阅读说明：本技术 一种向血液中补充一氧化氮（no）的装置 (Device for supplementing Nitric Oxide (NO) to blood ) 是由 郝云玲 于 2021-01-06 设计创作，主要内容包括：本公开涉及一种向血液中补充一氧化氮(NO)的装置。该装置可以包括气体生成部、气体补充部、气体排放部、浓度监控部和至少一个控制器。气体生成部生成NO气体并经由馈送管路输出含NO的气体,且在馈送管路上设置流量检测器以检测气体的第一流量。气体补充部接收血液并在补充NO气体后输出血液。气体排放部经由排放管路对多余气体进行处理后排放到空中,且在排放管路上设置流量检测器以检测其中的气体的第二流量。至少一个控制器可以配置为：基于第一流量、馈送管路的气体中NO气体的第一NO浓度、第二流量和排放管路的气体中NO气体的第二NO浓度,来自动且精准地确定向所述血液中补充NO的剂量补充状况。(The present disclosure relates to a device for supplementing Nitric Oxide (NO) to blood. The apparatus may include a gas generation section, a gas replenishment section, a gas discharge section, a concentration monitoring section, and at least one controller. The gas generation portion generates NO gas and outputs NO-containing gas via the feed line, and a flow rate detector is provided on the feed line to detect a first flow rate of the gas. The gas replenishing portion receives the blood and outputs the blood after replenishing the NO gas. The gas discharge portion discharges the surplus gas into the air after processing the surplus gas via a discharge line, and a flow rate detector is provided on the discharge line to detect a second flow rate of the gas therein. The at least one controller may be configured to: a dose replenishment condition for replenishing NO in the blood is automatically and accurately determined based on the first flow rate, the first NO concentration of NO gas in the gas of the feed line, the second flow rate, and the second NO concentration of NO gas in the gas of the discharge line.)

1. A device for supplementing Nitric Oxide (NO) to blood, comprising:

a gas generation portion configured to generate an NO gas and output the NO-containing gas via a feed line, and a first flow rate detector is provided on the feed line to detect a first flow rate of the gas;

a gas replenishing portion for receiving blood and outputting the blood after replenishing NO gas, and comprising:

a receiving member configured to receive blood;

a first interface configured to introduce gas output from the feed line and feed to blood;

a second interface configured to vent excess gas;

a gas discharge portion configured to interface with the second interface to discharge excess gas into the air after processing via a discharge line, and a second flow detector provided on the discharge line to detect a second flow rate of the gas therein;

a concentration monitoring section configured to: detecting a first NO concentration of NO gas in the gas of the feed line and a second NO concentration of NO gas in the gas of the discharge line; and

at least one controller configured to: determining a dose replenishment condition for replenishing NO in the blood based on the first flow rate, first NO concentration, the second flow rate, and the second NO concentration.

2. The apparatus of claim 1, wherein the at least one controller is further configured to: the determined NO replenishment dosage condition is compared to a preset dosage replenishment condition, and the gas generating section and/or other related components are adjusted based on the comparison.

3. The apparatus of claim 1, wherein the gas refill is configured to be selectively used with a plurality of blood infusion devices,

the at least one controller is further configured to: a pre-set dose replenishment condition is determined based on the blood infusion device with which the apparatus is to be used.

4. The apparatus according to claim 1, wherein the concentration monitoring section further comprises:

a first extraction member configured to: drawing gas from a feed line and the discharge line, respectively; and

a NO sensor configured to: a first NO content of NO in the extracted gas from the feed line and a second NO content of NO in the gas from the discharge line are detected.

5. The apparatus according to claim 2, wherein the feed line is provided with a second extraction member configured to provide a continuous flow of gas;

a flow regulating member is arranged on the discharge pipeline;

the at least one controller is further configured to: adjusting the concentration of NO gas in the gas via controlling the gas generating portion; and/or adjusting the flow and/or pressure of the gas via controlling the second extraction member and/or the flow adjustment member.

6. The apparatus of claim 5, wherein a pressure sensor is disposed on the feed line, the at least one controller further configured to: controlling the second extracting member and/or the flow regulating member based on the pressure detected by the pressure sensor such that the corresponding pressure reaches a preset pressure range.

7. The apparatus according to claim 1, wherein the concentration monitoring portion is single, and includes a switching member configured to switch between gas inputs from a feed line and the discharge line.

8. The apparatus of claim 1, wherein the gas supplement comprises a filter mechanism configured to: the introduced NO gas is filtered to remove particulate matter, bacteria and viruses therefrom.

9. The device of claim 8, wherein the filtering mechanism comprises a bacterial filter and a gas permeable semi-permeable membrane on a gas pathway between the first port and the second port,

the bacterial filter is configured to filter out particulate matter and bacteria,

the gas permeable semi-permeable membrane is configured to: with appropriate pore size to sequester viruses while allowing gas to permeate through to the blood.

10. The apparatus of claim 1, wherein the gas makeup further comprises:

a blood input port configured as a universal interface compatible with the blood storage bag and the outflow conduit of the blood circulation conduit, respectively, for docking to introduce blood to be treated into the gas replenishing portion; and

a blood outlet configured as a universal interface compatible with a blood transfusion tube and a return tube downstream of the outflow tube of the blood circulation tube, respectively, for delivering the NO gas-supplemented blood to a subject.

11. The apparatus according to claim 8, wherein the gas generating section is provided with:

a first filter configured to filter out impurities and moisture in air;

a second filter configured to filter out nitrogen dioxide (NO) in the generated gas₂)；

At least one first one-way locking member provided upstream of at least one of the first filter, the second filter, and the filtering mechanism in a gas flow direction, the at least one first one-way locking member being configured to: one-way flow in the direction of gas flow is permitted when the gas generating section is active and automatically closed to isolate the respective filter or filtering mechanism downstream from the air when the gas generating section is inactive.

