JPH08295630A - Plasma separation - Google Patents

Abstract

PURPOSE: To prepare whole blood capable of transfusing by separating plasma from blood in high separation rate through permeating a hollow fiber separation membrane, treating the separated plasma and again mixing the plasma with the blood while removing air bubbles. CONSTITUTION: This plasma separation is to continuously feed whole blood along the surface of a hollow fiber type separation membrane consisting of porous material having 0.1-0.6μm pore size at 5-1500cm/min. flow rate, permeate solely plasma by keeping an intermembrane pressure difference at <50mmHg, preferably 40-20mmHg to permeate plasma through the membrane, treat the permeate plasma by a treating device, joint the flow of the plasma treated with the treating device to the blood flow passed through the plasma separator in a bubble scavenging device to obtain the whole blood. By permeating solely the plasma under a specific condition, it is able to increase a plasma separation efficiency and separate the plasma even at a low intermembrane pressure difference without breaking blood cells or generating filter clogging compared with a usual method in which the plasma is permeated by feeding the whole blood at a relatively high pressure.

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a method of once separating plasma from human or animal blood, treating the plasma, and then rejoining it with blood.

[0002]

2. Description of the Related Art Conventionally, plasma is sometimes separated from blood in order to transfuse blood from a blood donor to another person or to handle the blood for some purpose. Is extracted, and after that, it is subjected to a centrifugal separator to centrifuge the plasma. Such a method is not only time-consuming, but also requires a great deal of manpower and complicated equipment and is troublesome to handle.

As a method for achieving the same purpose, a so-called "on-line type permeable plasma separation method" has been recently researched. According to such a method, blood is supplied to an on-line type separation device and the blood is separated from the blood. After separating the plasma, the plasma is temporarily stored, while the solute to be removed is treated and immediately returned to the blood supply source. This latest method is far simpler and more economical than the centrifugal plasma separation method described above in that blood is handled through a large amount of human hands, and that complicated equipment is used. is there. Moreover, when used for plasma treatment, most solutes to be removed are aggregated in plasma,
It has advantages over conventional methods that require a treatment material to be contacted with blood to remove solutes, such that blood can be cleaned quickly and easily.

In particular, the treatment material may be appropriately selected and used according to a predetermined treatment, and it is not necessary to consider the influence of the treatment material on blood cells. Moreover, since there is no interaction between the blood cells and the treatment material, any treatment material may be used as long as it meets the purpose. Since the treated material once used can be easily separated from the plasma before it is sent to the blood demand destination, the above-mentioned online membrane permeation plasma separation method is an extremely safe method, and it can be used in various fields. It is used.

As an example of such a plasma separation method, one disclosed in US Pat. No. 3,705,100 is known. The permeable membrane used in the plasma separation method disclosed in this U.S. Patent is a porous permeable membrane having a pore size of 0.1 to 0.8 microns. In contrast, blood must flow at a rate of 2 to 50 feet per minute (about 61 to 1525 cm / min) while maintaining a transmembrane pressure difference of 1 to 15 psi. This method is believed to be effective in separating plasma from blood.

Another method is as follows: Vol. XXIV Transactions, 1978, American Society of Internal Endovascular Management.
American Society Atrial Internal Orga
ns246, 1978) "Efficient Specific Adsorption Method for Liver Assistance"
and Blood Compatible Sorbent Syetem for
Hepatic Assistant) was published by Mr. Kouichi. According to this method, a filter made of cellulose acetate is used to separate plasma from blood, and at the time of use, blood is flown through a hollow fiber permeable membrane at a rate of 10 ml / min while the transmembrane pressure difference is increased. By maintaining at 60, 100 and 137 mmHg, plasma can be separated at a rate of 37 ± 2, 34 ± 2 and 32 ± 2 ml / min, respectively.

Recently, US Pat.
No. 911,182 discloses a continuous separation method of plasma by a so-called ultrafiltration method. According to such a US patent, the permeable membrane is operated at a pressure of 50 to 700 mmHg. In general, if the transmembrane pressure difference is high, it is easy to destroy the cell composition of blood, and it is necessary to adjust the transmembrane pressure difference to prevent clogging of the filter. Then 50-700mm
It is disclosed that it is desirable to use a transmembrane pressure difference of 100 to 400 mmHg among the Hg pressure.

