阅读说明：本技术 体内灌注系统 (Intracorporeal perfusion system ) 是由 C.安德烈塔 于 2018-05-02 设计创作，主要内容包括：一种可植入的灌注装置(2),包括管状输送管线(4),其具有入口端(6)、出口端(8)和位于两者之间的流量限制元件(10),由此,在入口端和流量限制元件之间限定输送管线的入口部段(12),在流量限制元件和出口端之间限定传输管线的出口部段(14)。而且,该装置包括含有一定装载量的生物活性细胞的灌注室(16),并设有流体入口(18)、流体出口(20)和在其间形成的室容积(22)。所述流体入口包括至少一个第一微通道薄片(24),并且所述流体出口包括至少一个第二微通道薄片(26),每个微通道薄片包括至少一个微通道阵列(28),其在各自的外部和内部薄片面之间限定流体通路,所述微通道具有0.2至10μm的开口。灌注室的流体入口(18)与输送管线的入口部段(12)流体连通；并且,流量限制元件(10)构造成在入口部段(12)中建立相对于出口部段(14)预定的压力超过量。(An implantable perfusion device (2) comprising a tubular delivery line (4) having an inlet end (6), an outlet end (8) and a flow restriction element (10) therebetween, whereby an inlet section (12) of the delivery line is defined between the inlet end and the flow restriction element and an outlet section (14) of the delivery line is defined between the flow restriction element and the outlet end. Furthermore, the device comprises a perfusion chamber (16) containing a load of biologically active cells and provided with a fluid inlet (18), a fluid outlet (20) and a chamber volume (22) formed therebetween. The fluid inlet comprises at least one first microchannel sheet (24) and the fluid outlet comprises at least one second microchannel sheet (26), each microchannel sheet comprising at least one microchannel array (28) defining a fluid passageway between respective outer and inner sheet faces, the microchannels having openings of 0.2 to 10 μm. The fluid inlet (18) of the perfusion chamber is in fluid communication with the inlet section (12) of the transfer line; and, the flow restriction element (10) is configured to establish a predetermined pressure excess in the inlet section (12) relative to the outlet section (14).)

1. An implantable perfusion device (2) comprising:

-a tubular transfer line (4) having an inlet end (6), an outlet end (8) and a flow restriction element (10) therebetween, whereby an inlet section (12) of the transfer line is defined between the inlet end and the flow restriction element and an outlet section (14) of the transfer line is defined between the flow restriction element and the outlet end,

-a perfusion chamber (16) comprising a fluid inlet (18), a fluid outlet (20) and a chamber volume (22) formed therebetween;

the perfusion chamber contains a load of biologically active cells;

the fluid inlet comprises at least one first microchannel sheet (24), the fluid outlet comprises at least one second microchannel sheet (26), each microchannel sheet comprising at least one microchannel array (28) defining a fluid passageway between respective outer and inner sheet faces, the microchannel having an opening of 0.2 to 10 μm;

each microchannel sheet is sealingly connected to a circumferentially surrounding wall portion (62) of the perfusion chamber;

wherein the content of the first and second substances,

-the fluid inlet (18) of the perfusion chamber is in fluid communication with the inlet section (12) of the transfer line;

and wherein

-the flow restriction element (10) is configured to establish a predetermined pressure excess in the inlet section (12) relative to the outlet section (14).

2. The infusion device according to claim 1, wherein a fluid outlet (20) of the infusion device is in fluid communication with the outlet section (14) of the delivery line.

3. The perfusion device of claim 1, wherein the fluid outlet (20) of the perfusion device is configured for delivering fluid to a interstitial body region.

4. Perfusion apparatus according to any one of claims 1 to 3, further comprising control means for controlling the restriction characteristics of the flow restriction element (10).

5. A perfusion device according to claim 4, wherein the control means comprises a driven reciprocating plug member (54).

6. Perfusion device according to any one of claims 1 to 5, further comprising supply means (38, 40, 42) for supplying a liquid reagent to the chamber volume (22).

7. A perfusion device according to claim 5 or 6, wherein the supply means comprises a pair of one-way valves which cooperate with a reciprocating plug member (54) which acts on a section of the fluid line connecting the pair of valves.

8. Perfusion apparatus according to one of claims 1 to 7, further comprising means (30, 32, 34, 36) for loading and unloading a cell population into and from the chamber volume (22).

9. Perfusion device according to one of claims 1 to 8, wherein the fluid inlet and/or the fluid outlet (58) comprise a plurality of micro-channel sheets (60).