12. The apparatus according to claim 1, wherein the gas discharge portion is provided with a third filter downstream of the second flow detector in the gas flow direction to filter out NO in the exhaust gas andNO₂a second one-way locking member provided downstream of the third filter in the gas flow direction, the second one-way locking member being configured to: allowing one-way flow in the gas flow direction when the gas discharge portion is operated, and automatically closing to isolate the third filter from air when the gas discharge portion is not operated.

13. The apparatus according to claim 7, wherein the single concentration monitoring portion is provided with a fourth filter on an air side in a gas flow direction to filter out NO and NO₂A third one-way locking member provided downstream of the fourth filter in the airflow direction, the third one-way locking member being configured to: allowing a unidirectional flow in a gas flow direction when the concentration monitoring part is operated, and automatically closing to isolate the fourth filter from air when the concentration monitoring part is not operated.

14. The apparatus according to claim 1, wherein a fourth one-way locking member is provided on a pipe section on a side of the gas replenishing portion on a feed line of the gas generating portion, and a fifth one-way locking member is provided on a pipe section on a side of the gas replenishing portion on a discharge line of the gas discharging portion, the fourth one-way locking member and the fifth one-way locking member being respectively configured to: allowing one-way flow in the gas flow direction when the device is operated, and automatically closing to isolate the gas generation part, the gas supplement part, and the gas discharge part from each other when the device is not operated.

Technical Field

The present disclosure relates to a blood processing apparatus, and more particularly, to an apparatus for supplementing Nitric Oxide (NO) into blood.

Background

Nitric Oxide (NO) is an extremely unstable biological free radical, is a gas at normal temperature, has small molecules, plays the role of messenger molecules in a human body, and can quickly permeate a biological membrane to diffuse to reach any tissue. The NO content of human body reaches the peak when the human body is 30-35 years old, the function of the human body for generating NO is gradually weakened with the increase of the age, particularly after the age of 40 years, the NO content required by the human body can not be reached, and the effects mainly appear in various aspects such as reduction of NO synthesis, increase of NO inactivation, increase of vasoconstriction substances released by vascular endothelium, obstruction of the process of NO diffusion from endothelium to smooth muscle, change of the function of some receptors (such as down-regulation of NO receptors) and the like. Although the reduction of NO affects microcirculation and does not cause serious problems in a short time, many diseases related to microcirculation begin from here, chronic disease symptoms appear from inside to outside with long-term accumulation, and the diseases mainly concentrate on the cardiovascular and cerebrovascular systems and are manifested as arteriosclerosis, myocardial infarction, hypertension, hyperlipidemia, hyperglycemia, microcirculation disturbance and the like.

Among the effects of NO, the vasodilatation is the most important, NO can play a role quickly after entering the blood circulation system of a human body, so that the deformability of red blood cells is increased, the blood viscosity is reduced, micro-vessels are expanded, the blood flow resistance is reduced, the blood flow speed is increased, the oxygen carrying capacity and the nutrient substance transporting capacity of blood are increased, the attachments on the inner wall of the blood vessels are cleaned, damaged endothelium of the blood vessels is repaired, the blood vessels are kept clean and smooth, thrombosis is prevented, atherosclerosis is prevented, the blood can better circulate in each organ, and clinical symptoms (such as hypertension, myocardial infarction, angina and the like) caused by poor microcirculation are relieved.

Currently, there are two main clinical methods for supplementing NO to the blood circulation: one is to provide NO donor drugs (such as nitrate drugs) by intravenous injection or sublingual administration, which will generate NO when the donor drugs enter the blood circulation; alternatively, NO donors are added to the blood during transfusion, and upon entering the blood, NO is produced and follows the blood into the systemic blood circulation.

Both of these current methods for supplementing NO involve the administration of a NO donor drug into the blood circulation, followed by the donor's generation of NO in the blood. The dosage of NO significantly and sensitively affects the therapeutic effect, with insufficient NO dosage having NO therapeutic effect at all and excessive NO dosage having toxicity. The dosage and the action time of the NO actually generated in blood by the existing NO supplementing method cannot be accurately controlled, and the achievable effect is difficult to control.

Disclosure of Invention

In view of the above technical problems in the prior art, the present disclosure provides a device for supplementing NO into blood, which can be used to supplement NO while infusing blood, and automatically and precisely determine the status of the NO dosage supplementation (such as but not limited to the supplemented NO dosage per unit time), so that the supplementation of NO at a proper dosage can be precisely controlled to ensure the therapeutic effect and avoid toxicity.

According to a first aspect of the present disclosure, a device for supplementing Nitric Oxide (NO) to blood is provided. The apparatus may include a gas generation section, a gas replenishment section, a gas discharge section, a concentration monitoring section, and at least one controller. The gas generation portion may be configured to generate NO gas and output NO-containing gas via a feed line, and a first flow rate detector is provided on the feed line to detect a first flow rate of the gas. The gas replenishing part may be for receiving blood and outputting the blood after replenishing NO gas, and may include: a receiving member configured to receive blood; a first interface configured to introduce gas output from the feed line and feed to blood; a second interface configured to vent excess gas. The gas discharge portion may be configured to interface with the second interface to discharge excess gas into the air after processing via a discharge line, and a second flow detector is provided on the discharge line to detect a second flow rate of the gas therein. The concentration monitoring portion may be configured to: a first NO concentration of NO gas in the gas of the feed line and a second NO concentration of NO gas in the gas of the discharge line are detected. The at least one controller may be configured to: determining a dose replenishment condition for replenishing NO in the blood based on the first flow rate, first NO concentration, the second flow rate, and the second NO concentration.

