阅读说明：本技术 适用于高原医学诊疗的一体化水凝胶的制备及其应用 (Preparation and application of integrated hydrogel suitable for plateau medical diagnosis and treatment ) 是由 鲁雄 李盈岐 谢超鸣 孙红玉 于 2021-09-07 设计创作，主要内容包括：本发明公开了一种适应于高原医学诊疗的一体化水凝胶的制备及其应用,属于生物材料技术领域。首先将钙离子与多巴胺还原氧化石墨烯鳌合原位制备形成过氧化钙-多巴胺还原氧化石墨烯(CaO-(2)-PGO)纳米片；然后利用甘油体系将CaO-(2)-PGO纳米片掺杂到含有多糖等水凝胶中制得CaO-(2)-PGO/AM。甘油体系赋予了水凝胶在高原低温环境下抗冻能力；CaO-(2)-PGO纳米片赋予了水凝胶在高原低氧环境释氧能力,并且能够在光热效应作用下能够进一步促进氧气释放；CaO-(2)-PGO纳米片为水凝胶提供了导电性、粘附性和组织亲和性。该水凝胶可应用于高原环境下的组织修复与肌电或心电生理传导监测。(The invention discloses preparation and application of an integrated hydrogel suitable for plateau medical diagnosis and treatment, and belongs to the technical field of biomaterials. Firstly, chelating calcium ions with dopamine reduced graphene oxide to prepare calcium peroxide-dopamine reduced graphene oxide (CaO) in situ 2 -PGO) nanoplatelets; then CaO is added by using a glycerol system 2 CaO is prepared by doping-PGO nano-sheets into hydrogel containing polysaccharide and the like 2 -PGO/AM. The glycerin system endows the hydrogel with freezing resistance in a plateau low-temperature environment; CaO (CaO) 2 The PGO nano sheets endow the hydrogel with oxygen release capacity in a plateau hypoxic environment, and can further promote oxygen release under the action of photothermal effect; CaO (CaO) 2 The PGO nanoplates provide conductivity, adhesion and tissue affinity to the hydrogel. The hydrogel can be applied to tissue repair and myoelectricity or electrocardio physiological conduction monitoring in plateau environments.)

1. A preparation method of an integrated hydrogel suitable for plateau medical diagnosis and treatment comprises the following steps:

step 1: adding a certain amount of CaCl₂Dissolving and dispersing the reduced graphene oxide and dopamine in an organic solvent, and fully stirring at a certain temperature; then, a certain amount of hydrogen peroxide H with the mass fraction of 30 percent is added into the mixture₂O₂Subsequently, an amount of 1mol/L NH was slowly added dropwise₃·H₂O and the mixture was allowed to react for 8 hours with stirring and finally let throughThe mixture is centrifuged to obtain CaO₂-dopamine-reduced graphene oxide nanoplatelets;

step 2: CaO obtained in the step 1₂Adding dopamine reduced graphene oxide nanosheets into glycerol/PBS mixed solution for uniform dispersion, adding acrylamide and polysaccharide, and adding an initiator and a cross-linking agent to obtain the required integrated hydrogel CaO suitable for plateau medical diagnosis and treatment₂-PGO/AM；

The organic solvent in the step 1 is methanol or ethanol, the dispersion is carried out by ultrasonic, and the treatment time is 5-10 min; the temperature condition is ice bath 0-4 ℃; the hydrogen peroxide H is 30 percent₂O₂Added volume with CaCl₂The mass ratio of (1) to (5 ml); 1mol/L NH 3. H2O described in step 1, the addition volume of which is added with CaCl₂The mass ratio of (1) to (5 ml); the mixed solution in the step 2 is glycerol/PBS with the proportion of 1:4, 1:3 and 1: 2; the uniform dispersion in the step 2 is dispersion by ultrasonic, and the treatment time is 1min-2 min.

2. The method for preparing an integrated hydrogel suitable for plateau medical diagnosis and treatment according to claim 1, wherein the slow dropwise addition of NH is performed by a syringe at a rate of 0.05ml/min to 0.1ml/min in step 1₃·H₂O。

3. The method for preparing an integrated hydrogel suitable for plateau medical diagnosis and treatment according to claim 1, wherein the polysaccharide in step 2 is one of fucoidan, astragalus polysaccharide and ophiopogon polysaccharide.