10. Perfusion device according to one of claims 1 to 9, wherein the microchannel sheet is made of Si and/or Si₃N₄And (4) preparing.

11. Perfusion apparatus according to one of claims 1 to 10, wherein the microchannel sheet is sealingly connected to a circumferentially surrounding wall portion of the perfusion chamber by anodic bonding.

12. Perfusion apparatus according to one of claims 1 to 11, wherein the tubular delivery line (4) is provided at its inlet and outlet ends with means for connection to the artery and vein, respectively, of the patient.

13. Perfusion device according to one of claims 1 to 11, wherein the bioactive cells loaded in the perfusion chamber are islets of Langerhans Cells (LC).

Technical Field

The present invention generally relates to an in vivo perfusion system. More particularly, the present invention relates to an implantable perfusion device containing a load of biologically active cells.

Background

According to the data of the world health Organization, the prevalence of diabetes in adults over 18 years of age worldwide in 2014 is estimated to be 9% (Global status report on non-communicative diseases 2014.Geneva, world health Organization, 2012). Treatment of diabetes involves lowering the levels of blood glucose and other known risk factors that damage blood vessels. For patients with type 1 diabetes, as well as for patients with advanced type 2 diabetes, the necessary intervention includes administration of insulin. Due to inevitable variations in external influencing factors, and often due to lack of continence, the glucose level in the blood often fluctuates widely, which may lead to many complications of the vascular and nervous systems. Insulin pumps have become increasingly popular for such patients. Most of these pumps continuously release insulin in a low dose basal dose, which can be increased as needed, especially before meals. In order to optimize the use of insulin pumps, there is an urgent need for a system with continuous or periodic monitoring of blood glucose levels.

The combination of an insulin pump and a suitable control system relying on feedback signals from a blood glucose monitoring system can be considered a "medical technology" variant of an artificial pancreas. Such a combination of a glucose measuring module and an insulin pump has been disclosed, for example, in WO 2004/110256a 2. Optimal control of such a device is a challenge, as can be appreciated from, for example, WO 2014/109898a1, which describes a model-based personalized approach to an artificial pancreas for type I diabetes applications.

Another type of artificial pancreas, which is more structurally similar to a real pancreas, is based on implanted bioengineered tissue, which contains islet cells that deliver endocrine insulin in response to glucose. One concept of this bio-artificial pancreas is to use encapsulated islet cells to form an islet sheet suitable for surgical implantation into a patient. The islet tablet typically comprises the following components: (1) an internal network of supporting fibers forming a sheet-like structure; (2) a plurality of islet cells encapsulated to avoid triggering an immune response and adhering to the reticular fibers; (3) a semi-permeable protective layer around the sheet which diffuses nutrients and hormones secreted by islet cells; (4) a protective overcoat to prevent foreign body reactions.

US 2002/0151055a1 discloses a bioartificial pancreas comprising live and physiologically active islet cells capable of producing insulin encapsulated within a semipermeable spherical membrane comprising an agar gel. The artificial pancreas may be mounted in a diffusion chamber or perfusion chamber containing hollow fibers. An exemplary perfusion device consists of a membrane inside an acrylic housing through which blood flows axially, while the islets secrete insulin into the blood radially. Such a perfusion-based bioartificial pancreas has been disclosed in US 5741334.

One significant difficulty encountered when operating a bioartificial pancreas of the type described above is related to the requirement for a sufficiently large and sustainable rate of mass transfer into and out of the encapsulated islet cells. On the one hand, it must be ensured that the islet cells are supplied with a sufficient supply rate of nutrients and, of course, that a corresponding removal rate of the insulin produced by the islet cells is ensured. On the other hand, the composition of the bioartificial pancreas needs to have constant characteristics over a long period of time. In particular, any clogging or collapse of the semipermeable protective layer should be avoided.

Disclosure of Invention

It is therefore an object of the present invention to provide an improved system suitable for operating as a bioartificial pancreas, which does not have the above-mentioned disadvantages.

According to one aspect of the present invention, there is provided an implantable perfusion device comprising:

a tubular transfer line having an inlet end, an outlet end and a flow restriction element therebetween, thereby defining an inlet section of the transfer line between the inlet end and the flow restriction element and an outlet section of the transfer line between the flow restriction element and the outlet end,

-a perfusion chamber comprising a fluid inlet, a fluid outlet and a chamber volume formed therebetween;

the perfusion chamber contains a load of biologically active cells:

the fluid inlet comprises at least one first microchannel sheet and the fluid outlet comprises at least one second microchannel sheet, each microchannel sheet comprising at least one microchannel array defining a fluid passageway between respective outer and inner sheet faces, the microchannels having openings of 0.2 to 10 μm;

each microchannel sheet is sealingly connected to a circumferential wall portion of the perfusion chamber.

