the carrier substrate 400 can include a rigid layer 410 formed of a rigid material that is electrically conductive or non-conductive, such as silicon, silicon oxide, glass, low-resistance silicon, indium tin oxide glass, etc. In addition, in other embodiments, the carrier substrate 400 can further include a sacrificial layer 420 formed of a sacrificial material on one side of the rigid layer 410 to facilitate subsequent separation of the carrier substrate 400 from the physiological parameter monitoring device 100. Depending on the specific separation method, a suitable sacrificial material can be employed. For example, in the case where the sacrificial material is removed by wet etching to separate the carrier substrate 400 and the physiological parameter monitoring device 100, the sacrificial material can include at least one of silver, copper, platinum, aluminum, titanium, chromium, and nickel; while in the case where the sacrificial material is removed by electrolysis to separate the carrier substrate 400 and the physiological parameter monitoring device 100, the sacrificial material can be an electrolytic material, such as including at least one of magnesium, aluminum, zinc, chromium, iron, nickel, copper, and silver, as will be described in more detail later. In some embodiments, the sacrificial layer 420 can be deposited on the rigid layer 410 based on evaporation (e.g., electron beam evaporation), sputtering (e.g., magnetron sputtering), atomic layer deposition, etc. in a semiconductor process, and can be unpatterned.

[0150] Then, as shown in FIGS. 10, 11(b) to 11(d), and 12(a) to 12(c), the method for manufacturing the physiological parameter monitoring device can include:

[0151] Step S912, forming a first flexible substrate layer 111 above the carrier substrate 400;

[0152] Step S913, forming a patterned first filling layer 194; and

[0153] Step S914, forming a first flexible structure layer 112.

[0154] The first flexible substrate layer 111 can be formed of a flexible material as described above. In a specific embodiment, the first flexible substrate layer 111 can be unpatterned or in the form of a continuous thin film, as shown in FIG. 11(b). In this case, the flexible material can be deposited on the carrier substrate 400 in a desired thickness by, for example, spin coating, chemical vapor deposition, atomic layer deposition, spray coating, inkjet printing, etc., and the excess liquid, if any, can be removed by drying, etc. to form the first flexible substrate layer 111.

[0155] The first fill layer 194 can be formed of a fill material, and the first fill layer 194 can include a patterned first fill portion above the first flexible base layer 111, as shown in FIG. 11(c). The first fill layer 194 can correspond to an area where a main cavity portion of the implant cavity is located. In a subsequent process, the implant cavity 190 can be released by removing the flexible material in a portion of the first flexible base layer 111 and the fill material in the first fill layer 194, where the guide cavity portion of the implant cavity can be formed by removing the flexible material, and the main cavity portion of the implant cavity can be formed by removing the fill material. In the subsequent process, the flexible material can be removed by etching. In addition, the fill material can be removed by wet etching, and accordingly, the fill material can include at least one of gold, silver, copper, platinum, aluminum, titanium, chromium, and nickel. In other embodiments, the fill material can also be other non-metallic materials, provided that the fill material can be selectively removed. Specifically, a patterned mask can be formed above the first flexible base layer 111 by spin coating, exposure, development, and the like. Then, in some embodiments, especially when the fill material is a metallic material, the first fill layer 194 with a sub-micron thickness can be formed based on the mask by sputtering, evaporation, and the like. Then, the excess fill material can be removed by peeling and the like to form the first fill portion. Alternatively, in other embodiments, a fill material layer with a certain thickness can be formed by electron beam evaporation, magnetron sputtering, and the like, and then a patterned mask can be formed on the fill material layer based on spin coating, exposure, development, and the like, and then the fill material layer can be dry etched or wet etched based on the mask, and then the residual mask can be removed to form the first fill portion.

[0156] In another specific embodiment, the first flexible base layer 111 can be patterned, as shown in FIG. 12(a). In this case, a flexible material with a desired thickness can be first deposited above the carrier substrate 400 by, for example, spin coating, chemical vapor deposition, atomic layer deposition, spraying, and the like, and the excess liquid in the solution can be removed by drying and the like; then, a portion of the flexible material can be removed based on exposure, development, etching, and the like in a standard semiconductor process to form the patterned first flexible base layer 111. The area in the first flexible base layer 111 not occupied by the flexible material can correspond to an area where a portion of the implant cavity 190 (e.g., the guide cavity portion 192 of the implant cavity 190) is located.

[0157] The first filling layer 194 can be formed of a filling material, and the first filling layer 194 can include a patterned first filling portion located above the first flexible base layer 111 and a second filling portion filling the space of the first flexible base layer 111 not occupied by the flexible material. The first filling layer 194 corresponds to the area where the implantation cavity is located. In subsequent processes, the implantation cavity 190 can be released by removing the filling material in the first filling layer 194. Depending on the way of removing the filling material in the subsequent processes, a suitable filling material can be used. For example, in the case of using a wet etching method to remove the filling material, the filling material can include at least one of gold, silver, copper, platinum, aluminum, titanium, chromium, and nickel; and in the case of using an electrolytic method to remove the filling material, the filling material can be an electrolytic material, such as at least one of magnesium, aluminum, zinc, chromium, iron, nickel, copper, and silver. Specifically, a patterned mask can be formed above the first flexible base layer 111 by spin coating, exposure, development, and the like. Then, in some embodiments, especially in the case of the filling material being a metal material, the first filling layer 194 with a sub-micron thickness can be formed based on the mask by sputtering, evaporation, and the like. Here, the filling material can first fill the space of the first flexible base layer 111 not occupied by the flexible material, i.e., form the second filling portion; and then the filling material can be deposited above the first flexible base layer 111, and the excess filling material can be removed by peeling and the like, to form the patterned first filling portion. Alternatively, in other embodiments, the space of the first flexible base layer 111 not occupied by the flexible material can be filled, i.e., form the second filling portion, by inkjet, dispensing, electroplating, and the like; then a filling material layer with a certain thickness can be formed by electron beam evaporation, magnetron sputtering, and the like, and then a patterned mask can be formed on the filling material layer based on uniform coating, exposure, development, and the like, and then the filling material layer can be dry etched or wet etched based on the mask, and then the residual mask is removed, to form the first filling portion.

