SYSTEM FOR RAPID ANALYSIS OF A CAPILLARY BLOOD SAMPLE FROM A SUBJECT, INTENDED FOR DETECTING THE PRESENCE OF AT LEAST ONE ANALYTE IN SAID CAPILLARY BLOOD SAMPLE

Disclosed is a system for rapid analysis of a capillary blood sample from a subject, intended for detecting the presence of at least one analyte in the capillary blood sample. The rapid analysis system includes an analysis module in which is incorporated at least one immunochromatographic strip. The analysis module includes: a pricking member, suitable for generating a drop of capillary blood; and a collecting member, including a fixed duct, suitable for capillary blood to flow therethrough. The duct has an inlet suitable for collecting the drop of capillary blood, and an outlet, arranged opposite the deposition area and suitable for depositing the drop of capillary blood onto the deposition area, and a container, separate from/independent of the analysis module, in which is packed a buffer solution suitable for implementing the immunochromatographic technique.

TECHNICAL FIELD OF THE INVENTION

The present invention relates to the technique field of systems for rapid analysis of a capillary blood sample from a subject, intended for detecting the presence of at least one analyte in said capillary blood sample.

STATE OF THE ART

A rapid diagnostic test, also known as a “rapid screening test”, is a test that rapidly establishes (within a few minutes) the presence of at least one analyte of interest in a biological sample.

This approach conventionally uses the phenomena of chemical reactions using immunochromatography on strips (also known as the “lateral flow test”), which produce a specific colouring for immediate interpretation of the result.

This technique has for interest to be simple, rapid and low cost. Moreover, such tests can be used in the doctors office, but also at the patient's bedside or in the field.

In practice, an immunochromatography strip is conventionally implanted in a box (also called “cassette”) that is adapted to receive biological samples in liquid form.

To detect the presence of at least one analyte in a capillary blood sample, the rapid analysis system has to also include the following elements:a pricking member, suitable for generating a drop of capillary blood,a collecting member, suitable for collecting said drop of capillary blood then depositing this drop of capillary blood on an deposition area of the strip, anda buffer solution suitable for implementing the immunochromatographic technique.

Generally, these different elements of the analysis system are independent, requiring may manipulations.

There however exist analysis modules that integrate such elements as an “all-in-one” device.

Such devices are in practice rather interesting and of simple use. However, they have in particular the drawback of taking up a lot of space for manipulations near the patient.

It would thus be interesting to propose a new rapid analysis system that combines the above-mentioned elements, while preserving simplicity of use and optimized footprint.

DISCLOSURE OF THE INVENTION

In order to remedy the above-mentioned drawback of the state of the art, the present invention proposes a new system for rapid analysis of a capillary blood sample from a subject, intended for detecting the presence of at least one analyte in said capillary blood sample.

More particularly, the invention proposes a rapid analysis system comprising:(i) an analysis module into which is incorporated at least one immunochromatographic strip, designed to detect the presence of said at least one analyte by an immunochromatographic technique,wherein said at least one immunochromatographic strip includes a deposition area intended to receive said capillary blood sample and a capture area intended to detect the presence of said at least one analyte, wherein said analysis module includes:a pricking member, suitable for generating a drop of capillary blood, anda collecting member, comprising a fixed duct, suitable for capillary blood to flow therethrough,said duct having an inlet suitable for collecting said drop of capillary blood, and an outlet, arranged opposite said deposition area and suitable for depositing said drop of capillary blood onto said deposition area, and(ii) a container, separate from/independent of said analysis module, in which is packed a buffer solution suitable for implementing said immunochromatographic technique.

Other non-limiting and advantageous features of the product according to the invention, taken individually or according to all the technically possible combinations, are the following:the analysis module has an elongated shape, delimited by two ends; the pricking member is implanted at a first end of said analysis module, and the collecting member is implanted at a second end of said analysis module;the collecting member also includes a through-hole suitable for receiving the buffer solution, arranged opposite the deposition area, advantageously, as the case may be, in said at least one connecting part and opposite the deposition window; the through-hole advantageously includes an annular surface delimited by an inlet edge and an outlet edge, connected by a flared annular surface; preferably, the duct outlet leads to the through-hole; the duct advantageously has a gutter shape, whose downstream outlet is cantilevered/protruding with respect to the through-hole;the analysis module includes a gripping portion, arranged near the pricking member, advantageously on the connecting part.