The present disclosure can automatically and precisely determine the dosage supplement condition of supplementing NO into the blood by combining these parameters by providing a first flow detector on the feeding line to detect a first flow of gas, a second flow detector on the discharging line to detect a second flow of gas therein, a first NO concentration of NO gas in the gas of the feeding line and a second NO concentration of NO gas in the gas of the discharging line, thereby precisely controlling the supplementation of NO with a proper dosage to ensure the therapeutic effect and avoid toxicity.

Drawings

In the drawings, which are not necessarily drawn to scale, like reference numerals may describe similar components in different views. Like reference numerals having letter suffixes or different letter suffixes may represent different instances of similar components. The drawings illustrate various embodiments generally by way of example and not by way of limitation, and together with the description and claims serve to explain the disclosed embodiments. The same reference numbers will be used throughout the drawings to refer to the same or like parts, where appropriate. Such embodiments are illustrative, and are not intended to be exhaustive or exclusive embodiments of the present apparatus or method.

Fig. 1 is a configuration diagram of a device for supplementing NO to blood according to an embodiment of the present disclosure;

fig. 2 is a configuration diagram of a concentration monitoring portion according to an embodiment of the present disclosure;

FIG. 3 is a block diagram of an apparatus for supplementing NO into blood in accordance with an embodiment of the present disclosure;

fig. 4 is a configuration diagram of an example of a gas replenishing portion according to an embodiment of the present disclosure;

FIG. 5 is a schematic view of the connection of NO supplementation to blood at the time of transfusion using an apparatus for supplementing NO to blood (particularly, a gas supplementation portion) according to an embodiment of the present disclosure;

FIG. 6 is a schematic connection diagram of NO supplementation into blood using a device for supplementing NO into blood (particularly, a gas supplementation portion) according to an embodiment of the present disclosure at the time of hemodialysis; and

fig. 7 is a schematic connection diagram of a device for supplementing NO into blood (particularly a gas supplementing part) according to an embodiment of the present disclosure for supplementing NO into blood during extracorporeal circulation.

Detailed Description

For a better understanding of the technical aspects of the present disclosure, reference is made to the following detailed description taken in conjunction with the accompanying drawings. Embodiments of the present disclosure are described in further detail below with reference to the figures and the detailed description, but the present disclosure is not limited thereto.

The use of "first," "second," and similar terms in this disclosure is not intended to indicate any order, quantity, or importance, but rather are used to distinguish one element from another. The word "comprising" or "comprises", and the like, means that the element preceding the word covers the element listed after the word, and does not exclude the possibility that other elements are also covered. "upper", "lower", "left", "right", and the like are used merely to indicate relative positional relationships, and when the absolute position of the object being described is changed, the relative positional relationships may also be changed accordingly.

In the present disclosure, when a specific device is described as being located between a first device and a second device, there may or may not be intervening devices between the specific device and the first device or the second device. When a particular device is described as being coupled to other devices, that particular device may be directly coupled to the other devices without intervening devices or may be directly coupled to the other devices with intervening devices.

All terms (including technical or scientific terms) used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs unless specifically defined otherwise. It will be further understood that terms, such as those defined in commonly used dictionaries, should be interpreted as having a meaning that is consistent with their meaning in the context of the relevant art and will not be interpreted in an idealized or overly formal sense unless expressly so defined herein.

Techniques, methods, and apparatus known to those of ordinary skill in the relevant art may not be discussed in detail but are intended to be part of the specification where appropriate.

A configuration diagram of a device for supplementing NO to blood according to an embodiment of the present disclosure is shown in fig. 1. As shown in fig. 1, the apparatus may mainly include a gas generation section 1, a gas supplement section 4, a gas discharge section 9, a concentration monitoring section 11, and at least one controller 12.

The gas generating portion 1 may be configured to generate NO gas and output NO-containing gas via a feed line 2, and a first flow detector 3 may be provided on the feed line 2 to detect a first flow rate of the gas. Specifically, the gas generating section 1 may include various NO gas generators 1' to generate NO gas. In some embodiments, the NO gas generator 1' may include a high concentration NO gas cylinder (typically 800-1000ppm) and a nitrogen cylinder to output NO gas of a desired concentration after mixing the NO gas output from the NO gas cylinder with nitrogen gas output from the nitrogen cylinder (as a balance gas). In some embodiments, the NO gas generator 1' may also include a NO generator and NO₂The NO generator can generate NO and NO by taking input air or air-oxygen mixture as a medium₂Of the mixture of (3), NO₂The filter can be made from the mixture containing NO and NO₂Filtering NO from the gas mixture₂To ensure NO replenishment into the blood₂The concentration does not exceed the clinically acceptable safety range. The latter NO gas generator 1' is smaller in design volume, convenient to use (does not require frequent replacement of the steel cylinder), lower in use cost, and easy to obtain with air as a source.

The gas replenishing portion 4 is connected to the feed line 2 of the gas generating portion 1, and includes a housing member 5, a first port 6, and a second port 7. The containing member 5 may be configured to contain blood to be supplemented with NO gas. The first port 6 may be configured to introduce gas (including NO gas) output from the feed line 2 and feed it to blood so as to replenish the NO gas into the blood. The second connection 7 can be designed to discharge excess gas. In some embodiments, the gas replenishing part 4 may be provided with a blood input port 13 and a blood output port 14, the blood input port 13 may be used to introduce blood to be replenished with NO gas, and the blood output port 14 may be used to output blood replenished with an appropriate dose of NO gas. In this way, the gas replenishing part 4 can replenish the blood with an appropriate dose of NO gas at the same time as the blood is infused.

The gas discharge portion 9 may be configured to interface with the second interface 7 to discharge excess gas into the air after processing via a discharge line 8, and a second flow detector 10 may be disposed on the discharge line 8 to detect a second flow rate of the gas therein. By providing the gas discharge portion 9, it is possible to discharge excess gas, so that fresh gas is continuously fed into the accommodating member 5, and the NO concentration and pressure therein are kept stable.