[0158] After the first filling layer 194 is formed, the first flexible structure layer 112 can be continuously formed. Similarly, the first flexible structure layer 112 can be formed of a flexible material as described above, which can be formed of the same flexible material as the first flexible base layer 111 or can be formed of a different flexible material, which is not limited here. The first flexible structure layer 112 can be covered on the exposed top surface of the first flexible base layer 111 and the first filling layer 194, as shown in FIG. 11(d) and FIG. 12(c), so that the first flexible base layer 111 and the first flexible structure layer 112 can jointly form the first flexible layer 110. In some specific embodiments, a relatively thin first flexible structure layer 112 can be formed by spin coating, chemical vapor deposition, atomic layer deposition, spraying, inkjet printing, and the like.

[0159] Further, as shown in FIG. 10, FIG. 11 (e) and FIG. 12 (d), the method for preparing the physiological parameter monitoring device can further comprise:

[0160] Step S915, forming a first sensing layer above the first flexible layer 110.

[0161] As described above, the first sensing layer can comprise one or more physiological parameter sensors 121, each of which can be configured to monitor a corresponding physiological parameter and generate a corresponding sensing signal, and conductive wirings 122, which can be electrically connected with at least one of the physiological parameter sensors 121 and configured to transmit the sensing signal from the at least one of the physiological parameter sensors 121 and / or transmit an excitation signal to the at least one of the physiological parameter sensors 121. The types and numbers of the physiological parameter sensors 121 can be reasonably configured according to the monitoring needs, for example, one or more of the pressure sensor, the oxygen partial pressure sensor, the glucose concentration sensor, the temperature sensor, the neuronal electrical signal sensor, the electrolyte concentration sensor and the neurobiomarker sensor as described above can be configured, and the number of each type of sensor can be one or more, which is not limited herein. The required physiological parameter sensors 121 and corresponding conductive wirings 122 can be prepared on one side of the first flexible layer 110 based on standard semiconductor processes. In this process, processes such as uniform coating, exposure, development, sputtering or evaporation, stripping, etching, etc. can be involved, so as to form the desired patterned layer on the first flexible layer 110, thereby forming the corresponding structure of the physiological parameter sensors 121 and / or the conductive wirings 122. In addition, in the case of using liquid conductive polymer, etc. to form the conductive wiring, the conductive liquid can also be distributed at the appropriate position based on processes such as shadow mask, screen printing and pipetting (e.g. using a pipette to transfer the liquid to the desired position), etc., and then the excess liquid is removed by heating to solidify the conductive structure.

[0162] Further, as shown in FIG. 10, FIG. 11 (f) and FIG. 12 (e), the method for preparing the physiological parameter monitoring device can further comprise:

[0163] Step S916, forming a second flexible layer 130 above the first sensing layer.

[0164] As described above, the second flexible layer 130 can be formed of the same or different flexible material as the first flexible layer 110. Similarly, a thin film deposition process such as spin coating, chemical vapor deposition, atomic layer deposition, spray coating, inkjet printing, etc. or a liquid synthesis solidification method can be employed to cover the second flexible layer 130 over the first sensing layer. Here, the second flexible layer 130 can serve as a protective layer to wrap and protect the physiological parameter sensor 121 and the conductive wiring 122, so as to isolate the outside environment, on the one hand, to avoid the invasion of oxygen, water vapor and other external factors on the devices or conductive wires in the first sensing layer, and on the other hand, to serve as an insulating layer to avoid the direct contact of the body tissue (e.g., brain tissue) with the physiological parameter sensor and the conductive wiring.

[0165] In addition, as described above, in order to enable the physiological parameter sensor 121 to accurately monitor the corresponding physiological parameter, it can be necessary to expose its sensing area (e.g., an electrical signal recording site or a stimulation site, etc.) to the body tissue to be monitored via the sensing window 180. Accordingly, enclosing at least part of the non-sensing area of the first sensing layer between the second flexible layer 130 and the first flexible layer 110 can include forming a patterned sensing mask layer on one of the first flexible layer 110 and the second flexible layer 130, wherein the sensing mask layer covers an area corresponding to at least part of the non-sensing area of the first sensing layer; and performing etching to remove the flexible material in the area of one of the first flexible layer 110 and the second flexible layer 130 that is not covered by the sensing mask layer. In the specific example shown in FIGS. 11(f) and 12(e), a patterned sensing mask layer can be formed over the second flexible layer 130, then a dry or wet etching process is employed to remove the flexible material in the area not covered by the sensing mask layer, and finally the residual sensing mask layer (e.g., photoresist) is removed, thereby forming the sensing window 180 in the second flexible layer 130 that exposes the sensing area to ensure the monitoring effect. However, it can be understood that in some other embodiments, the sensing window can also be formed at a suitable position in the first flexible layer as needed, which is not limited herein.

[0166] Finally, as shown in FIGS. 10, 11(g)-11(h) and 12(f), the method for preparing the physiological parameter monitoring device can further include:

[0167] Step S917, removing the filling material and the carrier substrate 400.