According to a preferred embodiment, the analysis module includes a cassette into which is incorporated said at least one immunochromatographic strip; the pricking member and the collecting member are assembled to said cassette through assembly means, for example through fitting means.

Other non-limiting and advantageous features of this preferred embodiment according to the invention, taken individually or according to all the technically possible combinations, are the following:the pricking member and the collecting member are carried by at least one connecting part, advantageously forming an adapter, which cooperate with the cassette through said assembly means;the pricking member and the collecting member are carried by a single connecting part, which includes means for assembly to the cassette, or two distinct connecting parts, each including means for assembly to the cassette;the pricking member cooperates with said at least one connecting part through assembly means;the cassette has two front walls that are connected by a lateral wall, wherein a first front wall includes two windows, a deposition window, arranged opposite the deposition area of said at least one immunochromatographic strip, and a reading window, arranged opposite the capture area of said at least one immunochromatographic strip, and said at least one connection part has at least a front wall placed on said first front wall of the cassette and a skirt placed on said lateral wall of the cassette; preferably, the pricking member is implanted opposite and in the continuation of the lateral wall of the cassette.

The present invention also relates to the analysis module for a system for rapid analysis of a capillary blood sample from a subject, intended for detecting the presence of at least one analyte in said capillary blood sample.

The analysis module incorporates at least one immunochromatographic strip, designed to detect the presence of said at least one analyte by an immunochromatographic technique.

Said at least one immunochromatographic strip includes a deposition area intended to receive said biological sample and a capture area intended to detect the presence of said at least one analyte.

Said analysis module includes:a pricking member, suitable for generating a drop of capillary blood, anda collecting member, comprising a fixed duct, suitable for capillary blood to flow therethrough, said duct having an inlet for collecting said drop of capillary blood, and an outlet for depositing said drop of capillary blood onto said deposition area.

The analysis module is devoid of container in which is packed a buffer solution suitable for implementing said immunochromatographic technique.

Of course, the different features, alternatives and embodiments of the invention can be associated with each other according to various combinations, insofar as they are not mutually incompatible or exclusive.

It is to be noted that, in these figures, the structural and/or functional elements common to the different alternatives may have the same references.

The rapid analysis system1according to the invention, described in relation with the figures, is suitable for rapid analysis of a capillary blood sample E (also called “drop of capillary blood”) from a subject, intended for detecting the presence of at least one analyte A in said capillary blood sample E.

By “detecting”, it is meant qualitative determination (advantageously the presence or the absence), or even quantitative determination, of one or several analytes A in the capillary blood sample E.

By “analyte”, it is meant any chemical, biochemical or biological entity, that is desired to be detected in a capillary blood sample E.

This chemical entity advantageously consists of an entity from the living world, preferably present in humans.

Among the analytes detected by the system and method according to the present invention, mention may be made to proteins, peptides, antibodies, hormones, steroids, antigens derived from infectious agents or tumour cells, infectious agents such as bacteria, viruses or parasites, nucleic acids (DNA or RNA), therapeutic compounds, drugs or antibiotics.

Said at least one analyte A is still preferably selected among the antigens specific of an infectious agent.

By “infectious agent”, it is preferably meant viruses, in particular viruses responsible for pneumopathies, advantageously Coronaviridae, still preferably Orthocoronavirinae or coronaviruses.

By “capillary blood sample”, it is meant a mixture of blood from arterioles, venules, capillaries and interstitial and intracellular fluid, obtained by capillary puncture.

Such a sample is advantageously obtained by pricking the skin, generally on the finger or the heel.

For that purpose, the rapid analysis system1according to the invention comprises:(i) an analysis module2into which is incorporated at least one immunochromatographic strip4(visible inFIG.3) for analysing the capillary blood sample E, and(ii) a container5, separate from/independent of said analysis module2, in which is packed a buffer solution51suitable for implementing the immunochromatographic technique.