The concentration monitoring portion 11 may be configured to detect a first NO concentration of the NO gas in the gas of the feed line 2 and a second NO concentration of the NO gas in the gas of the discharge line 8. Although two NO sensors are shown in fig. 1 provided separately on the feed line 2 and the discharge line 8, this is merely an example of the concentration monitoring portion 11, and other numbers and configurations may also be adopted, and other modifications will be given below.

The at least one controller 12 may be configured to receive detection signals indicating the first flow rate, the second flow rate, the first NO concentration, and the second NO concentration from the first flow rate detector 3, the second flow rate detector 10, and the concentration monitor portion 11, respectively, and determine a dose replenishment condition for replenishing NO into the blood based on the first flow rate, the first NO concentration, the second flow rate, and the second NO concentration.

In this way, by calculating the NO output amount per unit time based on the first flow rate and the first NO concentration and subtracting the NO emission amount per unit time calculated based on the second flow rate and the second NO concentration, for example, but not limited to, subtracting the product of the second flow rate and the second NO concentration from the product of the first flow rate and the first NO concentration, the actual NO dose per unit time can be automatically and accurately determined as an example of a dose supplement condition, so that ineffectiveness due to insufficient NO dose can be avoided, toxicity due to excessive NO dose can be avoided, and accurate grasp of the medical effect of supplementing NO gas can be achieved.

Further, in addition to the actual NO dose delivered per unit time, the at least one controller 12 may determine other examples of dose delivery conditions. For example, by accumulating the NO doses replenished per unit time, the cumulative amount of NO actually replenished into the blood can be determined. For example, in the event that the product of the first flow rate and the first NO concentration (which may be referred to as a feed dose) is within a reasonable range, the product of the second flow rate and the second NO concentration (which may be referred to as an exhaust dose) is excessive, and the supplemental NO dose is insufficient, the at least one controller 12 may determine that the supplemental NO dose is insufficient due to the exhaust dose being excessive, and accordingly may instruct associated components in the gas discharge 9 to reduce the flow rate and/or increase the pressure, thereby avoiding excessive exhaust of NO to waste, and thereby efficiently increasing the supplemental NO dose. For another example, in the case where the discharged dose is reasonable, the fed dose is insufficient, and the supplemented NO dose is insufficient, the at least one controller 12 may determine that the supplemented NO dose is insufficient due to the insufficient fed dose, and accordingly may instruct the relevant components in the NO gas generator 1' to increase the supply amount of NO gas, instruct the relevant components in the gas generation section 1 to increase the pressure in the feed line 2, and thereby efficiently increase the supplemented NO dose. In some embodiments, the dose replenishment condition may further include at least one of timing of dose replenishment, a real-time replenishment dose, a profile of replenishment dose (a profile of replenishment dose vs time per unit time, a profile of cumulative replenishment dose vs time), dispensing of a feed dose/an expelled dose, and the like. By determining the timing of the dose supplementation, an adaptation of the timing of the NO supplementation to the timing of the blood infusion may be achieved, e.g. to ensure that the blood infused into the human body has been supplemented with the appropriate dose of NO and that NO has maintained sufficient activity. By determining the real-time supplemental dose and the profile of the supplemental dose, it can be precisely matched according to the specific needs of the patient and the various blood infusion devices.

In some embodiments, the at least one controller 12 may be further configured to: the determined NO-replenishment dosage condition is compared with a preset dosage condition, and the gas generating section 1 and/or other related components are adjusted according to the comparison result. For example, it is possible to analyze whether the actual dose replenishment situation has reached the preset dose replenishment situation, to determine a corresponding adjustment measure and to issue a corresponding adjustment indication, so that the actual dose replenishment situation approaches or reaches the preset dose replenishment situation. An exemplary description of the comparison and adjustment instructions, for example, of the NO supplement dosage per unit time has been given above and will not be described herein.

In some embodiments, gas replenish 4 may be configured to selectively cooperate with a variety of blood infusion devices, including, but not limited to, any of blood transfusion devices, hemodialysis devices, extracorporeal circulation devices, and the like. The at least one controller 12 may be further configured to: a pre-set dose replenishment condition is determined based on the blood infusion device with which the apparatus is to be used. In this way, the appropriate dose replenishment can be automatically matched in view of the different requirements of the blood infusion device for dose replenishment. Specifically, blood transfusion apparatuses use stored blood, which rapidly decreases in NO content over time, loses about 70% of NO over a day of storage, and loses 90% of NO over a few days of storage. In contrast, hemodialysis devices and extracorporeal circulation devices, which are treated to draw fresh blood from the patient themselves and return it to the patient, are not stored and have a much lower reduction in NO than stored blood. The respective pre-set dose supplementation condition can be determined for each blood infusion device, so that the pre-set dose supplementation condition of the blood infusion device can improve severe NO deficiency conditions, while the pre-set dose supplementation condition of the hemodialysis device and the extracorporeal circulation device can suitably improve the reduction of NO content caused during treatment and avoid toxicity caused by overdose of NO.