[0168] As described above, in some embodiments, the wet etching method can be employed to remove the filling material and the carrier substrate 400. For example, a process similar to backside silicon etching can be employed to remove the filling material.

[0169] In one embodiment, as shown in FIG. 11(g) and FIG. 11(h), removing the fill material can include forming a patterned cavity mask layer on the side of the carrier substrate 400 opposite the first flexible substrate layer 111. That is, the structure shown in FIG. 11(f) can be flipped upside down, and a cavity mask layer can be formed on the bottom side of the carrier substrate 400 shown in FIG. 11(f) by spin coating, exposure, development, etc. Then, removing the fill material can include performing etching to remove portions of the carrier substrate 400 not covered by the cavity mask layer to expose at least a portion of the first fill portion. Here, the respective portions of the carrier substrate 400 and the first flexible substrate layer 111 can be removed by dry etching (e.g., inductively coupled plasma etching) or wet etching to expose the fill material while forming a portion of the implant cavity 190. Finally, removing the fill material can include performing wet etching to remove the fill material of the first fill layer 194 to form one or more implant cavities 190 in the first flexible layer 110. Since a portion of the first fill layer 194 extends inside the first flexible layer 110, wet etching can be used here to remove the fill material as completely as possible to form the implant cavity 190 in the desired shape.

[0170] In another embodiment, as shown in FIG. 12(f), removing the fill material can include forming a patterned cavity mask layer on the side of the carrier substrate 400 opposite the first flexible substrate layer 111. That is, the structure shown in FIG. 12(e) can be flipped upside down, and a cavity mask layer can be formed on the bottom side of the carrier substrate 400 shown in FIG. 12(e) by spin coating, exposure, development, etc. Here, the cavity mask layer does not cover at least a portion of the second fill portion, and then removing the fill material can include performing etching to remove portions of the carrier substrate 400 not covered by the cavity mask layer to expose at least a portion of the second fill portion. Here, the respective portions of the carrier substrate 400 (and possibly the flexible material between the carrier substrate and the fill material) can be removed by dry etching (e.g., inductively coupled plasma etching) or wet etching to expose the fill material. Finally, removing the fill material can include performing wet etching to remove the fill material of the first fill layer 194 to form one or more implant cavities 190 in the first flexible layer 110. Similarly, since a portion of the first fill layer 194 extends inside the first flexible layer 110, wet etching can be used here to remove the fill material as completely as possible to form the implant cavity 190 in the desired shape.

[0171] Further, the physiological parameter monitoring device 100 can be separated from the carrier substrate 400 by etching or the like on the portion of the carrier substrate 400 in direct contact with the first flexible layer 110. For example, in the case that the carrier substrate 400 includes a sacrificial layer 420 formed of a sacrificial material in direct contact with the first flexible substrate layer 111, removing the carrier substrate 400 can include performing a wet etching to remove the sacrificial material of the sacrificial layer 420 to detach the carrier substrate 400 from the first flexible substrate layer 111. For example, depending on the materials of the sacrificial layer 420 and the first flexible substrate layer 111, the physiological parameter monitoring device 100 can be released from the carrier substrate 400 by immersion, spraying or the like using a suitable etchant or etchants.

[0172] In other embodiments, the electrolysis method can also be used to remove the filler material and the carrier substrate as described above. Accordingly, the carrier substrate can be formed of an electrically conductive material to be connected to a power source for the electrolysis reaction. In addition, the electrolytic material as described above can be used as the sacrificial material and the filler material, for example, the electrolytic material can be formed of a relatively active metal material including but not limited to magnesium, aluminum, zinc, chromium, iron, nickel, copper and silver, etc. In addition, in order to facilitate the electrolysis reaction, the first flexible layer 110 and the first filler layer 194 can be formed in the manner as shown in FIGS. 12(a) to 12(c), i.e., the first flexible substrate layer 111 is patterned and the first filler layer 194 includes a patterned first filler portion above the first flexible substrate layer 111 and a second filler portion filling the space of the first flexible substrate layer 111 not filled by the flexible material, so that the second filler portion can be removed by the electrolysis reaction to form the corresponding portion of the implant cavity. As shown in FIG. 13, removing the filler material and the carrier substrate can include electrically connecting the carrier substrate to the positive pole of the power source and connecting the negative pole of the power source to an inert material (e.g., a platinum rod, etc.), removing the electrolytic material by the electrolysis reaction occurring in the electrolyte solution to form one or more implant cavities in the first flexible layer and detach the carrier substrate from the first flexible substrate layer. The electrolyte solution can include a strong acid solution, a strong base solution, a salt solution, etc., for example, can include a strong electrolyte solution such as sulfuric acid, calcium carbonate, copper sulfate, sodium chloride, potassium chloride, etc., or the electrolyte solution can include a weak acid solution, a weak base solution, a small amount of salt solution, etc., for example, can include a weak electrolyte solution such as acetic acid, ammonia monohydrate, lead acetate, mercury chloride, etc. After turning on the direct current power source, an anodic oxidation reaction will occur at the carrier substrate and the physiological parameter monitoring device end, so that the sacrificial material and the filler material are sequentially removed by electrolysis, while forming one or more implant cavities and releasing the physiological parameter monitoring device from the carrier substrate.

[0173] In another exemplary embodiment of the present disclosure, to form more sensing layers and corresponding flexible layers, after step S916, the method for preparing the physiological parameter monitoring device can further include: forming a second sensing layer on the side of the second flexible layer 130 opposite to the first sensing layer; and forming a third flexible layer 150 on the second sensing layer.