According to the invention, the analysis module2also includes:a pricking member7, suitable for generating a drop of capillary blood, anda collecting member8, suitable for collecting said drop of capillary blood and suitable for depositing said drop of capillary blood on the immunochromatographic strip4.

In other words, the analysis module2forms a device including at least one support part, or even an assembly of at least two support parts, advantageously made of a plastic material, which carries said at least one immunochromatographic strip4, the pricking member7and the collecting member8.

Generally, and according to a preferred embodiment, the analysis module2has an elongated shape, advantageously a generally parallelepiped shape.

This analysis module2is delimited by two ends21,22, which are longitudinally opposite to each other.

This analysis module2also advantageously has an upper side23that includes at least one through-hole24in communication with said at least one immunochromatographic strip4.

The pricking member7and the collecting member8are advantageously distributed at the two ends21,22of the analysis module2:the pricking member7is implanted at a first end21of the analysis module2, andthe collecting member8is implanted at a second end22of the analysis module2.

It is then just necessary to turn the analysis module2upside down to generate the drop of capillary blood then to collect the latter.

Generally, according to the invention, the analysis module2is devoid of container5in which is packed a buffer solution51suitable for implementing the immunochromatographic technique.

This technical feature contributes to an optimum footprint of the analysis module2.

The analysis module2also advantageously includes a gripping portion25, arranged near the pricking member7and at the upper side23, advantageously carried by a connecting part10that will be described hereinafter.

This gripping portion25is useful for handling the analysis module2, in particular when the pricking member7is used.

The immunochromatographic strip4, also called “capillary diffusion means”, is designed to detect the presence of said at least one analyte A by an immunochromatographic technique.

These immunochromatographic strips4are formed of any means constituting or acting as a unit of continuous capillary diffusion, by lateral migration (i.e. perpendicular to the thickness of the capillary material(s) implemented for the capillary diffusion).

This capillary diffusion means advantageously consists of a porous solid support enabling the migration of a liquid by simple capillary diffusion.

The porosity of this support enables the capillary diffusion (or lateral migration) of the sample and/or the reagents at the liquid or wet state.

Such capillary diffusion means are very widely used, in particular in all the lateral-migration immunochromatographic techniques.

Such an immunochromatographic strip4here consists of a support elongated along the direction and/or orientation of the capillary diffusion (lateral migration).

The immunochromatographic strip4can be consisted of:a single and same capillary or porous material, orseveral different capillary or porous elements or materials, suitably arranged with respect to each other (for example, with overlap), to obtain a continuity of capillary flow from an element or a material to another, along the capillary diffusion direction.

Such an immunochromatographic strip4determines a direction and orientation of capillary diffusion of any liquid that is received or deposited at an upstream end, and that then moves towards a downstream end of the immunochromatographic strip4.

By way of example, the immunochromatographic strip4can be consisted of various immunochromatographic supports, for example cellulose, nylon, nitrocellulose, polyethylene or glass fibre.

As described in relation withFIG.3, the immunochromatographic strip4includes different successive areas, in the upstream to downstream capillary migration direction, i.e. at least:a deposition area41, intended to receive the capillary blood sample E and the buffer solution51,a release area42, which comprises at least one detection reagent conjugated with a visible and/or measurable marker, said detection reagent being capable of moving due to the migration of the buffer solution51along the immunochromatographic strip4, andat least one capture area43that comprises at least one capture reagent, immobilized on the immunochromatographic strip4, to detect said at least one analyte A.

The deposition area41and/or said at least one capture area43are advantageously accessible through at least one through-hole24arranged in the upper side23of the analysis module2.

In other words, the upper side23of the analysis module2advantageously includes:a first through-hole241, opposite said at least one capture area43, for reading the analysis, anda second through-hole242, opposite said deposition area41, for depositing the capillary blood sample E and the buffer solution51.

The release and capture areas advantageously consist of a transverse line or strip (extending perpendicular to the migration direction), having for example a width between 1 and 2 mm and a surface between 3 and 5 mm2.