Wherein the content of the first and second substances,

-the fluid inlet of the perfusion chamber is in fluid communication with the inlet section of the transfer line;

and wherein the one or more of the one,

the flow restriction element is configured to establish a predetermined pressure excess in the inlet section relative to the outlet section.

In this document, the singular forms used for expressing some features should be understood to include the possibility of having plural features that achieve technically equivalent effects. In particular, the term "perfusion chamber" shall also apply to embodiments in which a plurality of chambers effectively cooperate as a single functional unit.

The perfusion chamber is configured to contain the biologically active cells in a closed environment while ensuring adequate transport of substances into and out of the chamber. For this purpose, the microchannel sheets forming the fluid inlet and the fluid outlet of the perfusion chamber provide a suitable filtering function. Thus, the optimum size of the microchannel will depend on the particular application. Typically, it will be selected in the range of 0.2 to 10 μm. The lower limit is determined primarily by the available molding techniques, but is also determined as needed to have sufficient throughput. The upper limit is determined by the particle size that should be prevented from passing through the microchannel. For many applications, the opening of the microchannel should be in the range of 0.9 to 2.2 μm, most typically about 1.6 μm. In the case of microchannels having a circular cross-section, the term "opening" is to be understood as a diameter. For non-circular microchannels, the term "opening" is to be understood as the smallest transverse dimension of the cross-section. Currently available techniques for forming openings having the above-described diameter ranges typically require a height to diameter ratio ("aspect ratio") of up to 5. In other words, the thickness of the microchannel sheet in the region surrounding the microchannels needs to be sufficiently small, i.e. in the range of 1 to 50 μm, depending on the diameter of the microchannels. To provide sufficient rigidity of the front sheet, a reinforced region of significantly greater thickness is provided at a location offset from the microchannel.

In order to meet the basic requirements for cell containment, each microchannel sheet of the device is sealingly connected to a circumferentially surrounding wall portion of the perfusion chamber. The term "circumferentially" does not mean circular, but merely to define a closed loop as desired to form an uninterrupted seal along the edge of the sheet.

The perfusion device is intended to be implanted in a human or a mammal such that the tubular delivery line forms a so-called Arteriovenous (AV) shunt connecting the artery and the vein. For example, the device may be implanted in the forearm of a human patient. The large pressure difference between the arterial and venous systems can cause pressure gradients along the delivery line. This pressure gradient tends to drive arterial blood into the transfer line at its inlet end and out of the transfer line at its outlet end. The presence of the perfusion chamber in fluid communication with the tubular delivery line effectively forms a branch of the blood. Thus, as explained in further detail below, a flow of a portion of the blood through the perfusion chamber occurs, i.e., the blood flows into the perfusion chamber through its fluid inlet and exits the perfusion chamber through its fluid outlet. After leaving the perfusion chamber, the blood is either reintroduced into the tubular delivery line or allowed to flow into other body areas. For convenience, the flow path directly through the delivery line will hereinafter be referred to as the "AV stream", while the blood flow occurring through the perfusion chamber will be referred to as the "perfusion stream". The branching ratio between the perfusion flow and the AV flow is determined by the ratio of the flow conductances of the two paths, according to the flow dynamics of the substantially incompressible fluid.

The tubular transfer line typically has an opening of the order of a few millimeters, i.e. somewhere in the range of about 2 to about 10mm, in particular about 3 to 8mm, without any substantial flow restriction, its conductance is greater than the conductance through the perfusion chamber, which passes through a pair of microchannel sheets, thereby forming a fluid inlet and a fluid outlet of the perfusion chamber. Therefore, in order to establish a sufficient perfusion flow, the AV stream needs to be reduced by providing a flow restriction element of appropriate size. In practice, the flow restriction element can achieve a pressure build-up of about 100mbar in the inlet section of the conveying line.