[0174] As described above, the second sensing layer can include one or more physiological parameter sensors and conductive wiring. Similarly, the required physiological parameter sensors and corresponding conductive wiring can be prepared on the side of the second flexible layer based on standard semiconductor processes. In this process, processes such as glue spreading, exposure, development, sputtering or evaporation, stripping, etching, etc. can be involved to form the desired patterned layer on the second flexible layer, thereby forming the corresponding structure of the physiological parameter sensor and / or conductive wiring. In addition, in the case of using liquid conductive polymer, etc. to form the conductive wiring, the conductive liquid can also be distributed at the appropriate position based on processes such as shadow mask, screen printing, and pipetting (e.g., using a pipette to transfer liquid to the desired position), etc., and then the excess liquid is removed by heating to solidify the conductive structure.

[0175] As described above, the third flexible layer 150 can be formed of the same or different flexible material as the first flexible layer 110 or the second flexible layer 130. Similarly, thin film deposition processes such as spin coating, chemical vapor deposition, atomic layer deposition, spraying, inkjet printing, etc. can be used, or the third flexible layer 150 can be covered on the second sensing layer in a liquid synthesis and solidification manner. Here, the third flexible layer 150 can serve as a protective layer to wrap and protect the physiological parameter sensor and conductive wiring, to isolate the external environment, on the one hand, to avoid the invasion of oxygen, water vapor, etc. external factors to the devices or wires in the second sensing layer, on the other hand, to also serve as an insulating layer to avoid direct contact between the body tissue (e.g., brain tissue) and the physiological parameter sensor and conductive wiring.

[0176] In addition, as described above, in order to enable the physiological parameter sensor to accurately monitor the corresponding physiological parameter, it can be necessary to expose its sensing area (e.g., electrical signal recording site or stimulation site, etc.) to the body tissue to be monitored. For example, the third flexible layer 150 and the second flexible layer 130 can enclose at least part of the non-sensing area of the second sensing layer therebetween. In a specific example, a patterned sensing mask layer can be formed below the first flexible layer 110 or above the third flexible layer 150, and then a dry or wet etching process is used to remove the flexible material in the area not covered by the sensing mask layer, and finally the residual sensing mask layer (e.g., photoresist) is removed, thereby forming a sensing window 180 in the corresponding one or more flexible layers to expose the sensing area, to ensure the monitoring effect.

[0177] It can be understood that more sensing layers and corresponding flexible layers can be provided as needed. After all the sensing layers and corresponding flexible layers are formed, step S917 can be performed to form one or more implant cavities and release the physiological parameter monitoring device from the carrier substrate.

[0178] In yet another exemplary embodiment of the present disclosure, the implant cavity can also be provided in the flexible layer located at the top of the physiological parameter monitoring device 100. Accordingly, as shown in FIG. 14, the method for preparing the physiological parameter monitoring device can comprise:

[0179] Step S921, providing a pre-prepared assembly.

[0180] The pre-prepared assembly can comprise a fourth flexible layer formed of a flexible material and a third sensing layer provided above the fourth flexible layer. Similarly, the third sensing layer can comprise 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, and the conductive wiring can be electrically connected with at least one physiological parameter sensor and configured to transmit a sensing signal from the at least one physiological parameter sensor and / or transmit an excitation signal to the at least one physiological parameter sensor. For example, corresponding to the specific example shown in FIG. 5, the pre-prepared assembly can comprise a second flexible layer 130 (equivalent to the fourth flexible layer) located at the bottom and a first sensing layer (equivalent to the third sensing layer) located above the second flexible layer 130, and on the basis of this structure, the first flexible layer 110 located above the first sensing layer and containing the implant cavity 190 can be further formed in the manner as specifically described below.

[0181] In other embodiments, the pre-prepared assembly can further comprise a sixth flexible layer provided above the third sensing layer, wherein the sixth flexible layer is formed of a flexible material; and a fourth sensing layer provided above the sixth flexible layer, wherein the fourth sensing layer can comprise one or more physiological parameter sensors and conductive wiring, and the sixth flexible layer and the fourth flexible layer enclose at least part of the non-sensing area of the fourth sensing layer therebetween. For example, corresponding to the specific example shown in FIG. 7, the pre-prepared assembly can comprise a first flexible layer 110 (equivalent to the fourth flexible layer) located at the bottom and containing the implant cavity 190, a first sensing layer (equivalent to the third sensing layer) located above the first flexible layer 110, a second flexible layer 130 (equivalent to the sixth flexible layer) located above the first sensing layer, and a second sensing layer (equivalent to the fourth sensing layer) located above the second flexible layer 130. It can be understood that in other embodiments, the pre-prepared assembly can comprise more sensing layers or flexible layers, which are not limited herein.

[0182] Further, as shown in FIG. 14, the method for preparing the physiological parameter monitoring device can comprise:

[0183] Step S922, forming a patterned fifth flexible substrate layer above the pre-assembly;

[0184] Step S923, forming a patterned second filling layer; and

[0185] Step S924, forming a fifth flexible structure layer.

[0186] The fifth flexible substrate layer can be formed of a flexible material as described above. A desired thickness of the flexible material can be deposited above the pre-assembly by, for example, spin coating, chemical vapor deposition, atomic layer deposition, spray coating, inkjet printing, etc., and excess liquid in the solution, if any, can be removed by drying, etc. Then, part of the flexible material can be removed based on exposure, development, etching, etc. in standard semiconductor processes to form the patterned fifth flexible substrate layer. The area in the fifth flexible substrate layer not occupied by the flexible material can correspond to the area where a portion of the implant cavity (e.g., the main cavity portion of the implant cavity) is located.