The concentration monitoring portion 10 may take various configurations. As shown in fig. 2, in some embodiments, the concentration monitoring portion 10 may further include a first extraction member 11a and a NO sensor 11 b. The first extraction member 11a can perform a gas suction action in order to extract the gas coming from the discharge line 8 and the feed line 2, respectively, for example via the introduction branches 11c and 11 d. The NO sensor 11b may be configured to: a first NO content of NO in the extracted gas from the feed line 2 and a second NO content of NO in the gas from the discharge line 8 are detected. Although fig. 2 shows a single concentration monitoring portion 10 (which contains a single extraction member and a single NO sensor), this is by way of example only, and it is also possible to provide the feed line 2 and the discharge line 8 with respective concentration monitoring portions, see for example fig. 1. As shown in fig. 2, the single concentration monitoring portion 10 may include a switching member 11a, and the switching member 11a may be configured to switch between gas inputs (i.e., introduction branches 11c and 11d) from the feed line 2 and the discharge line 8, so that the gas of the single line is selectively input to the NO sensor 11b to detect the NO concentration in the corresponding line under the action of the first extraction member 11 a. By way of example, and not limitation, the switching member 11a may be implemented as a solenoid valve. The inventors have creatively found that, in the magnitude of the NO supplementary dose, the measurement differences of different NO sensors can significantly affect the calculation of the actual NO supplementary dose and even lead to invalid calculation results (e.g. the expelled dose is larger than the fed dose); with this configuration of the single concentration monitoring portion 10, the NO concentration of each line is detected by the same NO sensor 11b, and the influence of individual measurement differences of the NO sensors can be eliminated, thereby further ensuring the calculation accuracy of the NO supplementary dose. The gas for which concentration measurement by the concentration monitoring portion 10 is completed may be discharged into the air after being processed.

Fig. 3 shows a configuration diagram of a device for supplementing NO to blood according to an embodiment of the present disclosure, in which at least one controller 12 is not shown, and a partial configuration is similar to that of fig. 1, and the following description is mainly made about differences from the configuration of fig. 1.

As shown in FIG. 3, the feed line 2 may be provided with a second extraction member 2a (each extraction member in the present disclosure is, for example, but not limited to, a suction pump) configured to provide a continuous flow of gas to the NO generator 1a, and the NO generator 1a may generate a gas containing NO and NO by using the input air or air-oxygen mixture as a medium₂The mixed gas of (1). The at least one controller may be configured to control the gas generating section 1 (specifically, the NO generator 1a) to adjust the concentration of NO in the mixture gas. The at least one controller may regulate the gas flow of the NO-containing mixture by regulating the flow rate of the second extraction member 2 a. The discharge line 8 may be provided with a flow regulating member 8a (such as, but not limited to, a flow regulating valve) that can feedback control the flow of gas in the discharge line 8 under the direction of at least one controller. At least one controller can regulate the gas pressure in the gas make-up 4 by regulation of the gas flow on the feed line 2 and the discharge line 8. In particular, the feed tubeThe smaller the gas flow in the path 2, the larger the gas flow in the discharge line 8, the lower the gas pressure in the gas replenishing part 4, and the less NO gas can be replenished into the blood; the larger the gas flow in the feed line 2, the smaller the gas flow in the discharge line 8, the higher the gas pressure in the gas replenishing part 4, and the more NO gas can be replenished into the blood.

In some embodiments, a pressure sensor 2b may be provided on the feed line 2 to monitor the pressure of the gas therein, and the pressure sensor 2b may be provided on the feed line on a side adjacent to the gas replenishing portion 4 such that the monitored pressure thereof is comparable to the pressure within the accommodating member 5 of the gas replenishing portion 4. The at least one controller may further control the second extraction member 2a and/or the flow regulation member 8a based on the pressure detected by the pressure sensor 2b such that the corresponding pressure reaches a preset pressure range. In this way, the gas in the housing member 5 of the gas replenishing portion 4 can be maintained at an appropriate positive pressure, and a larger amount of NO gas can be replenished into the blood by the action of the appropriate positive pressure.

In some embodiments, the gas generating part 1 may be provided with (at least one) first one-way locking member 2v in sequence along the gas flow direction₁A first filter 2f, a second extraction member 2a, a NO generator 1a, a second filter 1f, a first flow detector 3, a fourth one-way locking member 2v₂And a pressure sensor 2 b. The first filter 2f may be configured to filter out impurities and moisture in the air. For example, the first filter 2f may comprise a filter screen for filtering out airborne impurities and an absorbent for absorbing airborne moisture and carbon dioxide, which may be lime particles, or other absorbent that achieves a similar effect, thereby providing a dry and clean source of air for the NO generator 1 a. The second filter 1f is configured to filter out nitrogen dioxide (NO) in the generated gas₂) To ensure NO replenishment into the blood₂The concentration does not exceed the clinically acceptable safety range. At least one first unidirectional locking member 2v₁At least one filtering means (not shown in fig. 3) that can be arranged between the first filter 2f, said second filter 1f and the gas supply 4One upstream in the direction of gas flow, so that: when the gas generating part 1 is in operation, unidirectional flow in the gas flow direction is allowed, and when the gas generating part 1 is not in operation, the gas generating part is automatically closed to isolate the corresponding downstream filter or filtering mechanism from air, so that the consumption of the filter or filtering mechanism caused by contacting with air is avoided. The fourth one-way locking member 2v may be provided on the pipe section on the side of the gas replenishing portion 4 on the feed line 2 of the gas generating portion 1₂It may be configured as: when the device is in operation, the device allows one-way flow in the gas flow direction, and when the device is not in operation, the device is automatically closed to isolate the gas generating part 1 and the gas supplementing part 4 from each other, so that waste gas backflow and pollution of the gas supplementing part 4 to the gas generating part 1 when the device is not in operation can be avoided, the maintenance of the gas generating part 1 and the gas supplementing part 4 respectively is facilitated, and the pollution to the environment is reduced when the device is not in operation.

