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1. WO2019115482 - FILTRE SANGUIN MOULÉ PAR INJECTION À RÉSISTANCE RÉDUITE

Note: Texte fondé sur des processus automatiques de reconnaissance optique de caractères. Seule la version PDF a une valeur juridique

[ EN ]

INJECTION-MOLDED BLOOD FILTER WITH REDUCED RESISTANCE

FIELD

The following relates generally to the immunoassay arts, blood filtering arts, injection molding arts, and related arts.

BACKGROUND

Existing point of care cartridges for handheld immune-assay testing of blood include a separate section containing a paper filter for the removing the red blood cells from the blood sample and releasing the resulting plasma towards the reaction chambers.

Recently, a potentially more cost effective and reliable solution for the filtering of the blood sample has been developed based on the injection molding on the cartridge of cylindrical pillars in a dedicated fluidic channel. By using an agent that causes aggregation of the red blood cells, red blood cell clusters are formed that are trapped by the filter structure. However, this flow path can become progressively clogged, thus negatively affecting the flow rate of plasma from the filter.

The following discloses new and improved systems and methods to overcome these problems.

SUMMARY

In one disclosed aspect, a device for filtering red blood cells includes a main body having at least one inlet and at least one outlet, a filtering region extending through the main body from the inlet to the outlet, and a filter including pillars disposed in the filtering region and grouped into islands. The pillars of each island have inter-pillar spacings effective to trap red blood cells. The islands have inter-island spacings that are larger than the inter pillar spacings. The islands are distributed in the filtering region to define tortuous flow paths between the islands from the inlet to the outlet.

In another disclosed aspect, a blood processing device includes a cell including a plate having fluidic passages defined in the plate of passage size effective to transport blood through the fluidic passages by capillary action, and a cover plate disposed on the plate and sealing the fluidic passages. The fluidic passages include a red blood cell filtering region having an inlet and an outlet. The red blood cell filtering region includes pillars grouped into islands. The pillars of each island have inter-pillar spacings effective to trap red blood cells. The islands have inter-island spacings that are larger than the inter-pillar spacings. The islands are distributed in the red blood cell filtering region to define tortuous flow paths between the islands from the inlet to the outlet.

In another disclosed aspect, a blood processing device manufacturing method includes: injection molding a plate having fluidic passages defined in the plate, wherein the fluidic passages include a red blood cell filtering region with pillars grouped into islands in the red blood cell filtering region, the pillars of each island having inter-pillar spacings, the islands having inter-island spacings that are larger than the inter-pillar spacings; and securing a cover plate onto the plate to seal the fluidic passages and form a cell.

One advantage resides in providing a cost-effective blood filtering device.

Another advantage resides in providing a red blood cell filtering device to effectively filter red blood cells from blood.

Another advantage resides in providing a red blood cell filtering device with decreased time needed to filter blood for an assay.

Another advantage resides in providing a red blood cell filtering device with reduced likelihood of clogging.

Another advantage resides in providing a red blood cell filtering device with one or more of the foregoing benefits which is integrated with a blood plasma assay device.

Another advantage resides in providing a device including pillars grouped into islands, in which inter-pillar spacings are less than inter-island spacings to trap red blood cells while decreasing a time needed to filter the red blood cells.

A given embodiment may provide none, one, two, more, or ah of the foregoing advantages, and/or may provide other advantages as will become apparent to one of ordinary skill in the art upon reading and understanding the present disclosure.

BRIEF DESCRIPTION OF THE DRAWINGS

The disclosure may take form in various components and arrangements of components, and in various steps and arrangements of steps. The drawings are only for purposes of illustrating the preferred embodiments and are not to be construed as limiting the disclosure.

FIGURE 1 diagrammatically shows a plan view of a device for filtering red blood cells according to one aspect.

FIGURES 2A and 2B diagrammatically show a blood processing device including the device of FIGURE 1 , shown in side view (FIGURE 2 A) and plan view (FIGURE 2B); and

FIGURE 3 illustratively shows an example operation of making the device of

FIGURE 1.