[0187] The second filling layer can be formed of a filling material, and the second filling layer can include a third filling portion filled in a space of the fifth flexible substrate layer not occupied by the flexible material, and a patterned fourth filling portion located above the fifth flexible substrate layer. It can be understood that the lateral feature size of the third filling portion can be greater than the lateral feature size of the fourth filling portion, so as to form a finger sleeve-shaped implantation cavity. The second filling layer corresponds to the area where the implantation cavity is located. In a subsequent process, the implantation cavity can be released by removing the filling material in the second filling layer. Depending on the way of removing the filling material in the subsequent process, a suitable filling material can be used. For example, in the case of removing the filling material by wet etching, the filling material can include at least one of gold, silver, copper, platinum, aluminum, titanium, chromium and nickel; and in the case of removing the filling material by electrolysis, the filling material can be an electrolytic material, for example, can include at least one of magnesium, aluminum, zinc, chromium, iron, nickel, copper and silver. Specifically, a patterned mask can be formed above the fifth flexible substrate layer by spin coating, exposure, development and the like. Then, in some embodiments, especially in the case of the filling material being a metal material, the second filling layer with a sub-micron level thickness can be formed based on the mask by sputtering, evaporation and the like. Here, the filling material can first fill the space in the fifth flexible substrate layer not occupied by the flexible material, i.e., form the third filling portion; and then the filling material can be deposited above the fifth flexible substrate layer, and the excess filling material can be removed by peeling and the like, to form the patterned fourth filling portion. Alternatively, in other embodiments, the space in the fifth flexible substrate layer not occupied by the flexible material can be filled, i.e., the third filling portion, by inkjet, dispensing and the like; then a filling material layer with a certain thickness can be formed by electron beam evaporation, magnetron sputtering and the like, and then a patterned mask can be formed on the filling material layer based on uniform coating, exposure, development and the like, and then the filling material layer is dry etched or wet etched based on the mask, and then the residual mask is removed, to form the fourth filling portion.

[0188] After the second filling layer is formed, a fifth flexible structure layer can be formed. Similarly, the fifth flexible structure layer can be formed of a flexible material as described above, which can be the same flexible material as the fifth flexible substrate layer or can be a different flexible material, without limitation. The fifth flexible structure layer can be formed on the exposed top surface of the fifth flexible substrate layer. In addition, in some embodiments, the top surface of the fifth flexible structure layer can be slightly lower than or flush with the exposed top surface of the second filling layer, so that the implant cavity formed after the filling material is removed has an opening to the outside environment. In this way, the fifth flexible substrate layer and the fifth flexible structure layer can collectively form a fifth flexible layer. In some specific embodiments, the fifth flexible structure layer can be formed by a thin layer through spin coating, chemical vapor deposition, atomic layer deposition, spray coating, inkjet printing, etc.

[0189] Further, as shown in FIG. 14, the method for preparing the physiological parameter monitoring device can further include:

[0190] Step S925, removing the filling material.

[0191] In some embodiments, similar to the above description, the filling material can be removed by wet etching to form one or more implant cavities in the fifth flexible layer. Specifically, depending on the selected flexible material and filling material, in some embodiments, the filling material can be directly removed by wet etching through immersion, spraying, etc. to form one or more implant cavities. Alternatively, in other embodiments, a patterned cavity mask layer can be formed above the fifth flexible layer, which does not cover at least a portion of the fourth filling portion, and then wet etching can be performed under the protection of the cavity mask layer to remove the filling material.

[0192] Alternatively, in other embodiments, in the case where the filling material is an electrolytic material, removing the filling material can include electrically connecting the filling material to the positive pole of the power supply, and the negative pole of the power supply is connected to the inert material, and the electrolytic material is removed by the electrolysis reaction occurring in the electrolyte solution to form one or more implant cavities in the fifth flexible layer. It can be understood that in order to facilitate the electrical connection of the filling material to the positive pole of the power supply, an additional electrical connection structure can also be provided, and the provided electrical connection structure is removed after the electrolysis is completed. The specific electrolysis method can refer to the above description, which is not repeated here.

[0193] Further, the method for preparing the physiological parameter monitoring device can further include enclosing at least part of the non-sensing area of the third sensing layer between the fifth flexible layer and the fourth flexible layer, which is similar to the way of forming the sensing window in the flexible layer described above. Specifically, enclosing at least part of the non-sensing area of the third sensing layer between the fifth flexible layer and the fourth flexible layer can include: forming a patterned sensing mask layer on one of the fourth flexible layer and the fifth flexible layer, wherein the sensing mask layer covers an area corresponding to at least part of the non-sensing area of the third sensing layer; and performing etching to remove the flexible material in the area of one of the fourth flexible layer and the fifth flexible layer that is not covered by the sensing mask layer.

[0194] As described above, in the physiological parameter monitoring device of the present disclosure, one or more sensing layers and corresponding flexible layers can be provided. Accordingly, the sensing window can be opened at a suitable position of the physiological parameter monitoring device as needed after the deposition of all the flexible layers is completed to expose the sensing area of the physiological parameter sensor. Alternatively, the sensing window can also be opened immediately after the deposition of only part of the flexible layers is completed, without limitation. In addition, one or more implant cavities can be formed at a suitable position in the outermost flexible layer of the physiological parameter monitoring device after the deposition of all the sensing layers and flexible layers is completed, so as to achieve the minimally invasive implantation of the physiological parameter monitoring device.