Generally, the “detection reagent” or the “capture reagent” consist of any chemical, biochemical or chemical entity, which is capable of binding specifically to form a complex enabling the determination of said analyte in the capillary blood sample E.

The detection reagent and/or the capture reagent are also so-called “binding” reagents.

Such binding reagents, enabling the determination of at least one analyte in the capillary blood sample E, are well known and can be selected as required for implementing the invention.

These binding reagents are advantageously selected from those which are capable of binding specifically with said analyte and/or of binding specifically with each other.

According to the test format implemented, the complementary binding reagents are intended to form different complexes:the binding reagents are capable of binding concomitantly with the analyte, to form a sandwich format test, orone of the binding reagents (detection or capture) is capable of binding to the analyte but also to the other binding reagent (respectively, capture or detection) to form a test in the competition format.

By “binding” or “bond”, it is advantageously meant any weak bond of the antigen/antibody type.

The binding reagents are advantageously selected from antibodies and antigens.

The analyte and the binding reagent thus typically form a couple capable of binding specifically with each other, as for example an antigen/antibody couple.

Therefore, if the analyte is an antigen or hapten, one at least of the binding reagents (the detection reagent and/or the capture reagent) is advantageously an analyte-specific antibody.

By “analyte-specific antibody”, it is meant an antibody capable of binding specifically with the analyte into a bond of the antigen/antibody type.

It is typically a polyclonal antibody or a monoclonal antibody, having a strong affinity with the analyte. Preferably, it is a monoclonal antibody.

If the analyte is an antibody, one at least of the binding reagents is advantageously the antigen recognised by the antibody.

The detection reagent(s) are advantageously conjugated to a visible and/or measurable marker, advantageously a particulate marker.

By “visible and/or measurable marker”, it is meant any marking enabling a direct or indirect detection with the naked eye, or using an apparatus, due to the emission of a signal at said at least one capture area43.

The signal is for example a fluorescence, a colouration, the presence of an isotope or a magnetic signal.

Examples include coloured particle markers such as colloidal gold, or fluorescent markers, coloured latex particles, fluorescent latex particles and the avidin and streptavidin conjugated particles.

Particulate markers, coloured or fluorescent, thus consist of small particles that are insoluble in water and therefore form suspensions, dispersions or solutions in liquid phase.

Among the markers allowing a direct naked-eye observation, mention can also be made to dextran-type markers (Hansen T. M., IVD Technology 4, 35-40, 2003). The binding reagent is then conjugated to a dextran chain (polysaccharide derivative) carrying fluorophores.

The markers can also consist of enzymes (in particular, alkaline phosphatase or AP, horseradish peroxidase or HRP), dyes or chemiluminescent compounds (in particular, fluorescein isothiocyanate or FITC).

To increase the sensitivity, a labelled antibody can be used, for example, according to techniques known by the person skilled in the art for indirect detection, such as for example a biotinylated antibody, allowing indirect detection by the formation of avidin-biotin and streptavidin-biotin entities.

This labelled and biotinylated antibody can also either be already directly deposited on a test-line, in the capture area, to increase the sensitivity, or be deposited with the specific detection antibody, to increase the time of contact and also the sensitivity, in particular, for example, due to the number of binding sites.

For its part, in the capture area43, the analyte-specific capture reagent is immobilized on the solid support by techniques known by the person skilled in the art.

This capture reagent is immobilized in such a way that it is not mobile when wet.

This immobilisation may be made for example by absorption or by covalent coupling.

In the system according to the figures, the detection reagents and the capture reagents are selected among the reagents suitable for detect the presence of said at least one analyte selected among the antigens, preferably specific of an infectious agent, preferably viruses, in particular viruses responsible for pneumopathies, advantageously Coronaviridae, still preferably Orthocoronavirinae or coronaviruses.

The detection reagents and the capture reagents are advantageously selected, without being in any way limiting, among:antibodies, advantageously selected among the anti-IgG antibodies (human) and the anti-IgM antibodies (human), preferably directed against the SRAS-Cov-2,antibodies specific of a micro-organism, advantageously of a virus, preferably SRAS-Cov-2, andadapted recombinant proteins.