PET ATT ED DESCRIPTION

This disclosure relates to a filter for removing red blood cells from a blood sample prior to performing immunoassay. In filter designs employing an injection molding on the cartridge of cylindrical pillars in a dedicated fluidic channel, the blood flow through the filter and the plasma flow towards the cartridge chambers is driven by capillary action. The fluid flow speed, and therefore also the time to fill the cartridge chambers is predominantly determined by the resistance of the blood flow in the filter section. For that reason, the inter-pillar distance should be large enough to provide sufficiently low flow resistance for the red blood cell filtering to be completed on a practical time scale of a few minutes or less. On the other hand, this distance should be small enough so that an effective collection of the agglomerated blood cells can take place. In practice the resistance of the blood flow in the filter is found to increase strongly due to the accumulation of blood cell agglomerates in the filter during the filtering process. This leads to an unacceptably long filtering time between the deposition of the blood sample and the filling the cartridge chambers for the assay (dependent on the hematocrit value of the blood it might be up to hours). This is much longer than the typical time available for the assay (i.e., less than ten minutes). Decreasing the length of the path through the filter would lead to larger flow rates but also to smaller filter efficiency, which results in plasma having too many red blood cells. Widening the structure would be not be cost effective because the number of pillars would increase the manufacturing costs. Furthermore, there is a limit to the sample size (e.g., based on blood volume).

In some illustrative embodiments disclosed herein, the red blood cell filter is integrated with an immunoassay cartridge. This cartridge is an injection-molded structure having a channel plate with channels and reaction chambers defined, and a cover plate that seals with the channel plate to seal those channels/chambers. Blood is introduced at one end, and is drawn by capillary action into the channels and chambers. The filter is integrated as an inlet channel that includes pillars, along with a chemical agent promoting red blood cell aggregation which is coated onto the channel surface prior to sealing with the cover plate. The filter operates as follows: red blood cell aggregations form as the blood moves through the filtering region via capillary action. The clusters (aggregations) of red blood cells are trapped at or between the pillars, while the remaining plasma (possibly including other blood

components such as white blood cells and platelets) continues to flow and enters the reaction chambers for immunoassay.

However, difficulties exist with this approach, in that the agglomerates of red blood cells can introduce excessive resistance to the capillary action-driven flow, which in turn can introduce unacceptable delay on the order of greater than 10 minutes between deposition of the blood sample and filling of the reaction chambers of the cartridge.

A solution disclosed herein is to arrange the pillars into islands with larger flow paths between the islands. The islands are arranged so that the flow paths are tortuous, so that the flow interacts with the islands so as to trap red blood cell agglomerates. In general, the pillar spacing within each island is uniform (although in other contemplated embodiments this could also be a design parameter) and is smaller than the inter-island spacing (i.e., corresponding to the widths of the flow paths). For example, the pillar spacing may be at a minimum value at a center area of an island and increases gradually towards outer borders of the island. This design advantageously provides some decoupling of the flow resistance parameter (controlled to first order by the inter-island spacing and the tortuous shape of the paths between the islands) and the red blood cell trapping efficacy (controlled to first order by the inter-pillar spacing within the islands).

Optionally, the concentration of islands, and hence the inter-island spacing, can be non-uniform, with density increasing (i.e., inter-island spacing decreasing) downstream along the flow. This has the effect of trapping larger red blood cell agglomerates first with minimal impact on flow resistance, then removing the smaller agglomerates further downstream where the lower overall density of red blood cells provides reduced impact on flow resistance.

As another variant, the island size can be adjusted along the flow. In general, at least the inter-pillar spacing, inter-island spacing, and island size may be design parameters for optimizing the red blood cell filtering balanced against minimizing the introduced flow resistance.

In embodiments disclosed herein, an injection molded red blood cell filter is provided in which the spacing between the pillars is not uniform, but rather is arranged in a non-uniform structure, typically with the pillars grouped into groups referred to herein as islands, with tortuous paths between the islands. The filter is designed to contain areas inside or at the peripheries of the islands where the pillar spacing is small enough to collect the agglomerated blood cells, however the tortuous paths have a lower density of pillars or no pillars at all. In that way, a residual blood flow path is sustained during the gathering of the red blood cells avoiding excessive blockage of the blood flow through the filter. As a result, the resistance of the blood flow can be limited to not surpass a certain resistance value.

To effectively filter out red blood cells, the spacing between the islands should be optimized to reduce the resistance of the filter. This spacing can be optimized by widening a channel between the pillars; reducing a channel length between the pillars, resulting in shorter filtering times and larger flow rates. These spacings may be designed in such a way so as to have minimal impact on tool costs (e.g., related to the total number of pillars), area on the cartridge footprint, a maximum sample input volume, or plasma quality in terms of the amount of remaining red blood cells.

In embodiments disclosed herein, a blood filtering device includes pillars, which are grouped into islands. The pillars in each island are spaced apart by inter-pillar spacings that are small enough to trap red blood cell agglomerates at (or between) the pillars of the island. The islands, in turn, are spaced apart by larger inter-island spacings so that tortuous flow paths are defined between the islands. The tortuous shape of the paths forces the red blood cells to interact with the islands while still providing flow paths between the islands to avoid clogging of the filter.