4. The method for preparing an integrated hydrogel suitable for plateau medical diagnosis and treatment according to claim 1, wherein the initiator in step 2 is an initiation system consisting of persulfate and N, N, N ', N' -tetramethyldiethylamine; the cross-linking agent is methylene bisacrylamide; wherein the persulfate comprises one of ammonium persulfate, potassium persulfate and sodium persulfate.

5. The application of the hydrogel prepared by the preparation method according to claim 1, 2, 3 or 4 is characterized in that the hydrogel can be applied to the restoration of the skin tissue of the organism and the electromyographic, electrocardio and physiological monitoring of the organism in the plateau environment, and can stably monitor the physiological signals of the organism in real time.

Technical Field

The invention relates to the technical field of biological materials, in particular to preparation and application of an integrated hydrogel suitable for plateau medical diagnosis and treatment.

Background

Medically, a skin wound may be defined as a defect or break in the skin caused by external stimuli or by factors of its own. The behavior of each cell type, as well as growth factors and matrix signals present at the wound site, is critical during the proliferation, migration, matrix synthesis and contraction phases. The influence of the details on how these signals control wound cell activity may cause the normal adult repair process to be re-adjusted. Due to the low plateau oxygen partial pressure (the altitude of 4000m is about 61 percent of sea level), dry and cold climate, strong ultraviolet ray and other reasons, the stress capability to the blood loss of the wound is reduced, if the wound occurs, the response of the organism to the wound is not completely the same as that of a low altitude area, the shock occurrence rate is high, the injury is serious, and the death rate is high. In addition, visceral complications are likely to occur. Therefore, the skin wound repair in the severe plateau environment needs to be combined with the characteristics of the environment specificity, namely hypoxia, low temperature, strong ultraviolet and low-temperature drying, and the requirement of physiological signal detection of patients is met.

The documents report that the plateau wound repair is promoted by using a liquid dressing or an oxygen-enriched dressing in a drug-loading mode, but the liquid dressing or the oxygen-enriched dressing cannot meet the requirement of plateau medical wound repair, namely the influences of environmental problems of thin oxygen, strong ultraviolet rays, cold weather and the like of plateaus can be overcome. The hydrogel has high water content, porous structure and other conditions favorable for cell growth, and can promote cell growth and propagation, induce cell to secrete more growth factors and promote tissue repair damage. Aiming at the skin wound repair in severe plateau environment, the subject group designs the integrated hydrogel for plateau medical diagnosis and treatment by combining the characteristics of environmental specificity, namely hypoxia, low-temperature drying and strong ultraviolet and meeting the requirement of physiological signal detection of patients, and aims to overcome the defects of various aspects, low-temperature failure, poor oxygen release effect, poor ultraviolet resistance effect, poor wound seepage absorption capability or defects in the aspect of promoting cell growth wound healing of the traditional dressing.

Disclosure of Invention

The invention aims to provide an integrated hydrogel suitable for diagnosis and treatment of plateau medicine, which has good tissue adhesion, releases oxygen for a long time and can conduct and detect physiological signals.

The technical solution for realizing the purpose of the invention is as follows:

a preparation method of an integrated hydrogel suitable for plateau medical diagnosis and treatment comprises the following steps:

step 1: adding a certain amount of CaCl₂Dissolving and dispersing the reduced graphene oxide and dopamine in an organic solvent, and fully stirring at a certain temperature; then, a certain amount of hydrogen peroxide H with the mass fraction of 30 percent is added into the mixture₂O₂Subsequently, an amount of 1mol/L NH was slowly added dropwise₃·H₂O and allowing the mixture to react and stir for 8 hours, and finally obtaining CaO by centrifuging the mixture₂-dopamine-reduced graphene oxide nanoplatelets;

step 2: CaO obtained in the step 1₂Adding dopamine reduced graphene oxide nanosheets into glycerol/PBS mixed solution for uniform dispersion, adding acrylamide and polysaccharide, and adding an initiator and a cross-linking agent to obtain the required integrated hydrogel CaO suitable for plateau medical diagnosis and treatment₂-PGO/AM；

The organic solvent in the step 1 is methanol or ethanol, the dispersion is carried out by ultrasonic, and the treatment time is 5-10 min; the temperature condition is ice bath 0-4 ℃; the hydrogen peroxide H is 30 percent₂O₂Added volume with CaCl₂The mass ratio of (1) to (5 ml); 1mol/L NH 3. H2O described in step 1, the addition volume of which is added with CaCl₂The mass ratio of (1) to (5 ml); the mixed solution in the step 2 is glycerol/PBS with the proportion of 1:4, 1:3 and 1: 2; the uniform dispersion in the step 2 is dispersion by ultrasonic, and the treatment time is 1min-2 min.