[0195] The technical solution of the present disclosure provides a flexible physiological parameter monitoring device with high biocompatibility and a physiological parameter monitoring system comprising the same. According to the need, various types of physiological parameter sensors can be provided in the physiological parameter monitoring device, thereby realizing highly integrated multi-modal and real-time monitoring of physiological parameters, such as quantification of changes in indicators such as brain electrophysiological activity after secondary brain trauma, etc. The physiological parameter monitoring device of the present disclosure can be simply and conveniently implanted into the body tissue based on minimally invasive implantation technology, can effectively reduce the mechanical mismatch with the body tissue after implantation, and has low requirements for implantation tools. In addition, the physiological parameter monitoring device of the present disclosure can be mass-produced based on semiconductor technology, which has simple process, low cost, high release rate of sensors, and can realize wide application.

[0196] The words "left," "right," "front," "back," "top," "bottom," "over," "under," "upper," "lower," and the like in the description and the claims, if any, are used for description and not necessarily for limiting relative positions. It will be appreciated with understanding that the words so used are interchangeable with the context in appropriate instances, such that an embodiment of the disclosure described herein, for example, can operate in other orientations than those depicted or otherwise described herein. For example, the apparatus in the drawings can be inverted, and features described as above other features can be described as below the other features. The apparatus can also be oriented in other ways (rotated 90 degrees or in other orientations), and relative spatial relationships will be correspondingly interpreted.

[0197] In the description and claims, when an element, or components are said to be "on," "attached" to, "connected" to, "coupled" to, or "in contact" with another element, it can be directly on, attached to, connected to, coupled to, or in contact with the other element, or one or more intervening elements can also be present. In contrast, when an element is referred to as being "directly on," "directly attached" to, "directly connected" to, "directly coupled" to, or "directly in contact" with another element, there are no intervening elements present. In the description and claims, an element being disposed "adjacent" to another element can mean that the element has a portion that overlaps the adjacent element or a portion that is above or below the adjacent element.

[0198] As used herein, the word "exemplary" means "serving as an example, instance, or illustration," and not "preferred" or "advantageous over other implementations." Furthermore, the disclosure is not limited to any expressed or implied theory of operation by any stated or implied aspects.

[0199] As used herein, the word "substantially" means including any minor variations as a result of design or manufacturing tolerances, instrument or component variations, environmental influences, and / or other factors. The word "substantially" also allows for differences between a perfect or ideal situation and a real-world situation due to, for example, parasitic effects, noise, and other practical considerations.

[0200] In addition, the terms "first", "second", and the like, herein can be used merely for distinguishing between similar elements and not necessarily for describing a sequential or chronological order. It is to be understood that the terms so used are interchangeable under appropriate circumstances such that the descriptive terms "first", "second", etc., are to be interpreted, by one of ordinary skill in the art, as a structural or functional pertinence but not a sequential or chronological precedence. For example, a first element discussed above could be discussed below as a second element. This is within the scope of the claims.

[0201] It will be further understood that the terms "comprises" and / or "comprising", when used in this specification, specify the presence of stated features, integers, steps, operations, elements, and / or components, but do not preclude the presence or addition of one or more other features, integers, steps, operations, elements, components, and / or groups thereof.

[0202] In the present disclosure, the term "provide" is used in a broad sense to encompass all means of obtaining an object, and thus "providing an object" includes, but is not limited to, "purchasing", "preparing / manufacturing", "arranging / setting", "installing / fitting", and / or "ordering" the object, etc.

[0203] As used herein, the term "and / or" includes any and all combinations of one or more of the associated listed items. The terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the present disclosure. As used herein, the singular forms "a", "an" and "the" are intended to include the plural forms as well, unless the context clearly indicates otherwise.

[0204] Those skilled in the art will realize that the boundaries between the above described operations merely illustrative. The multiple operations can be combined into a single operation, a single operation can be distributed in additional operations and operations can be executed at least partially overlapping in time. Moreover, alternative embodiments can include a number of instances of a particular operation, and the order of the operations can be altered in other various embodiments. Other modifications, variations, and alternatives are also possible. All such modifications, variations, and alternatives are intended to fall within the scope of the present disclosure. The foregoing description of the embodiments according to the present disclosure has been presented for the purposes of illustration and description. It is not intended to be exhaustive or to limit the present disclosure to the precise form disclosed. Many modifications and variations are possible in light of the above teachings. It is intended that the

[0205] While specific embodiments of the disclosure have been described in detail, those skilled in the art appreciate that the foregoing examples are merely illustrative of the principles of the disclosure, which are to be limited only by the claims that follow. Embodiments of the present disclosure can be combined in any manner without departing from the spirit and scope of the present disclosure. Those skilled in the art will also appreciate that modifications can be made to the embodiments described herein without departing from the scope and spirit of the disclosure. The scope of the present disclosure is defined by the claims that follow.

Claims

1. A physiological parameter monitoring device, comprising: a first flexible layer formed of a flexible material, wherein one or more implant cavities are formed in the first flexible layer, each implant cavity having an opening disposed on a first side of the first flexible layer; a first sensing layer disposed on a second side of the first flexible layer opposite the first side, wherein the first sensing layer comprises one or more physiological parameter sensors and conductive wiring, each physiological parameter sensor being configured to monitor a respective physiological parameter and generate a respective sensing signal, and the conductive wiring being electrically connected to at least one physiological parameter sensor and configured to transmit a sensing signal from and / or an excitation signal to the at least one physiological parameter sensor; and a second flexible layer formed of a flexible material, wherein the second flexible layer and the first flexible layer enclose at least a portion of a non-sensing region of the first sensing layer therebetween.