[0008]

OBJECTS OF THE INVENTION The present invention is more efficient than the above-mentioned conventional methods, does not destroy blood cells and does not cause clogging of the filter, and has an extremely low transmembrane pressure difference. It is also an object of the present invention to provide a method of separating plasma from human or animal blood, which can be sufficiently carried out.

[0009]

The method for separating plasma from blood according to the present invention is a blood processing method for processing plasma after separating plasma from blood, wherein the blood is forcibly pre-pressurized by blood supply means. The pore size inside the plasma separator is 0.1
The separation membrane is formed by continuously supplying the hollow fiber type separation membrane made of a porous material of ˜0.6 μm along one surface at a flow rate of 5-1500 cm / min, and at the same time adjusting at least the supply pressure of the blood. The pressure difference between the membranes is just 50 mmHg
The blood plasma contained in the blood is forcibly permeated through the separation membrane while maintaining the amount below, and then the plasma separated from the blood in the separation membrane is sequentially processed by the treatment device, and the treatment device is used. It is a plasma separation method, characterized in that the treated plasma and the blood that has passed through the plasma separator are combined by a bubble trap.

According to the present invention, the transmembrane pressure difference is less than 50 mmHg,
In particular, when operated at a transmembrane positive pressure difference of 8.5 mmHg to less than 50 mmHg, contrary to most expectations, the plasma separation rate was 50%.
The above-mentioned object of the present invention is to separate plasma from blood based on the finding that it can be increased as compared with the case of operating at a transmembrane pressure difference exceeding mmHg. The surface of the separation membrane composed of hollow fibers having a large number of pores with a pore size of 0.1 to 0.6 micron is suitable for the surface of blood at a depth sufficient to achieve plasma separation. , While supplying at a flow rate of 5 to 1500 cm / min, the transmembrane pressure difference is just less than 50 mmHg, especially 8.5 mmHg to 50 mmHg for permeating plasma through the membrane.
This can be achieved by maintaining the blood pressure below less than about 40 to 20 mHg and collecting the plasma separated by such a separation membrane.

The method according to the present invention is different from the ultrafiltration method, which is generally considered to increase the separation rate as the transmembrane pressure difference increases. Therefore, for the present invention, since blood is a mixture of various particles intricately gathered, the common general knowledge does not apply in separating plasma from blood.

According to the present invention, it has been found that there is a further advantage when the plasma separation is carried out with a relatively low transmembrane pressure difference as described above. That is, blood is a very complicated fluid composed of various solutes, and the solutes have different particle sizes of molecules. Therefore, at present, the quality of plasma separation is judged not only by the amount of separated plasma, but also by the amount or composition of the filtrate.
As one measure, the sieving coefficient, that is, the amount of the desired component contained in the filtrate with respect to the amount of the desired component contained in the raw blood is used. However, it was found that not only can the amount of separated plasma be increased by carrying out under a low transmembrane pressure difference, but also the sieving coefficient of various components of plasma can be increased. .

The plasma separation apparatus for carrying out the method according to the present invention has at least a blood supply means and a pore size of 0.1 to 0.6.
Plasma separator having a built-in separation membrane composed of hollow fibers having a large number of micron holes, and a flow rate of 5 to 1500
means for supplying blood along one surface of the separation membrane in cm / min with a depth sufficient to separate plasma from blood, and a positive pressure differential between the separation membrane and the membrane of exactly less than 50 mmHg, In particular, a means for permeating plasma in blood through the separation membrane while maintaining it at less than about 8.5 mmHg to 50 mmHg, a processor for treating the plasma separated by the separation membrane, and the processor It is composed of a bubble trap for joining the treated plasma and the blood passing through the plasma separator and trapping bubbles.

[0014]

BEST MODE FOR CARRYING OUT THE INVENTION Hereinafter, an embodiment of the present invention will be described in detail with reference to the accompanying drawings. First, in FIG. 1, 10 is a blood supply pump, the suction port of which is connected to a blood source through a pipe 11. On the other hand, pump 1
The discharge port of 0 is connected to the inlet of the plasma separator 13 via the tube 12 having the bubble trap 12a. The downstream end of this separator 13 is connected to a bubble trap 15 via a pipe 14.
The bubble trap 15 is connected to a blood demand destination via a pipe 16. The filtrate chamber side of the separator 13 is connected via a pipe 17 to a plasma reservoir 18 and to a suction port of a plasma delivery pump 19. The discharge port of the feed pump 19 is connected to a processing device 21 such as an adsorption cartridge and a pipe 23 via a three-way valve 20.
The outlet end of the processor 21 is connected to the bubble trap 15 via the particle filter 22, while the tube 23 is a collector for collecting plasma for the purpose when needed, or further plasma. It is adapted to be connected to other parts of the device for processing.