In some embodiments, the gas discharge portion 9 is provided with a third filter 8f downstream of the second flow detector 10 in the gas flow direction to filter and absorb NO and NO in the exhaust gas₂And the environment pollution caused by the waste gas discharged into the air is avoided. A second one-way locking member 8v is provided downstream of the third filter 8f in the gas flow direction₁Said second unidirectional locking member 8v₁The structure is as follows: one-way flow in the gas flow direction is allowed when the gas discharge portion 9 is operated, and is automatically closed to isolate the third filter 8f from air when the gas discharge portion 9 is not operated. A fifth one-way locking member 8v may be provided on the pipe section on the side of the gas replenishing portion 4 on the discharge line 8₂It may be configured as: one-way flow in the gas flow direction is allowed when the apparatus is in operation, and is automatically closed to isolate the gas discharge part 9 and the gas supplement part 4 from each other when the apparatus is not in operation, so that backflow and contamination of the gas discharge part 9 to the outside air of the gas supplement part 4 when the apparatus is not in operation can be prevented, and maintenance of the gas discharge part 9 and the gas supplement part 4, respectively, when the apparatus is not in operation is facilitated and environmental pollution is reduced.

In some embodiments, a single one of the concentration monitoring portions 11 may be provided with a fourth filter 11f on the air side in the gas flow direction to filter out NO and NO₂So as to avoid the pollution of the waste gas discharged to the air to the environment. A third one-way locking member 11v may be provided downstream of the fourth filter 11f in the airflow flow direction, and the third one-way locking member 11v may be configured to: one-way flow in the gas flow direction is allowed when the concentration monitoring portion 11 is operated, and is automatically closed to isolate the fourth filter 11f from air when the concentration monitoring portion 11 is not operated.

Each one-way locking member in the present disclosure may be implemented as various one-way valves. When the apparatus is operated, specifically, when the gas generating part 1 is to be operated, the first one-way locking member 2v₁Fourth unidirectional locking member 2v₂Fifth unidirectional locking member 8v₂A second unidirectional locking member 8v₁And the third one-way locking member 11v is automatically opened by the pressure that can be generated by the second and first extraction members 2a and 11a, ensuring the one-way flow of the gas flow in each gas branch of the gas generation part 1, the gas supplement part 4 and the gas discharge part 11 without the occurrence of the backflow. When the apparatus stops operating, for example, when the gas generating part 1 is about to stop operating, the second extracting member 2a and the first extracting member 11a also stop operating, and the first one-way locking member 2v stops operating₁Fourth unidirectional locking member 2v₂Fifth unidirectional locking member 8v₂A second unidirectional locking member 8v₁And the third one-way locking member 11v is automatically closed to isolate the respective filters and filtering mechanisms from the air environment, thereby preventing the filters and filtering mechanisms from being consumed by contacting air, thus prolonging the service life thereof and facilitating maintenance thereof.

Fig. 4 shows a schematic structural view of an example of the gas replenishing part 4 according to an embodiment of the present disclosure. As shown in fig. 4, the gas replenishing portion 4 may include a filter mechanism 403 configured to: the introduced NO gas (as indicated by the following arrows) is filtered to remove particulate matter, bacteria and viruses therefrom.

As shown in fig. 4, the first port 401 serves as an NO gas introduction port for interfacing with a feed line of the gas generating portion to introduce NO gas (or gas containing NO); the second port 402 serves as an exhaust gas discharge port for interfacing with a discharge line of the gas discharge portion to discharge excess exhaust gas. The gas generated by the gas generation portion and output via the feed line contains NO, and is purified by the filter mechanism 403 and then delivered into the accommodation member 405 of the gas replenishment portion 4 to be sufficiently in contact with blood therein. NO has good lipid solubility, and a part of NO gas can be dissolved in blood by means of fat substances in plasma (these lipid substances include cholesterol, triglyceride, phospholipid, non-free fatty acid, etc., which are combined with different proteins in blood and exist in the form of lipoprotein), so that the NO concentration in blood is rapidly increased, and the redundant gas is discharged through the second interface 402.

In some embodiments, the filtering mechanism 403 may include a bacterial filter 403a and a gas permeable semi-permeable membrane 403b in the gas path between the first port 401 and the second port 402. The bacterial filter 403a may be configured to filter out particulate matter and bacteria. For example, the filter pore size of the bacterial filter 403a may be set to 0.22-0.45 microns for filtering out larger diameter bacteria and particulate matter. The gas permeable semi-permeable membrane 403b may be configured to: with a suitable pore size to sequester viruses while allowing gas (e.g., NO gas) to permeate through to permeate the blood. Specifically, the gas permeable semipermeable membrane 403b may divide the passage passing through the gas replenishing part 4 into a gas passage (i.e., the gas permeable semipermeable membrane 403b itself) and a liquid passage 407, and the NO gas passing through the gas passage permeates into the liquid passage 407 through the gas permeable semipermeable membrane 403b, is merged with the blood, and then enters the blood circulation of the human body. In particular, the gas permeable semi-permeable membrane 403b has a much smaller pore size than the bacterial filter 403a, and may serve to isolate viruses to prevent contamination of blood.

As shown in fig. 4, in some embodiments, the gas supplementing portion 4 may further include a blood input port 408 and a blood output port 409. In some embodiments, the blood input port 408 and the blood output port 409 may employ a common interface, such as, but not limited to, a luer interface. The universal interface may also be implemented in other ways, for example, but not by way of limitation, by implementing the blood input port 408 and the blood output port 409 as regions of a layer of an elastic material (e.g., medical grade silicone) such that corresponding infusion tubing of various designs may be inserted via an infusion needle to achieve universal docking. As such, the blood input port 408 may be configured as a universal interface compatible with respective outflow lines of a blood storage bag (for blood transfusion), a blood circulation line (for hemodialysis, extracorporeal circulation, and the like), to introduce blood to be treated into the gas replenishing portion 4. The blood output port 409 may be configured as a universal interface compatible with interfacing with a return line downstream of the outflow line of a blood transfer vessel (for blood transfusion), a blood flow line (for hemodialysis, extracorporeal circulation, etc.), respectively, to infuse NO gas-supplemented blood into a subject. Through the design of various universal interfaces, the gas supplementing part 4 can be flexibly compatible with application scenes suitable for various blood conveying, and can supplement a proper amount of NO gas to the conveyed blood while conveying the blood in various application scenes so as to improve the quality of the blood. That is, a doctor can cope with a variety of different application scenarios with only a single gas supplement portion 4, thereby significantly improving convenience and reducing manufacturing costs.