2. The physiological parameter monitoring device of claim 1, further comprising: a second sensing layer disposed on a side of the second flexible layer opposite the first sensing layer, wherein the second sensing layer comprises one or more physiological parameter sensors and conductive wiring; and a third flexible layer formed of a flexible material, wherein the third flexible layer and the second flexible layer enclose at least a portion of a non-sensing region of the second sensing layer therebetween.

3. The physiological parameter monitoring apparatus of claim 2, wherein, one or more implant cavities are formed in the third flexible layer, each implant cavity having an opening disposed on a side of the third flexible layer opposite the second sensing layer.

4. The physiological parameter monitoring device of any one of claims 1 to 3, wherein, the flexible material comprises a biocompatible material; and / or a difference between a Young’s modulus of the flexible material and a Young’s modulus of a biological tissue monitored by the physiological parameter monitoring device is less than or equal to a pre-set modulus threshold.

5. The physiological parameter monitoring device of any one of claims 1 to 3, wherein, the flexible material comprises 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, polysiloxane ether, polyvinylpyrrolidone, polylactic-co-glycolic acid, polyvinyl alcohol, polyglycerol sebacate, silk protein, linagliptin, collagen, chitosan, polymaleic acid octamethylene (anhydride) citrate, poly-L-lactic acid, and polycaprolactone.

6. The physiological parameter monitoring apparatus of any one of claims 1 to 3, wherein, the same flexible layer is formed of one or more flexible materials; or at least two flexible layers are formed of the same flexible material; or different flexible layers are formed of different flexible materials, respectively.

7. The physiological parameter monitoring apparatus of any one of claims 1 to 3, wherein, the at least one implant cavity comprises: a main cavity portion located inside the flexible layer in which the implant cavity is located; and a guide cavity portion communicating between the main cavity portion and the opening of the implant cavity; wherein a corner is present in a region where the main cavity portion and the guide cavity portion meet each other.

8. The physiological parameter monitoring apparatus of claim 7, wherein, a lateral characteristic dimension of the main cavity portion in a layer plane of the physiological parameter monitoring device is greater than a lateral characteristic dimension of the guide cavity portion in the layer plane of the physiological parameter monitoring device.

9. The physiological parameter monitoring apparatus of any one of claims 1 to 3, wherein, An overlapping area between a projection of the at least one implant cavity in a plane of the physiological parameter monitoring device and projections of all physiological parameter sensors and all conductive wirings in the physiological parameter monitoring device in the plane of the physiological parameter monitoring device is less than or equal to a preset area threshold.

10. The physiological parameter monitoring apparatus of any one of claims 1 to 3, wherein, A thickness of the flexible material between the implant cavity and the sensing layer nearest to the implant cavity is greater than or equal to a preset distance threshold.

11. The physiological parameter monitoring apparatus of any one of claims 1 to 3, wherein, The physiological parameter sensor comprises a flexible sensor.

12. The physiological parameter monitoring apparatus of any one of claims 1 to 3, wherein, The physiological parameter sensor comprises 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.

13. The physiological parameter monitoring apparatus of any one of claims 1 to 3, wherein, The conductive wiring is formed of a biocompatible and flexible conductive material; and / or The conductive wiring is further coated on at least a partial outer surface thereof with an insulating material.

14. The physiological parameter monitoring apparatus of any one of claims 1 to 3, wherein, The conductive wiring comprises at least one of silver, gold, magnesium, molybdenum, copper, platinum, aluminum, titanium, chromium, nickel, carbon nanotube, polyaniline, poly(3,4-ethylenedioxythiophene)-poly(styrenesulfonic acid), and carbon black; and / or The conductive wiring is further coated on at least a partial outer surface thereof with at least one of polyethylene terephthalate and nylon.

15. A physiological parameter monitoring system comprising the physiological parameter monitoring device according to any one of claims 1 to 14; and the physiological parameter monitoring system further comprises at least one of: 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 the sensing signals from the physiological parameter monitoring device; and an implant tool configured to be removably disposed in the respective implant cavity of the physiological parameter monitoring device.

16. A method for preparing a physiological parameter monitoring device, comprising: providing a carrier substrate; forming a first flexible substrate layer over the carrier substrate, wherein the first flexible substrate layer is formed of a flexible material; forming a patterned first filler layer, wherein the first filler layer is formed of a filler material, and the first filler layer comprises a patterned first filler portion over the first flexible substrate layer; forming a first flexible structure layer, wherein the first flexible structure layer is formed of a flexible material, the first flexible structure layer covers on exposed top surfaces of the first flexible substrate layer and the first filler layer, and the first flexible substrate layer and the first flexible structure layer collectively form a first flexible layer; forming a first sensing layer over the first flexible layer, wherein the first sensing layer comprises one or more physiological parameter sensors and conductive wirings, each physiological parameter sensor is configured to monitor a respective physiological parameter and generate a respective sensing signal, and a conductive wiring is electrically connected with 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; forming a second flexible layer over 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 a non-sensing area of the first sensing layer therebetween; and removing the filler material and the carrier substrate.

17. The method of claim 16, wherein, The carrier substrate is a rigid substrate.

18. The method of claim 16, wherein, The fill material includes at least one of gold, silver, copper, platinum, aluminum, titanium, chromium, and nickel.

19. The method of claim 16, wherein, Removing the fill material includes: forming a patterned cavity mask layer on a side of the carrier substrate opposite the first flexible substrate layer; performing etching to remove portions of the carrier substrate and the first flexible substrate layer not covered by the cavity mask layer; and performing wet etching to remove fill material of the first fill layer to form one or more implant cavities in the first flexible layer.