The implantable perfusion devices of the present invention are generally intended to contain biologically active cells that produce one or more useful substances, hereinafter also referred to as "cell products", to be provided to a host organism in need thereof. To achieve this, the perfused cells should have a volume large enough to accommodate the appropriate number of cells. Furthermore, the perfusion flow for ensuring a proper supply rate of nutrients and a proper removal rate of cellular products needs to be sufficiently large. In a typical configuration, the chamber volume of the perfusion chamber may be a few milliliters, e.g., about 5 to 6 milliliters, containing about 5000 ten thousand cells per milliliter. By having a flat and elongated dimension of a length of up to about 10cm, the perfusion chamber may have a few hundred mm²The total area of the microchannel.

As used herein, the term "biologically active cells" is to be understood in a broad sense. In particular, such biologically active cells may be obtained as classically differentiated cells starting from human stem cells and applying suitable genetic or non-genetic differentiation mechanisms. Alternatively, they may be provided as transplanted cells, i.e., as xenografted cells, including bacteria (as the case may be), or as autologous or allogeneic human cells.

Advantageous embodiments are defined in the dependent claims and are described below.

According to one embodiment (claim 2), the fluid outlet of the perfusion device is in fluid communication with the outlet section of the delivery line. In other words, the perfusion flow is directed back into the AV flow at a position downstream of the flow restriction element. This means that the cellular product is delivered into the venous blood stream.

It is contemplated that the cellular product may be delivered to a specific area or organ, in which case the perfusion flow would have to be directed by appropriate means.

In another embodiment (claim 3), the fluid outlet of the perfusion device is configured for delivering a fluid to the interplastid region. Thus, the device is implanted in such a way that the microchannel sheets forming the fluid outlet are in direct contact with the surrounding tissue. This embodiment is considered useful, for example, for testing animals.

Advantageously (claim 4), the device further comprises means for controlling the restriction characteristics of the flow restriction element. In particular, this may comprise a flow restriction element having a movable member controlled by a suitable steering unit. In this way, a controlled change in flow restriction can be achieved, accompanied by a change in the ratio of perfusion and AV flow. In one embodiment, the flow restriction operates in an oscillating manner, which may be an on-off scheme having fully open and fully closed positions. It is contemplated that the on-off scheme may have a duty cycle, i.e., a ratio of "on" to "off" times that is different than 1. An important advantage of having a controllable flow restriction is related to the adverse side effects caused by the uninterrupted, unimpeded blood flow from the artery to the vein, which can lead to hand tingling.

According to one embodiment (claim 5), the control means comprise a driven reciprocating plug member, the plug cooperating with a suitably formed counterpart acting as a seat. For example, the plug member may be a bar magnet which is movable bidirectionally in the channel-like counterpart and is driven by an external magnet performing a cyclic motion.

In many applications it is advantageous, or even necessary, to provide certain anticoagulants, such as heparin or citrate. Thus, according to a further embodiment (claim 6), the device further comprises means for supplying a liquid reagent to the chamber volume. Such a device may comprise a suitable container, which may be configured as a subcutaneous injection port, a supply line connecting the container and the perfusion chamber, and a suitable pumping means. In some embodiments, the inner surface of the implantable perfusion device is provided with an anticoagulant coating, such as a heparin coating.

According to a particularly advantageous embodiment (claim 7), the supply means comprise a pair of non-return valves cooperating with a reciprocating plug member acting on a fluid line segment connecting said pair of valves. In other words, a reciprocating plug driven by an external magnet, for example, may be used both to produce intermittent perfusion flow regulation and to pump a liquid medicament such as citrate through the perfusion chamber.

In some cases, particularly when used on test animals for relatively short days or up to weeks, the perfusion apparatus may be operated with an initial load of viable cells. However, in most applications, fresh viable cells must be provided. Therefore, according to an advantageous embodiment (claim 8), the perfusion apparatus further comprises means for loading and unloading the cell population into and from the container. These may be realized as subcutaneously implantable injection ports equipped with a tubing forming a connection to the perfusion chamber and also provided with a suitable valve.

An important factor for achieving efficient operation of the perfusion apparatus is having a sufficiently large total area of the microchannels. However, it is impractical to produce very large microchannel sheets given the inevitable production failures that result in channels of occasional over-size. Obviously, a single oversized channel would result in lost cell containment and is therefore unacceptable. Thus, according to an advantageous embodiment (claim 9), the fluid inlet and/or the fluid outlet comprises a plurality of micro-channel lamellae. With this modular design, which utilizes multiple small sheets rather than a single large sheet, failure of a single channel requires only discarding a relatively small unit of the entire surface.