Further, the slow dropwise addition in the step 1 is dropwise addition of NH at a rate of 0.05ml/min to 0.1ml/min by a syringe₃·H₂O。

Further, the polysaccharide in the step 2 is one of fucoidin, astragalus polysaccharide and ophiopogon polysaccharide.

Further, the initiator in the step 2 is an initiation system consisting of persulfate and N, N, N ', N' -tetramethyl diethylamine; the cross-linking agent is methylene bisacrylamide; wherein the persulfate comprises one of ammonium persulfate, potassium persulfate and sodium persulfate.

Furthermore, the application of the hydrogel prepared by the preparation method of the integrated hydrogel suitable for plateau medical diagnosis and treatment is characterized in that the hydrogel can be used for repairing the skin of an organism and monitoring the myoelectricity and the electrocardio of the organism in a plateau environment, and can stably monitor the physiological signals of the organism in real time.

According to the technical measures and preparation, the integral hydrogel CaO suitable for plateau medical diagnosis and treatment is obtained preliminarily₂-PGO/AM; named as the calcium peroxide-loaded dopamine reduced graphene oxide nanosheet acrylamide hydrogel.

The invention has the beneficial effects that:

(1) according to the method for preparing the calcium peroxide-dopamine reduction-oxidation graphene nanosheet in situ, calcium peroxide can be prepared in situ by chelating calcium ions in the dopamine reduction-oxidation graphene, so that the calcium peroxide can be uniformly distributed on the surface of the dopamine reduction-oxidation graphene; due to the large specific surface area of PGO, calcium peroxide can be loaded efficiently, and the nano composite capable of supplying oxygen and conducting electricity is provided.

(2) The calcium peroxide-dopamine reduction-oxidation graphene nanosheet prepared by the method can endow hydrogel with the capability of releasing oxygen in a plateau low-oxygen environment, and the oxygen release efficiency is accelerated by combining the photo-thermal effect of PGO; in addition, dopamine on the calcium peroxide-dopamine reduction graphene oxide nanosheets has tissue affinity; the polysaccharide component can improve the biocompatibility of the hydrogel; and the tissue repair under the plateau environment can be realized by combining the freezing resistance of a glycerol system.

(3) The calcium peroxide-dopamine reduction graphene oxide nanosheet prepared by the method can endow hydrogel with conductive capability. Meanwhile, the dopamine on the nanosheets can improve the adhesion of the hydrogel. Therefore, the hydrogel can stably monitor physiological signals of organisms in real time in a plateau environment.

Drawings

FIGS. 1A, 1B, and 1C are SEM images of hydrogels prepared according to embodiments of the present invention in different proportions.

FIGS. 2A, 2B, 2C and 2D are diagrams illustrating the application states of the hydrogels prepared according to the embodiments of the present invention.

FIG. 3 is a graph of the ultraviolet transmittance of the hydrogel measured by the ultraviolet resistance comparison experiment of the hydrogel.

FIG. 4 is a graph of oxygen release performance measured by the hydrogel oxygen dissolution test of the present invention.

FIG. 5 is a graph showing that hydrogel prepared by the embodiment of the invention is used as a self-adhesive electrode for monitoring electrocardiosignals of an organism.

FIG. 6 is a graph showing that hydrogel prepared by the embodiment of the invention is used as a self-adhesive electrode for monitoring the electromyogram of the organism.

Detailed Description

The invention is further described in detail with reference to the accompanying drawings and examples:

description of the drawings fig. 1A, fig. 1B, fig. 1C show SEM images of the hydrogel of the present invention, and it can be seen from the respective (500 μm, 100 μm, 1 μm) scales that the hydrogel has a uniform porous structure inside, a smooth structure, and a good distribution of internal crosslinks; the calcium peroxide-dopamine reducing-oxidizing graphene nanosheets are distributed in the hydrogel, and the calcium peroxide grows on the dopamine reducing-oxidizing graphene nanosheets in situ.