Various modifications can be considered in the above-mentioned structure. For example, the plasma reservoir 18 can be incorporated into the separator 13 and the reservoir 18 need not be vented. In particular, in the case where the reservoir 18 is not provided with a vent hole, it is necessary to control the discharge speed of the pump 19 to adjust the pressure in the reservoir 18, and thus the transmembrane pressure difference in the separator 13.

Most of the components of the separation device are known, such as blood supply pumps, plasma reservoirs, plasma supply pumps, adsorption cartridges, particle filters and bubble traps. In particular, the plasma separator may also be one of various known filters and is generally unaffected by blood or blood components and is suitable for separating plasma from blood. It has a separation membrane made of different materials. As a material for the separation membrane, US Pat. No. 4,031,0
Hydrophilic materials such as cellulose acetate, cuprophan and cellophane disclosed in No. 10, polycarbonate and polypropylene may be used. In particular, cellulose acetate and sold by Nuclepore Co. under the trade name "Nuclepore 040". The polycarbonates mentioned are preferred.

The pore size is 0.1 to 0.6 micron, and the separation membrane in the separator is a membrane sufficient to separate, ie, filter, plasma from blood flowing along one surface of the separation membrane. Any arrangement may be used as long as the inter-pressure difference can be obtained.

The separation membrane composed of hollow fibers has a plurality of fibers, the inside of the fibers communicating with the blood supply port and the outlet end of the separator, and the space around the fibers communicating with the filtrate outlet of the separator. It is stored in the separator in the state vice versa or vice versa. In particular, it is desirable that blood be configured to flow inside each fiber. As a hollow fiber suitable for the present invention, a cellulose acetate hollow fiber sold by Asahi Medical Co. is preferable. In the parallel plate-shaped separation membrane and the hollow fiber, the latter is particularly the geometrical arrangement of the hollow fibers so that the dimensions do not collapse even when the transmembrane pressure difference required to obtain a desired plasma flow is applied. It is strong and therefore does not require a hollow fiber support.

Therefore, there are advantages that the structure of the separator as a whole is simple and relatively inexpensive. This advantage of using hollow fibers is especially necessary given the large effect that fluid dynamics have on the separation and sieving coefficients. That is, when a hollow fiber made of a porous material is used for the separation membrane, the size of the hollow fiber and the number of pores can be freely selected as required, and the plasma passage characteristics of the pores are improved to allow long-term use. Also, it is possible to prevent clogging and to easily adjust the membrane pressure of the separation membrane by freely setting the flow velocity of blood to the hollow fiber in a wide range. In particular, when the positive pressure difference between the separation membranes is extremely low, a particularly effective separation effect can be exhibited.

In order to process the separated plasma into blood to be returned to the patient by the plasma separation method of the present invention, the reservoir 1
A three-way valve 20 such that the plasma supplied from 8 is returned to the patient via a processor 21, eg an adsorption cartridge, a particle filter 22, a bubble trap 15, and a tube 16.
Should be set. At this time, while flowing from the three-way valve 20 to the bubble trap 15, the treatment material particles contained in the plasma are filtered and removed, and then supplied to the bubble trap 15 via the pipe 14. It joins the blood.

If the separation apparatus used in the plasma separation method of the present invention is used for treating separated plasma, the adsorbent in the cartridge 21 may be any adsorbent effective for removing undesirable components from plasma. Anything is fine. U.S. Pat. No. 4,013,564 discloses types of such adsorbents for a particular purpose.