Advantageously, the microchannel sheetMade of a material suitable for lithographic processing, is a very convenient technique for forming narrow structures with well-defined shapes. Thus, according to an advantageous embodiment (claim 10), the microchannel sheets are made of silicon (Si) and/or silicon nitride (Si)₃N₄) And (4) preparing. Furthermore, at least the circumferentially surrounding wall portion of the perfusion chamber is made of a material which is compatible with the material of the front sheet and has advantageous properties with respect to any fluid connection to be attached thereto. From Si and Si₃N₄Suitable sandwich structures made of layers are generally known in the field of microtechnology. In some embodiments, the microchannel sheet is functionalized, i.e. provided with a suitable coating. The type and thickness of such a coating will depend on the particular application. For contact with blood, functionalization is known which aims at preventing the formation and coagulation of blood clots.

According to an advantageous embodiment (claim 11), the microchannel sheets and the circumferentially surrounding wall portion are bonded to each other by anodic bonding. In particular, the method allows for the formation of a strong and moderately tight connection between Si and the glass structure. Alternatively, the connection may be formed by means of an adhesive.

Suitable locations and configurations for implantable infusion devices are the straight forearm (radial to cephalic vein), the circular forearm (brachial artery to cephalic vein), and the straight upper arm (brachial artery to basilic vein or axillary vein). Further possibilities are thigh grafts, neck grafts (axillary artery to axillary vein) and axillary atrial grafts. Thus, according to an advantageous embodiment, the tubular delivery line is provided at its inlet end and outlet end with means for connection to the artery and vein, respectively, of the patient (claim 12). Preferably, these are releasable connecting means. This embodiment will allow the tubular line of the device, typically made of biocompatible thermoplastic with advantageous formability, to be connected to the corresponding part consisting of a synthetic graft tube connected to the artery or vein of the patient. Such graft tubes are typically made of Polytetrafluoroethylene (PTFE).

As already mentioned, the perfusion device is suitable for use with a load of biologically active cells, which may be selected according to the specific task to be achieved. According to one embodiment, the bioactive cells contained in the perfusion chamber are islets of Langerhans Cells (LC). It will be appreciated that in this case the cell product will be insulin and thus the perfusion apparatus may be implemented to form part of an artificial pancreas apparatus.

Drawings

The above-mentioned and other features and objects of this invention, and the manner of attaining them, will become more apparent and the invention itself will be better understood by reference to the following description of various embodiments of the invention taken in conjunction with the accompanying drawings, wherein:

fig. 1 shows a first embodiment of a fluid interface device in cross-section;

FIG. 2 illustrates a second embodiment of a fluid interface device in cross-section;

FIG. 3 illustrates a third embodiment of a fluid interface device in cross-section;

fig. 4 shows a fourth embodiment of a fluid interface device in cross-section;

FIG. 5 is a perspective view of the middle section of the first embodiment;

FIG. 6 shows a portion of FIG. 6 in a top view;

FIG. 7 shows a portion of FIG. 6 in cross-section;

FIG. 8 shows a portion of FIG. 6 in a longitudinal cross-sectional view;

fig. 9 shows an intermediate section of a fifth embodiment in a perspective view;

FIG. 10 shows a portion of FIG. 9 in a top view;

FIG. 11 shows a portion of FIG. 10 in longitudinal cross-section;

FIG. 12 shows the portion of FIG. 10 in a cross-sectional view according to section A-A of FIG. 10;

FIG. 13 shows the portion of FIG. 10 in a cross-sectional view according to section B-B of FIG. 10; and

fig. 14 shows the arrangement of 5 x 4 microchannel sheets in a top view.

Detailed Description

It will be understood that the figures are not necessarily to scale. In some cases, the relative dimensions may be significantly distorted for easy viewing.

The perfusion apparatus 2 shown in fig. 1 is implanted as a shunt between an artery a and a vein V and comprises a tubular delivery line 4, the delivery line 4 having an inlet end 6, an outlet end 8 and a flow restriction element 10 therebetween. As shown in fig. 1, the flow restriction element 10 defines on the left an inlet section 12 between the inlet end 6 and the flow restriction element 10, and it further defines an outlet section 14 between the flow restriction element and the outlet end 8. The flow restriction element 10 is used to establish a predetermined pressure overshoot in the inlet section 12 relative to the outlet section 14.

The device also has a perfusion chamber 16 that includes a fluid inlet 18, a fluid outlet 20, and a chamber volume 22 formed therebetween. In the example shown, the perfusion chamber actually comprises an upper part and a fully equivalent lower part, which, for the sake of simplicity, is not provided with a reference numeral and is not discussed further here.