Fig. 2A, 2B, 2C, and 2D are diagrams of the application states of the hydrogel prepared in the embodiment of the present invention, and it can be seen that the glycerol and the water molecule form a strong hydrogen bond effect, so that water freezing can be inhibited at low temperature. By an anti-freezing experiment, after the hydrogel is placed in an environment at the temperature of-20 ℃ for 7 days, the anti-freezing performance and the use modes of different states of the hydrogel are shown in a picture mode.

FIG. 3 is a graph of the ultraviolet transmittance of the hydrogel measured by the ultraviolet resistance contrast experiment of the hydrogel according to the present invention, the ultraviolet resistance experiment method of the hydrogel is to determine the ultraviolet transmittance of the hydrogel at-20 ℃ to prove the ultraviolet resistance of the hydrogel according to the present invention; experimental group CaO₂-PGO acrylamide hydraulic; and the control group is acrylamide hydrogel. The transient degree-wavelength ratio is very low, and the principle is that the dopamine reduced graphene has an anti-ultraviolet function and is uniformly distributed in the hydrogel and endowed with anti-ultraviolet performance.

FIG. 4 is a graph of oxygen release performance measured by the hydrogel oxygen dissolution test of the present invention. The oxygen release experimental method comprises the following steps: experimental group CaO₂-PGO acrylamide hydraulic, blank group hypoxic water; placing the hydrogel in a place of exclusion under hypoxic conditions at 0-4 ℃: (<0.1mg/ml dissolved oxygen) in water, and the dissolved oxygen was measured to confirm the oxygen release property of the hydrogel. The oxygen release mechanism is that calcium peroxide is uniformly distributed in the hydrogel along with the dopamine graphene nanosheets and reacts with water in the hydrogel networkThe oxygen is generated.

Fig. 5 and 6 show that the hydrogel prepared by the embodiment of the invention is used as a self-adhesive electrode for monitoring electrocardiosignals and electromyographic signals of an organism. It can be seen that the self-adhesive electrode for electrocardio and myoelectricity detection is obtained by testing under the low-temperature condition simulating the plateau condition. The hydrogel is adhered to the outside of a machine body as a sensor at the temperature of minus 20 ℃, and a multichannel physiological signal acquisition and processing system is used for recording electromyographic signals and electrocardiosignals. The hydrogel of the example of the present invention showed excellent conductive properties under low temperature conditions.

Except that the dopamine-reduced graphene is prepared and reserved in a laboratory (material science and engineering key laboratory of the southwest department of transportation university education), the materials required by the experiment are all derived from an alatin chemical reagent purchased in the laboratory.

A preparation method of diagnosis and treatment integrated hydrogel for plateau medical tissue repair comprises the following steps:

step 1: adding a certain amount of CaCl₂Dissolving and dispersing the reduced graphene oxide and dopamine in an organic solvent, and fully stirring at a certain temperature; then, a certain amount of H with the mass fraction of 30 percent is added into the mixture₂O₂Subsequently, an amount of 1mol/L NH was slowly added dropwise₃·H₂O and allowing the mixture to react and stir for 8 hours, and finally centrifuging the mixture to obtain CaO₂-dopamine-reduced graphene oxide nanoplatelets;

wherein the organic solvent is methanol or ethanol, the dispersion is carried out by ultrasonic, and the treatment time is 5-10 min; the temperature condition is ice bath 0-4 ℃; the hydrogen peroxide H₂O₂30 percent of mass fraction, the addition volume of the catalyst and CaCl₂The mass ratio of (1) to (5 ml); 1mol/L NH described in step 1₃·H₂O, its addition volume with CaCl₂The mass ratio of (1) to (5 ml);

step 2: CaO obtained in the step 1₂Adding the dopamine reduced graphene oxide nanosheets into a glycerol/PBS mixed solution for uniform dispersion,adding acrylamide and polysaccharide, and adding initiator and cross-linking agent to obtain the required adhesive hydrogel.

The polysaccharide is one of fucoidin, Astragalus polysaccharides and radix Ophiopogonis polysaccharides; the initiator is an initiation system consisting of persulfate and N, N, N ', N' -tetramethyl diethylamine; the cross-linking agent is methylene bisacrylamide; wherein the persulfate comprises one of ammonium persulfate, potassium persulfate and sodium persulfate.