The operation of the device for supplementing NO to blood according to the embodiment of the present disclosure is described below with reference to three application scenarios of blood transfusion, hemodialysis, and extracorporeal circulation, but it should be understood that the device may also be flexibly applied to other application scenarios, and thus, the description thereof is omitted here.

Fig. 5 is a schematic view showing connection of NO supplementation into blood at the time of transfusion using the apparatus for supplementing NO into blood according to the embodiment of the present disclosure (particularly, the gas supplementation portion 501), and most of the configurations of the gas generation portion and the gas discharge portion are omitted in fig. 5 for the convenience of description.

As shown in fig. 5, the device is used for supplying NO to the stored blood to be infused into a human body when the device is used for blood transfusion, and the supplement dosage of the NO can be accurately controlled according to clinical needs. When the blood transfusion system is used, the blood input port 502 on the gas supplementing part 501 is connected with the blood storage bag 503, the blood transfusion tube 505 connected with a patient is connected with the blood output port 504 of the gas supplementing part 501, and after the blood in the blood storage bag 503 enters the liquid channel of the gas supplementing part 501 and fills the blood transfusion tube 505, the other end of the blood transfusion tube 505 can be connected with a human body to start blood transfusion. The gas generation unit is then activated, and the output NO gas is sent to the gas replenishment unit 501 via the feed line 506a, specifically, to the gas replenishment unit 501 after being purified by the filter mechanism 507. In the gas replenishing portion 501 shown in fig. 4, the output NO gas is fed through the feeding line 506a, purified by the filter mechanism 507 and then fed into the gas passage of the gas replenishing portion 501, and then continuously replenished into the blood in the liquid passage 407 after passing through the gas permeable semipermeable membrane 403b of the gas passage, and the excess NO gas in the gas passage can be filtered and purified by the gas discharging portion through the discharging line 506b and discharged to the air.

Clinically, a series of physiological, morphological and functional changes, called storage injury, occur in the course of in vitro storage of RBC, and are mainly reflected in that cell membrane fluidity and permeability are changed, aggregation is increased, and cell elasticity is reduced to harden cells and reduce deformability. The RBC deformability is one of the main factors for maintaining the effective perfusion of the microcirculation, and the RBC deformability not only can influence the oxygen supply of organs, but also can influence whether the RBC can pass through narrow capillaries in tissues and influence the effect of blood transfusion, so that the adverse reaction of blood transfusion after blood transfusion, and the morbidity and mortality are increased.

These changes in RBC in the stored blood are associated with the absence of NO, which is found to be a substantial and rapid decrease in the amount of NO in the stored blood. Over the course of a day storage, blood loses 70% of its NO. After a few days, up to 90% NO is missing. Reduced NO levels, RBC butterfly cells become rigid (significantly reduced flexibility and elasticity), and therefore cannot easily enter the narrow microvessels in the tissue. On the other hand, when free hemoglobin in the blood stock enters the blood circulation, it reacts with NO, and consumes NO thousands times faster than in red blood cells, which results in excessive "scavenging" of NO in the body after transfusion, and when the level of NO in the body decreases, it causes vasoconstriction in these tissues, abnormal platelet aggregation, blood coagulation promotion, thrombosis, ischemia and hypoxia in the tissue cells at specific sites, and if the tissue just diseased is the myocardium, the consequences of blood transfusion may cause heart disease.

Experiments of the present inventors have confirmed that, before blood transfusion, by using the NO supplementation apparatus according to various embodiments of the present disclosure, as shown in the operation flow of fig. 5, accurate injection of an appropriate amount of NO into stored blood can rapidly recover the ability of stock blood to dilate blood vessels, increase RBC deformability, decrease blood viscosity, decrease blood flow resistance, increase blood flow velocity, improve rheological properties of blood, increase oxygen carrying capacity and transport capacity of nutrients of blood, significantly improve hemorheology, further improve the effect of blood transfusion, and reduce adverse reactions of patient blood transfusion.

Fig. 6 is a schematic connection diagram of a device for supplementing NO into blood (particularly, a gas supplementing unit) according to an embodiment of the present disclosure during hemodialysis to supplement NO into blood. Most of the configurations of the gas generating part and the gas discharging part are omitted in fig. 6 for convenience of description.

The device is used for supplementing NO into blood to be returned to a human body after passing through a dialyzer 610 during hemodialysis. Specifically, blood is drawn out of the body through blood pumps 608a and 608b, anticoagulant 609 and substitution fluid 611 are introduced, and excess substances (including but not limited to nitrogen-containing compounds, metabolic products, excess drugs, etc.) in the body are removed by dialysis, filtration, adsorption, membrane separation, etc. using dialyzer 610, the electrolyte balance is adjusted, and the purified blood is drawn back into the body, and the excess substances are discharged through waste fluid 612. Devices according to various embodiments of the present disclosure may be used with hemodialysis devices to replenish NO into the blood while performing hemodialysis on a patient so that the blood returned to the body is replenished with an appropriate dose of NO.