With reference to FIGURE 1, an illustrative device 10 for filtering red blood cells is shown. It will be appreciated that FIGURE 1 shows a plan view of the device 10. As shown in FIGURE 1, the device 10 includes a main body 12 made up of an injection molded plate into which fluidic channels are formed, with a cover plate (see side view of FIGURE 2). The fluidic channels include at least one inlet 14 disposed on a first side (e.g., a“left” side as shown in FIGURE 1) of the main body and at least one outlet 16 disposed on an opposing second side (e.g., a“right” side as shown in FIGURE 1). The fluidic channels further include a filtering region 18 that extends through the main body 12 from the inlet 14 to the outlet 16, so that blood can enter the filtering region 18 via the inlet 14 and exit via the outlet 16. While a single inlet 14 and single outlet 16 are shown in FIGURE 1, more than one inlet and/or more than one outlet are also contemplated. A filter 20 is disposed in the filtering region 18. The filter 20 includes pillars 22 disposed in the filtering region 18. In some illustrative embodiments, the pillars 22 have a size in a range between 10 pm and 500 pm inclusive, preferably between 30 pm and 200 pm.

The pillars 22 are grouped into islands 24 within the filtering region 18. Each island 24 can include a suitable number of pillars 22. For example, as shown in FIGURE 1, some islands 24 can include three or less pillars 22, while others can include four or more pillars 22. In some illustrative embodiments, the islands 24 have a size in a range between one to several tens or several hundredths of pillars 22. For example, the islands 24 can typically include 10 to 300 pillars 22, and thus have a size ranging between 100 pm - 5,000 pm to 3000 pm to 150,000 pm. The size of the islands 24 should be smaller than a total width of the main body 12 of the device 10, so that at least one continuous tortuous flow path exists between the inlet 14 and the outlet 16.

The islands 24 are distributed in the filtering region 18 to define tortuous flow paths 26 (denoted by arrows in FIGURE 1) between the islands from the inlet 14 to the outlet 16. In some examples, the islands 24 are distributed in the filtering region 18 to create alternating stacks of low and high density channels to define the tortuous flow paths 26.

As shown in FIGURE 1, the pillars 22 of each island 24 have an inter-pillar spacing A effective to trap red blood cells (RBCs), which are drawn into the device 10 via the inlet 14 by capillary action. The inter-pillar spacings are small enough to trap aggregations of the red blood cells RBCs at (or between) the pillars of the island. In some illustrative embodiments, the inter-pillar spacings (A) (e.g., in regions within the islands 24) are in a range between 10 pm and 30 pm inclusive. In some embodiments, the inter-pillar spacing A can be selected to be non-uniform. This arrangement allows for transporting red blood cells RBCs can be separated from areas in the filtering region 18 in which the blood cells are being collected.

The islands 24 have inter-island spacings B that are larger than the inter-pillar spacings A. The inter-island spacings B are larger than the inter-pillar spacings A so that the tortuous flow paths 26 are defined between the islands 24, which forces the red blood cells to interact with the islands while following the tortuous paths between the islands to avoid clogging of the filter 20. The inter-island spacings B are effective to not trap red blood cells in the tortuous paths 26. This enables decoupling of the design of the flow resistance, which is controlled to first order by the design of the tortuous paths 26 (e.g. widths, extent of twisting/turning) from the design of the trapping of the red blood cell agglomerates, which is controlled to first order by the design of the islands 24 (e.g. number of pillars per island, inter pillar spacing A, island sizes). Moreover, as the red blood cell agglomerates are principally trapped at the islands 24, the tortuous paths 26 remain substantially free of trapped red blood cells so that the trapped red blood cell agglomerates do not substantially impede blood flow, i.e. the trapped red blood cell agglomerates do not strongly impact the flow resistance. In some illustrative embodiments, the inter-island spacings B are at least 100 pm.

In some embodiments, the inter-island spacings B decrease along the tortuous flow paths 26 from the inlet 14 to the outlet 16. Advantageously, this arrangement allows a

large amount of red blood cells RBCs to pass between the islands 24 arranged closer to the inlet 14. Once the filtered blood contains fewer red blood cells RBCs, the filtered blood passes through this higher concentration of islands 24, to effectively remove the remaining red blood cells. The filtered blood can more quickly move through the remaining portion of the flow paths 26 towards the outlet 16, advantageously decreasing the amount of time necessary to get the filtered blood out of the device 10.