In a preferred embodiment, the capture area43can also comprise a control capture reagent.

This control capture reagent provides a positive control to ensure the effective capillary diffusion of the liquid sample from the deposition area41to the capture area43.

This control capture reagent is permanently immobilized downstream from the “analyte” capture reagents (“Control line”).

It may be for example an antibody binding to the detection reagent(s).

As an alternative, this control capture reagent is independent of the analyte A and is simply used to check the diffusion of the liquid sample along the immunochromatographic strip4(for example by capture of a marked control reagent).

Buffer Solution

The buffer solution51is suitable for rinsing the collecting member8of the analysis module2and being mixed with the capillary blood sample E for implementing the immunochromatographic technique.

This buffer solution51is in particular intended for migrating along the chromatographic strip4in such a way as to cause, or at least facilitate, the migration of the capillary blood sample E (and in particular of said at least one analyte A).

The buffer solution51is for example selected among the diluents composed of a buffered saline solution. It can also comprise a detergent or any other component necessary in particular for the migration or the reactions on the immunochromatographic strips4.

To control the added quantity of this buffer solution51, the buffer solution51is advantageously packaged in a container5which includes a dropper.

Pricking Member

The pricking member7, also called “self-prick” or “lancet”, is conventional per se and single-use.

It advantageously consists of a single-use device serving to prick or puncture the skin, comprising a surgical blade or a needle that retracts irreversibly after use.

Such a pricking member7is suitable for generating a capillary blood flow at the pricking point.

Such a pricking member7is advantageously suitable for making a transcutaneous pricking, advantageously of 2.2 to 2.5 mm depth, generally on the lateral edges of the fingertip or on the heel.

Collecting Member

The collecting member8comprises a fixed duct81, suitable for capillary blood to flow therethrough.

By “fixed”, it is advantageously understood a duct81that is immobile on the collecting member8, with an identical position for collecting the drop of capillary blood and for depositing this drop of capillary blood on the immunochromatographic strip4.

The duct81includes two ends:an inlet811, suitable for collecting the drop of capillary blood, andan outlet812, arranged opposite the deposition area41of the immunochromatographic strip4and suitable for depositing the drop of capillary blood onto this deposition area41.

The capillary blood sample is thus intended to flow naturally, advantageously by capillarity and/or by gravity along the duct81, from the inlet811to the outlet812.

The duct81is advantageously suitable for collecting a volume of capillary blood suitable for the analysis, for example of the order of 10 μL.

The duct81has here advantageously a gutter or channel shape, with advantageously a generally U or V-shaped cross-section, having advantageously an upper longitudinal opening (opening away from the immunochromatographic strip4).

This embodiment is interesting for rinsing the duct81with the buffer solution51.

The collecting member8also advantageously includes a through-hole82suitable for receiving the buffer solution51, arranged opposite the deposition area41of the immunochromatographic strip4and advantageously leading to the outlet812of the duct81.

This through-hole82advantageously corresponds to the above-mentioned second through-hole242, arranged in the upper side23of the analysis module2.

The through-hole82can take different shapes, adapted to the passage of the buffer solution51.

According to an embodiment illustrated inFIG.5, the through-hole82advantageously has an annular surface823delimited by two edges:a circular inlet edge821, anda circular outlet edge822.

The two edges821,822are connected by a flared annular surface823, for example in the shape of a truncated cone, the cross-section of which increases from the outlet edge822(small diameter) to the inlet edge821(great diameter).

Such a through-hole82, in the general shape of a funnel, is useful for facilitating/concentrating the supply of buffer solution51to the deposition area41.

Preferably, the outlet812of the duct81leads to the through-hole82. This approach is interesting for rinsing the duct81with the buffer solution51.

The downstream outlet812of the duct81is advantageously cantilevered/protruding with respect to the through-hole82and in particular the outlet edge822thereof (see in particularFIG.3).

This shape advantageously ensures an optimum deposition of the sample, without contact with the outlet812of the duct81.

The duct81advantageously extends further along the flared annular surface823, between these two edges821,822.

This arrangement also contributes to optimizing its rinsing with the buffer solution51.