As shown in fig. 6, in use, the blood input port 602 of the gas supplementing unit 601 may be connected to the blood outflow pipe 603 passing through the dialyzer 610, so as to introduce dialyzed blood into the gas supplementing unit 601. The blood outlet 604 of the gas replenishing part 601 may be connected to a blood return line 605 connected to the human body, and used to deliver the dialyzed blood supplemented with an appropriate amount of NO into the human body. After the blood flows stably in the tube and fills the liquid channel of the gas supplementing unit 601, the gas generating unit can be started again, the output NO gas is sent into the gas supplementing unit 601 through the feeding line 606a, specifically, the NO gas can enter the gas channel of the gas supplementing unit 601 after being purified by the filtering mechanism 607, and then, for example, the NO gas after isolating the virus is supplemented into the blood in the liquid channel through the gas permeable semipermeable membrane of the gas channel, the fresh blood supplemented with NO can enter the human body through the blood returning line 605, and the surplus gas in the gas channel can be filtered and purified by the gas discharging unit through the discharging line 606b and then discharged into the air.

The inventor proves through experiments that NO with proper concentration is supplemented into blood during hemodialysis, so that the concentration of NO in the blood is rapidly increased, the kidney is obviously protected, the kidney blood dynamics is mainly regulated, normal renal blood flow is maintained, mesangial cell proliferation and glomerular thrombosis are inhibited, and the effects of diuresis and natriuresis are achieved; and can effectively reduce blood pressure and reduce damage to kidney.

Fig. 7 is a schematic connection diagram of a device for supplementing NO into blood (particularly, a gas supplementing part 701) according to an embodiment of the present disclosure for supplementing NO into blood during extracorporeal circulation. Most of the configurations of the gas generating part and the gas discharging part are omitted in fig. 7 for convenience of description.

Extracorporeal circulation is a life support technique, also known as cardiopulmonary bypass (CPB), that utilizes a series of special artificial devices, such as a blood pump 710 to draw cardiovenous blood out of the body, exchange gas manually (e.g., via artificial lung 709), adjust temperature (e.g., via temperature changer 708), and filter before returning to the arterial system of the body. Heparin solution 711 is typically supplied to the blood during extracorporeal circulation to relieve the coagulation. Extracorporeal circulation, while addressing the maintenance of the blood supply to the tissues and organs throughout the body when performing open heart surgery, introduces several other problems: on one hand, lung injury generally exists after open heart surgery, which is manifested by non-cardiogenic pulmonary edema, reduced oxygenation and ventilation functions, increased alveolar-arterial oxygen difference, intra-pulmonary circulation, pulmonary microvascular leakage and pulmonary vascular resistance, and although the incidence is low, the death rate is high; on the other hand, during the extracorporeal circulation process, the hemodynamics is changed, and blood cells and plasma components are activated after contacting with the oxygenator and the extracorporeal circulation pipeline, so that various inflammation mediums are generated, thereby causing severe inflammation reaction and forming thrombus.

As shown in fig. 7, the gas supplement part 701 of the device according to various embodiments of the present disclosure may supplement NO to extracorporeal blood during extracorporeal circulation. In use, the blood input port 702 of the gas replenishing section 701 may be connected to the upstream (closer to the oxygenator) 703 of the blood flow channel oxygenated by an oxygenating device (e.g., the artificial lung 709), and the blood output port 704 of the gas replenishing section 701 may be connected to the downstream 705 (closer to the human body) of the blood flow channel. After the blood flows stably in the tube and fills the liquid channel of the gas supplementing unit 701, the gas generating unit is activated, the output NO gas can be introduced into the gas supplementing unit 701 through the feeding line 706a, purified by the filtering mechanism 707 and then introduced into the gas supplementing unit 701, so as to supplement NO into the oxygenated blood, and the excess gas can be filtered and purified by the gas discharging unit through the discharging line 706b and then discharged into the air.

The inventor proves through experiments that in the extracorporeal circulation process, by adopting the operation flow shown in fig. 7 and adding a proper amount of NO into blood by using the device according to each embodiment of the disclosure, the device not only can inhibit or reverse platelet activation, inhibit neutrophil activation and adhesion, inhibit the generation of various inflammation media and prevent thrombosis, but also can effectively reduce pulmonary artery pressure, obviously improve oxygenation, has good curative effects on hypoxemia, inflammation and thrombus related to non-infection factors such as extracorporeal circulation or blood transfusion, and reduces complications, so that patients can recover more quickly.

Moreover, although exemplary embodiments have been described herein, the scope thereof includes any and all embodiments based on the disclosure with equivalent elements, modifications, omissions, combinations (e.g., of various embodiments across), adaptations or alterations. The elements of the claims are to be interpreted broadly based on the language employed in the claims and not limited to examples described in the present specification or during the prosecution of the application, which examples are to be construed as non-exclusive. It is intended, therefore, that the specification and examples be considered as exemplary only, with a true scope and spirit being indicated by the following claims and their full scope of equivalents.

The above description is intended to be illustrative and not restrictive. For example, the above-described examples (or one or more versions thereof) may be used in combination with each other. For example, other embodiments may be used by those of ordinary skill in the art upon reading the above description. In addition, in the foregoing detailed description, various features may be grouped together to streamline the disclosure. This should not be interpreted as an intention that a disclosed feature not claimed is essential to any claim. Rather, the subject matter of the present disclosure may lie in less than all features of a particular disclosed embodiment. Thus, the following claims are hereby incorporated into the detailed description as examples or embodiments, with each claim standing on its own as a separate embodiment, and it is contemplated that these embodiments may be combined with each other in various combinations or permutations. The scope of the disclosure should be determined with reference to the appended claims, along with the full scope of equivalents to which such claims are entitled.

The above embodiments are merely exemplary embodiments of the present disclosure, which is not intended to limit the present disclosure, and the scope of the present disclosure is defined by the claims. Various modifications and equivalents of the disclosure may occur to those skilled in the art within the spirit and scope of the disclosure, and such modifications and equivalents are considered to be within the scope of the disclosure.