The mixed solution in the step 2 is glycerol/PBS with the proportion of 1:4, 1:3 and 1: 2; the uniform dispersion in the step 2 is dispersion by ultrasonic, and the treatment time is 1min-2 min.

Example 1

A preparation method of diagnosis and treatment integrated hydrogel for plateau medical tissue repair comprises the following steps:

CaO₂-preparation of dopamine reduced graphene oxide nanoplatelets: adding 1g of CaCl₂Dissolving 0.1g of dopamine reduced graphene oxide in absolute ethyl alcohol, and dispersing by ultrasonic treatment for 10min, and then fully stirring at the temperature of 0-4 ℃ under an ice bath condition; thereafter, 5ml of 30% by weight H were added to the mixture₂O₂(ii) a Subsequently, 5ml of 1mol/L NH were slowly added dropwise₃·H₂O solution and allowing the mixture to react for 8 hours with stirring; finally obtaining CaO by centrifuging the mixture₂-dopamine-reduced graphene oxide nanoplatelets; wherein the temperature condition is ice bath condition of 0-4 ℃;

preparing diagnosis and treatment integrated hydrogel: preparing 10ml of glycerol and PBS mixed solution, wherein the proportion is 1:4, 1:3 and 1: 2; this example selects glycerol: PBS volume ratio is 1: 4; 2.6g of acrylamide and 0.3g of fucoidan, 0.01g of 0.01g N, 0.2g of CaO after addition of N-methylene bisacrylamide₂And (3) uniformly dispersing the dopamine reduced graphene oxide nanosheets, namely ultrasonically dispersing for 1min, adding 0.5g of ammonium persulfate and 25 mu l of N, N, N ', N' -tetramethylethylenediamine, and fully reacting to obtain the hydrogel.

Example 2

A preparation method of diagnosis and treatment integrated hydrogel for plateau medical tissue repair comprises the following steps:

CaO₂-preparation of dopamine reduced graphene oxide nanoplatelets: adding 1g of CaCl₂And 0.1g of dopamine reduced graphene oxide are dissolved in absolute ethyl alcohol and dispersed by ultrasonic, and the mixture is fully stirred under the ice bath condition of 0-4 ℃ after the treatment time is 10 min. Thereafter, 5ml of 30% by weight H were added to the mixture₂O₂(ii) a Subsequently, 5ml of 1mol/L NH were slowly added dropwise₃·H₂O solution and allowing the mixture to react overnight; finally obtaining CaO by centrifuging the mixture₂-dopamine-reduced graphene oxide nanoplatelets; wherein the temperature condition is ice bath condition of 0-4 ℃.

Preparing diagnosis and treatment integrated hydrogel: preparing 10ml of mixed solution of glycerol and PBS, wherein the volume ratio of the glycerol to the PBS is 1:3, adding 2.6g of acrylamide, 0.3g of fucoidan and 0.01g of 0.01g N, performing ultrasonic dispersion for 1min, adding 0.5g of ammonium persulfate and 25 mu l of N, N, N ', N' -tetramethyl ethylenediamine, and fully reacting to obtain the hydrogel.

Example 3

A preparation method of diagnosis and treatment integrated hydrogel for plateau medical tissue repair comprises the following steps:

CaO₂-preparation of dopamine reduced graphene oxide nanoplatelets: adding 1g of CaCl₂And 0.1g of dopamine reduced graphene oxide are dissolved in absolute ethyl alcohol and dispersed by ultrasonic, and the mixture is fully stirred under the ice bath condition of 0-4 ℃ after the treatment time is 10 min. Thereafter, 5ml of 30% by weight H were added to the mixture₂O₂(ii) a Subsequently, 5ml of 1mol/L NH were slowly added dropwise₃·H₂O solution and allowing the mixture to react overnight; finally obtaining CaO by centrifuging the mixture₂-dopamine-reduced graphene oxide nanoplatelets; wherein the temperature condition is ice bath condition of 0-4 ℃.