When blood is allowed to flow under a certain condition in the separation apparatus used in the plasma separation method of the present invention having the above-mentioned structure and is operated under a specific transmembrane pressure difference, the rate of conversion from normal blood is increased. It has been found that plasma can be separated and the sieving coefficient is increased. The flow rate of blood sent to the plasma separator must be selected so that the flow rate of blood along one surface of the separation membrane in the plasma separator is 5 to 1500 cm / min. At the same time, the transmembrane pressure difference in the plasma separator is just 50.
It is necessary to select the operating conditions of the pump 10 so that it is less than mmHg, particularly in the range of 8.5 mmHg to 50 mmHg.

Preferably, the apparatus of the present invention is operated under the transmembrane pressure difference range of 40 to 20 mmHg. By doing so, the plasma separation rate, that is, the rate of separating plasma from blood through the separation membrane can be maximized.
The transmembrane positive pressure difference means the transmembrane pressure difference which is the difference between the high pressure on the whole blood side of the filter and the low pressure on the plasma side of the same filter.

To prove this, an experiment was carried out using dogs. Dogs were used because dog blood resembles human whole blood, which has a normal protein content, so the results of experiments conducted using dog blood suggest that human blood should be processed. This is because it can be an index of the effectiveness of all the methods of the present invention. At any rate, blood was extracted from dogs in each experiment, and the extracted blood was processed by the apparatus shown in FIG. 1 under the above-mentioned conditions.
The pressure on the plasma side of the filtration membrane was atmospheric pressure, and the device according to the present invention was used as it was considered to be a so-called open system. The method according to the invention was applied to 3 normal dogs for a total of 7
Circulated. Of these, the N-type plasma filter was used three times and the S-type filter was used the remaining four times as the separator 13 shown in FIG.

Both the N type filter and the S type filter are hollow fiber type filters made of cellulose acetate sold by Asahi Medical Co., Ltd., having an inner diameter of 370 μm and a wall thickness of 190 μm.
It has a porosity of 84% and a nominal pore size of 0.2 μm.
However, between N type and S type, the number of fibers of N type is 2500 and the effective length is 240 m.
m, the surface area is about 0.7 m ² , while the S type has 3300 fibers and an effective length of 2
They are different in that they have a diameter of 00 mm and a surface area of 0.75 m ² .

The tubing used to connect the dog to the separator and to interconnect the individual components of the separator is sold under the trademark "LifeMed" by LifeMed Deviation, Inc. of Bernitron, USA. I used the one. Before operating the separation device, 40 ml of blood was filled in advance. Blood was extracted from dogs from the femoral artery or carotid artery and then returned to the femoral vein or jugular vein. At that time, FC-100 cannula sold by Extracopolyol Co., USA was used. In treating the blood of each dog, 2 mg / kg heparin (AH Robbins) was injected before the start of the experiment, and 0.5 mg / kg / hr heparin was injected in the rest of the experiment. Heparin was systematically added to the blood.

Further, by operating the pump 10, the amount of blood supplied to the separator was maintained at 100 ml / min. This pump 10 is a roller pump manufactured by Drake-Walcock Co., Ltd., and the above-mentioned blood supply amount of 100 ml / min is sufficient to make the flow velocity along the membrane approximately 25 to 40 cm / min. It was The separation rate, the pressure at the inlet and outlet of the separator, and the pressure at the inlet and outlet of the adsorption cartridge were measured periodically. The transmembrane pressure difference and the flow rate are plotted in the graph of FIG. From the plot of each measured value,
The curve drawn in order to show the tendency found experimentally is the curve in the figure, which is also plotted when the transmembrane pressure difference exceeds 50 mmHg to obtain one curve.

From the above, when the fluid is separated by the separator, unlike the normal state in which the flow of the filtrate passing through the filter decreases with the decrease of the transmembrane pressure difference,
As is clear from the graph of FIG. 2, according to the present invention, the amount of plasma separated through the separation membrane is lower than the pressure value which was conventionally considered to be the minimum transmembrane pressure difference when performing plasma separation. It is clear that it increases from that point and reaches the maximum value when the transmembrane pressure difference reaches 30 mmHg. In view of this graph, transmembrane pressure differences suitable for achieving maximum plasma separation from normal whole blood are just below 50 mm Hg to about 8.
It is clear that maximum efficiency is obtained in the range of 5 mmHg, especially in the range of about 40 to about 20 mmHg.