In other embodiments, sizes of the islands 24 increase along the tortuous flow paths 26 from the inlet 14 to the outlet 16. _Advantageously, this arrangement allows the larger islands 24 disposed closer to the outlet 26 to trap remaining RBCs that have not yet been captured by the islands disposed closer to the inlet 14.

In further embodiments, a red blood cell aggregating agent 28 disposed on at least one surface of the filtering region 18. The agent 28 facilitates the capture of RBCs by the islands 24. The agent 28 can be any suitable red blood cell aggregating agent.

With reference to FIGURES 2A and 2B, and with continuing reference to FIGURE 1 , an illustrative blood processing device 30 for filtering red blood cells is shown. The blood processing device 30 includes a cell 32 including a plate 34 having fluidic passages defined in the plate, and a cover plate 36 (shown in phantom, i.e. by dashed lines, lifted away from the plate 34 and only shown in the side view of FIGURE 2A). The fluidic passages are of a size effective to transport blood through the fluidic passages by capillary action. The cover plate 36 covers and seals the fluidic passages. The fluidic passages include the red blood cell filtering region 18, the inlet 14, and the outlet 16. In some examples, the red blood cell filtering region 18 comprises the device 10. The red blood cell filtering region 18 (or the device 10) includes the pillars 22 (grouped into islands 24, as described above) disposed in the filtering region 18. The pillars 22 may or may not touch or contact the cover plate 36, but preferably at least come close enough to the cover plate 36 (when it is secured to the plate 34) so that red blood cells have a high probability to agglomerate proximate to the gap (if any) between the tops of the pillars 22 and the cover plate 36. As described above, the pillars 22 of each island 24 having inter-pillar spacings A effective to trap red blood cells. The islands 24 have inter island spacings B that are larger than the inter-pillar spacings A. The islands 24 are distributed in the red blood cell filtering region 18 to define the tortuous flow paths 26 (one of which is diagrammatically shown in FIGURE 2B) between the islands from the inlet 14 to the outlet 16.

FIGURES 2A and 2B also shows the fluidic passages including at least one (illustrative three) reaction chamber region 38. Each reaction chamber region 38 is in fluid communication with an outlet 16 of the filtering region 18. Each reaction chamber region 38

contains at least one blood assay reagent that reacts with the (at least mostly) plasma exiting from the filtering region 18 via the outlet 16 to perform a clinically useful blood assay or test. The agent 38 can be any suitable blood assay agent. As the filtered blood (typically wholly or mostly plasma but optionally including other components such as white blood cells, platelets, and/or so forth) exits the filtering region 18 via the outlet 16, the reagent reacts with the filtered blood so as to perform an immunoassay procedure.

With continuing reference to FIGURES 1 and 2A and 2B, and with reference to FIGURE 3, an illustrative embodiment of a blood processing device manufacturing method or process 100 is diagrammatically shown as a flowchart. At 102, the plate 34 is injection molded. The injection molding can be performed with any suitable injection molding process, and operates to form the plate with the fluidic channels 14, 16, 18, 38 with the filtering region 18 including the pillars 22 on a surface thereof. The pillars 22 are grouped into islands 24 on the surface. The pillars 22 of each island 24 include inter-pillar spacings A. The islands 24 include inter-island spacings B that are larger than the inter-pillar spacings A so that tortuous flow paths 26 defined between the islands 24 forces the red blood cells RBCs to interact with the islands while still providing the larger tortuous paths between the islands to avoid clogging of the filtering region 18.

At 104, after the injection molding operation 102, a red blood cell aggregating agent 28 is disposed onto a surface of the plate 34. Alternatively, it is contemplated for the RBC aggregating agent to be coated onto the cover plate 36. The red blood cell aggregating agent 28 facilitates the capture of RBCs by the islands 24.

At 106, the cover plate 36 is secured to the plate 34 to form a cell 32. The cover plate 36 covers, and preferably seals, the fluidic passages 14, 16, 18, 38 except for an opening (not shown) to inject blood into the inlet 14 and, optionally, an opening at or connected with the reaction chamber(s) 38 to enable drawing blood through the fluidic passages by capillary action. Capillary action is produced by plasma flow out of the cell 32 via the fluidic channels 14, 16, 18, 38 with the filtering region 18.

The disclosure has been described with reference to the preferred embodiments. Modifications and alterations may occur to others upon reading and understanding the preceding detailed description. It is intended that the invention be construed as including all such modifications and alterations insofar as they come within the scope of the appended claims or the equivalents thereof.