20. The method of claim 16, wherein, The first flexible substrate layer is patterned, and the first fill layer further includes a second fill portion filling spaces of the first flexible substrate layer not filled by the flexible material; Removing the fill material includes: forming a patterned cavity mask layer on a side of the carrier substrate opposite the first flexible substrate layer, wherein the cavity mask layer does not cover over at least a portion of the second fill portion; performing etching to remove portions of the carrier substrate not covered by the cavity mask layer to expose the at least a portion of the second fill portion; and performing wet etching to remove fill material of the first fill layer to form one or more implant cavities in the first flexible layer.

21. The method of claim 16, wherein, The carrier substrate includes a sacrificial layer of a sacrificial material in direct contact with the first flexible substrate layer, and removing the carrier substrate includes: performing wet etching to remove the sacrificial material of the sacrificial layer to detach the carrier substrate from the first flexible substrate layer.

22. The method of claim 21, wherein, The sacrificial material includes at least one of silver, copper, platinum, aluminum, titanium, chromium, and nickel.

23. The method of claim 16, wherein, The first flexible substrate layer is patterned, and the first fill layer further includes a second fill portion filling spaces of the first flexible substrate layer not filled by the flexible material, the carrier substrate includes a conductive layer of a conductive material and a sacrificial layer of a sacrificial material on the conductive layer, and the sacrificial material and the fill material are electrolytic materials; Removing the fill material and the carrier substrate includes: electrically connecting the carrier substrate to a positive pole of a power source and a negative pole of the power source to an inert material, removing the electrolytic materials through electrolytic reactions occurring in an electrolyte solution to form one or more implant cavities in the first flexible layer and detach the carrier substrate from the first flexible substrate layer.

24. The method of claim 23, wherein, The electrolytic materials include at least one of magnesium, aluminum, zinc, chromium, iron, nickel, copper, and silver.

25. The method of claim 16, wherein, Enclosing the at least a portion of the non-sensing region of the first sensing layer between the first flexible layer and the second flexible layer includes: forming a patterned sensing mask layer on one of the first flexible layer and the second flexible layer, wherein the sensing mask layer covers an area corresponding to the at least a portion of the non-sensing region of the first sensing layer; and performing etching to remove flexible material in areas of the one of the first flexible layer and the second flexible layer not covered by the sensing mask layer.

26. The method of claim 16, further comprising: forming a second sensing layer on a side of the second flexible layer opposite the first sensing layer, wherein the second sensing layer includes one or more physiological parameter sensors and conductive wiring; and forming a third flexible layer over 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 a non-sensing area of the second sensing layer therebetween.

27. A method for preparing a physiological parameter monitoring device, comprising: providing a pre-assembly, wherein the pre-assembly includes a fourth flexible layer formed of a flexible material and a third sensing layer disposed over the fourth flexible layer, wherein the third sensing layer includes one or more physiological parameter sensors and conductive wiring, each physiological parameter sensor is configured to monitor a respective physiological parameter and generate a respective sensing signal, and the conductive wiring is electrically connected with at least one physiological parameter sensor and configured to transmit a sensing signal from and / or an excitation signal to the at least one physiological parameter sensor; forming a patterned fifth flexible base layer over the pre-assembly, wherein the fifth flexible base layer is formed of a flexible material; forming a patterned second fill layer, wherein the second fill layer is formed of a fill material, and the second fill layer includes a third fill portion filled in spaces of the fifth flexible base layer that are not filled by the flexible material and a patterned fourth fill portion located over the fifth flexible base layer; forming a fifth flexible structure layer, wherein the fifth flexible structure layer is formed of a flexible material, the fifth flexible structure layer covers an exposed top surface of the fifth flexible base layer, and the fifth flexible base layer and the fifth flexible structure layer collectively form a fifth flexible layer; and removing the fill material.

28. The method of claim 27, wherein, The fill material includes at least one of gold, silver, copper, platinum, aluminum, titanium, chromium, and nickel.

29. The method of claim 27, wherein, The fill material is removed by wet etching to form one or more implant cavities in the fifth flexible layer.

30. The method of claim 27, wherein, The fill material is an electrolytic material; Removing the fill material includes: The fill material is electrically connected to a positive pole of a power source, and a negative pole of the power source is connected to an inert material, the electrolytic material is removed by an electrolytic reaction occurring in an electrolyte solution to form one or more implant cavities in the fifth flexible layer.

31. The method of claim 30, wherein, The electrolytic material includes at least one of magnesium, aluminum, zinc, chromium, iron, nickel, copper, and silver.

32. The method of claim 27, further comprising enclosing at least a portion of a non-sensing area of the third sensing layer therebetween by the fifth flexible layer and the fourth flexible layer, including: forming a patterned sensing mask layer on one of the fourth flexible layer and the fifth flexible layer, wherein the sensing mask layer covers an area corresponding to at least a portion of a non-sensing area of the third sensing layer; and performing etching to remove flexible material in an area of the one of the fourth flexible layer and the fifth flexible layer that is not covered by the sensing mask layer.

33. The method of claim 27, wherein, The pre-assembly further includes: a sixth flexible layer disposed over the third sensing layer, wherein the sixth flexible layer is formed from a flexible material; and a fourth sensing layer disposed over the sixth flexible layer, wherein the fourth sensing layer includes one or more physiological parameter sensors and conductive wiring, and the sixth flexible layer and the fourth flexible layer enclose at least a portion of a non-sensing area of the fourth sensing layer therebetween.

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