When the plot of the minimum transmembrane pressure difference on the data is seen, the plasma flow rate approaches the maximum, but the minimum transmembrane pressure difference of 8.5 mmHg on the data achieves this maximum plasma flow rate. Not an accurate pressure value. In other words, since the low pressure pulsating roller pump is used and the characteristics and measurement error of the measuring instruments used for various measurements are also related, it is not possible to accurately know the pressure of 10 mmHg or less. . As the model name indicates, a pump does not operate at a steady pressure in the first place, and the maximum discharge pressure and the minimum discharge pressure have a difference of 10 mmHg which is customary for separating plasma from blood. May be accompanied. Therefore, each plot on the data was obtained by taking the average value of the pump pressure. Therefore, when the pump pressure is low, it may be somewhat below the average value, which may be about 3.5 mm Hg.

Moreover, the pressure gauge used is at least ± 2
It had an error of mmHg. In addition, the pressure of the fluid at the pressure measurement point also fluctuated, and in fact, the height of the mercury column constantly fluctuated during the measurement. Variables such as these errors are not important for the high transmembrane pressure difference, but cannot be ignored below 10 mmHg. In view of the above, it is possible that the transmembrane pressure difference may even be a positive pressure value close to zero, and even with such a transmembrane pressure difference close to zero, a higher plasma pressure than that generally expected. The flow rate can be obtained. From the above, the method according to the present invention is 50 mmHg
It can be performed under a positive pressure of less than. Furthermore, from the above, 8.5 mmHg, which is the minimum transmembrane pressure difference in the data, is only an approximate value, and in fact, it may even be a much lower positive pressure. For this reason, in the present specification and claims, “about” 8.5 mmHg ”is described, but this is 8.5 m.
It should be understood to include positive pressures below mHg.

From the above, when the fluid is separated by the separator, unlike the normal state in which the flow of the filtrate passing through the filter decreases with the decrease of the transmembrane pressure difference,
As is clear from the graph of FIG. 2, according to the present invention, the amount of plasma separated through the separation membrane is lower than the pressure value which was considered to be the lowest transmembrane pressure difference in the conventional plasma separation. It is clear that it increases from that point and reaches the maximum value when the transmembrane pressure difference reaches 30 mmHg. From this graph, it is found that the transmembrane pressure difference suitable for separating plasma from normal whole blood is just less than 50 mmHg, and especially about 40-
It is clear that maximum efficiency is obtained in the range of about 20 mmHg.

[0032]

As described in detail in the above embodiments, the present invention is
As a method of separating plasma from normal whole blood, whole blood is
A pore size suitable for separating plasma from the whole blood is 0.1 to 0.
The pressure difference between the membranes was just less than 50 mmHg, and only the blood plasma was allowed to permeate through the separation membrane consisting of hollow fibers having a large number of 6 micron pores. By supplying whole blood at a relatively high pressure, Compared with the conventional method of permeating plasma, it is possible to increase the separation efficiency of plasma, and as a result, to obtain blood in which plasma components are appropriately treated and bubbles are removed. The object can be effectively achieved with a simple configuration.

[Brief description of drawings]

FIG. 1 is a schematic view of an example of a plasma separation device used in the plasma separation method of the present invention.

FIG. 2 is a graph showing the plasma separation rate with respect to the transmembrane pressure difference.

[Explanation of symbols]

 10 ... Blood supply pump 13 ... Separator 18 ... Plasma reservoir 20 ... Three-way valve 21 ... Processor 22 ... Particle filter.

 ─────────────────────────────────────────────────── ─── Continuation of the front page (72) Inventor Paul S. Marcheski United States Ohio 44077, Plainsville Township, Burlington Ridge 239

Claims (1)

[Claims] 1. A blood processing method for separating plasma from blood and then processing the plasma, wherein blood preliminarily forcibly pressurized by a blood supply means has a pore size of 0.1. The separation membrane is formed by continuously supplying the hollow fiber type separation membrane made of a porous material of ˜0.6 μm along one surface at a flow rate of 5-1500 cm / min, and at the same time adjusting at least the supply pressure of the blood. The transmembrane pressure difference of just 5
While maintaining the pressure below 0 mmHg, the plasma contained in the blood is forcedly permeated through the separation membrane, and thereafter, the plasma separated from the blood in the separation membrane is sequentially processed by a processor.
A blood treatment method, characterized in that the plasma treated by the treatment device and the blood passing through the plasma separation device are brought together by a bubble trap.