The fluid inlet comprises a first microchannel sheet 24 and the fluid outlet comprises a second microchannel sheet 26, each of these sheets comprising an array of microchannels 28 defining a fluid passageway between respective outer and inner sheet faces. As can also be seen from fig. 1, the fluid inlet 18 of the perfusion chamber is in fluid communication with the inlet section 12 of the transfer line.

In the example shown in fig. 1, the fluid outlet 20 of the perfusion device is configured for delivering a cell product fluid formed in the chamber volume 22 to the interstitial tissue located between the artery a and the vein V.

The perfusion apparatus 2 shown in fig. 2 has many of the features already discussed with reference to fig. 1, and it does not require further discussion. Unlike the embodiment of fig. 1, however, the fluid outlet 20 of the perfusion apparatus opens into the outlet section 14 of the delivery line. Thus, the cell product formed in the chamber volume 22 is directed through the outlet section 14 and into the venous blood flow.

The perfusion apparatus 2 shown in fig. 3 corresponds to the embodiment shown in fig. 2 and further comprises means for loading and unloading the cell population into the chamber volume 22. These means include a loading line 30 and an unloading line 32, each provided with suitable valves, schematically indicated 34 and 36 respectively.

The perfusion apparatus 2 shown in fig. 4 still corresponds to the embodiment shown in fig. 2 and further comprises means for supplying a liquid reagent, such as a citrate solution, to the chamber volume 22. These means include a container 38, a supply line 40 connecting the container 38 and the perfusion chamber 22, and a suitable pumping device 42.

In practice, the two embodiments of fig. 3 and 4 are typically implemented together, and are shown separately here only for ease of drawing.

An embodiment intended for delivery to the interstitial tissue is shown in more detail in fig. 5 to 8, while an embodiment intended for delivery to the venous blood flow is shown in more detail in fig. 9 to 14. Any features already explained above will generally not be discussed again; in some cases, they are denoted only by the corresponding reference numerals.

The device 2 shown in fig. 5 to 8 is characterized by an elongated, substantially cylindrical shell 44 forming an intermediate section of the tubular delivery line 4, which has an inlet section 12 and an outlet section 14. Housing 44 houses two perfusion chambers 16a and 16b located in a symmetrical manner on opposite sides of the delivery line. Each perfusion chamber comprises a first microchannel sheet 24 adjacent to the transfer line and a second microchannel 26 substantially parallel to and radially displaced from the first microchannel sheet. Thereby, a chamber volume 22 is formed between the two sheets. As also shown particularly in fig. 7, each microchannel sheet is sealingly connected to a wall portion of the housing. In particular, a first wall portion 46 connected to the first microchannel sheet 24 and a second wall portion 48 connected to the second microchannel sheet 26 are joined together in a sandwich manner at a contact region 50.

The device 2 shown in figures 9 to 12 comprises an elongate, substantially elliptical-cylindrical housing 52. The entire device is configured in a relatively flat shape which allows the construction of a relatively long microchannel area, thereby providing a large fluid exchange surface with a large perfusion flow rate. The device has a cell loading line 30 and a cell unloading line 32 of flattened shape, each provided with a suitable valve 34 and 36 respectively.

Fig. 12 shows the flow path of the device configured in a three-compartment manner. Arterial blood supplied via the tubular delivery line 4 is located in the innermost first compartment from which it can flow through the first microchannel sheet 24 into the perfusion chamber 22, the perfusion chamber 22 forming a second compartment containing a population of viable cells. From the second compartment, the blood containing the cell product flows through the second microchannel sheet 26 into the exit section 20, the exit section 20 forming a third compartment communicating with the outlet section 14 of the device.

Fig. 13 shows the working principle of the controllable flow restriction element 10. The flow restriction element 10 includes a pair of reciprocating plug members 54, each containing a permanent magnet. Each plug member is reciprocable between a retracted position (as shown) and an inserted position (not shown) in which the plug pushes inwardly and compresses a section of the tubular delivery line 4. The reciprocating motion is caused by a disc-shaped external magnet 56 rotating about the axis R. In the example shown, plug member 54 also acts as a squeezing member for the flexible section of anticoagulant supply line 40, which is located between a pair of one-way valves (not shown) having a common flux direction.

As can be seen from fig. 14, the chamber walls 58, which serve as fluid inlets or fluid outlets, are formed by a plurality of microchannel lamellae 60, which in the example shown are arranged in a 4 x 5 matrix. Each lamella is sealingly connected to a circumferentially surrounding wall portion 62 of the chamber wall.