Preparing diagnosis and treatment integrated hydrogel: 10ml of glycerol and PBS mixed solution is prepared, wherein the volume ratio of the glycerol to the PBS is 1: 2. 2.6g of acrylamide and 0.3g of fucoidan, 0.01g of 0.01g N, 0.2g of CaO after addition of N-methylene bisacrylamide₂And (3) carrying out ultrasonic dispersion on the-dopamine reduced graphene oxide nanosheets for 1min, adding 0.5g of ammonium persulfate and 25 mu l of N, N, N ', N' -tetramethylethylenediamine, and carrying out full reaction to obtain the hydrogel.

Example 4

A preparation method of diagnosis and treatment integrated hydrogel for plateau medical tissue repair comprises the following steps:

CaO₂-preparation of dopamine reduced graphene oxide nanoplatelets: adding 1g of CaCl₂Dissolving 0.1g of dopamine reduced graphene oxide in absolute ethyl alcohol, and dispersing by ultrasonic treatment for 10min, and then fully stirring at the temperature of 0-4 ℃ under an ice bath condition; thereafter, 5ml of 30% by weight H were added to the mixture₂O₂(ii) a Subsequently, 5ml of 1mol/L NH were slowly added dropwise₃·H₂O solution and allowing the mixture to react for 8 hours with stirring; finally obtaining CaO by centrifuging the mixture₂-dopamine-reduced graphene oxide nanoplatelets; wherein the temperature condition is ice bath condition of 0-4 ℃.

Preparing diagnosis and treatment integrated hydrogel: preparing 10ml of glycerol and PBS mixed solution, wherein the volume ratio of the glycerol to the PBS is 1:2, adding 2.6g of acrylamide, 0.3g of astragalus polysaccharide and 0.01g N, adding 0.2g of CaO after N-methylene bisacrylamide₂And (3) carrying out ultrasonic dispersion on the-dopamine reduced graphene oxide nanosheet for 1min, adding 0.5g of ammonium persulfate and 25 mu l of N, N, N ', N' -tetramethylethylenediamine, and carrying out full reaction to obtain the hydrogel.

Example 5

A preparation method of diagnosis and treatment integrated hydrogel for plateau medical tissue repair comprises the following steps:

CaO₂-preparation of dopamine reduced graphene oxide nanoplatelets: adding 1g of CaCl₂Dissolving 0.1g of dopamine reduced graphene oxide in absolute ethyl alcohol, and dispersing by ultrasonic treatment for 10min, and then fully stirring at the temperature of 0-4 ℃ under an ice bath condition; thereafter, 5ml of 30% by weight H were added to the mixture₂O₂(ii) a Subsequently, 5ml of 1mol/L NH were slowly added dropwise₃·H₂O solution and mixingStirring for 8 hours; finally obtaining CaO by centrifuging the mixture₂-dopamine-reduced graphene oxide nanoplatelets; wherein the temperature condition is ice bath condition of 0-4 ℃.

Preparing diagnosis and treatment integrated hydrogel: preparing 10ml of mixed solution of glycerol and PBS, wherein the volume ratio of the glycerol to the PBS is 1:2, adding 2.6g of acrylamide, 0.3g of ophiopogon root polysaccharide and 0.01g N, adding 0.1g of CaO after N-methylene bisacrylamide₂And (3) carrying out ultrasonic dispersion on the-dopamine reduced graphene oxide nanosheet for 1min, adding 0.5g of ammonium persulfate and 25 mu l of N, N, N ', N' -tetramethylethylenediamine, and carrying out full reaction to obtain the hydrogel.

The invention firstly prepares a calcium peroxide nano-sheet, and the calcium peroxide is prepared in situ by chelating calcium ions with dopamine-reduced graphene oxide to form CaO₂-dopamine-reduced graphene oxide nanoplatelets; then adding CaO₂Doping dopamine reduction graphene oxide nanosheets into hydrogel to prepare integrated hydrogel suitable for high-altitude medical diagnosis and treatment; CaO (CaO)₂The graphene oxide hydrogel grows on the surface of the dopamine-reduced graphene oxide in situ uniformly, so that the oxygen release efficiency of the hydrogel is improved, and the hydrogel can be further promoted to release oxygen under the action of a photo-thermal effect; meanwhile, due to the conductivity of the reduced graphene, the nano sheet can endow hydrogel sensing performance, and can be used for myoelectric or electrocardio monitoring. The hydrogel can preliminarily overcome the specificity of the plateau environment, promote tissue repair and monitor electrocardio-electromyographic physiological signals.