The inlet811of the duct81advantageously protrudes with respect to the through-hole82(and protrudes with respect the upper side23of the analysis module2), to facilitate the collection of the capillary blood sample E.

Pricking Member and Collecting Member Assembled to a Cassette

As illustrated inFIG.4in particular, the analysis module2advantageously includes a cassette3into which is incorporated said at least one immunochromatographic4.

This cassette3is advantageously formed by an assembly of at least two support parts, forming a casing, which are made of a plastic material.

Within this framework, the pricking member7and the collecting member8are advantageously assembled to this cassette3through assembly means9, for example through fitting means (advantageously through elastic fitting means), which are advantageously carried by a connecting part10described hereinafter.

The pricking member7and the collecting member8thus advantageously form accessories that are added on the cassette3.

This embodiment has for interest to be able to provide additional functions to a cassette3, which may be conventional per se, in such a way as to enable the analysis of capillary blood samples without requiring the implementation of a combination of distinct devices.

The cassette3of the analysis module2has advantageously a generally parallelepiped, elongated shape, delimited by two ends31,32(longitudinally opposite to each other).

The cassette3advantageously includes two front walls33,34that are connected by a peripheral lateral wall35.

The first (advantageously upper) front wall33advantageously includes two windows:a deposition window37, arranged opposite the deposition area41of said at least one immunochromatographic strip4, anda reading window38, arranged opposite the capture area43of said at least one immunochromatographic strip4.

For the assembly thereof, the pricking member7and the collecting member8are advantageously carried by at least one connecting part10, advantageously forming an adapter adapted to be assembled to the cassette3.

Said at least one connecting part10then cooperates with the cassette3through the above-mentioned assembly means9.

Generally, the pricking member7and the collecting member8can be carried by:a single connecting part10, which includes means9for assembly to the cassette3(FIGS.1to6), ortwo distinct connecting parts10, each including means9for assembly to the cassette3(FIGS.7and8).

A single connecting part10is advantageously intended to cooperate with the two ends31,32of the cassette3.

In the presence of two distinct connecting parts10(FIGS.7and8), the pricking member7and the connecting part8are advantageously each carried by one of said connecting parts10:a first connecting part101carries the pricking member7, anda second connecting part102carries the connecting part8.

These two connecting parts101,102are then intended to be placed at one of the two ends31,32of the cassette3, respectively.

Generally, said at least one connecting part10advantageously includes different walls intended to conform the cassette3, i.e. at least:a front wall105that is placed on the first front wall33of the cassette3, anda skirt106that is placed on the lateral wall35of the cassette3.

In the case of a single connecting part10, the front part105advantageously includes a through-hole1051intended to come opposite the reading window38of the cassette3, to form together the first through-hole241opposite said at least one capture area43for reading the analysis.

Moreover, the through-hole82of the collecting member8, arranged opposite the deposition area41, is here advantageously arranged through the connecting part10(in particular its front wall105) and opposite the deposition window37of the cassette3.

In other words, the front part105advantageously includes a through-hole1052intended to come opposite the reading window37of the cassette3, to form together the second through-hole242opposite said at least one deposition area41.

Generally, the assembly means9can consist of fitting means, for example elastic fitting means (for example, ribs), arranged between said at least one connecting part10and said cassette3.

As shown inFIG.3, the assembly means9can also consist of at least one additional and lower added part, which cooperate with said at least one connecting part10to form together a casing enveloping the cassette3.

The cassette3is then sandwiched between the front wall105of the connecting part10and the underlying, additional added part9.

Moreover, the pricking member7advantageously consists of an added part, cooperating with said at least one connecting part10through assembly means11(FIG.3), for example elastic assembly means.

The assembly means11for the pricking member7may also be formed by the above-mentioned added part9(seeFIG.3).

The pricking member7is advantageously implanted opposite and in the continuation of the lateral wall35of the cassette3, on the side of the first end31of said cassette3(at the opposite of the deposition window37).

This pricking member7advantageously extends in the longitudinal continuation of the cassette3and in the thickness of the cassette3, ensuring a minimum thickness.

Implementation

In practice and as the case may be, the analysis module2is assembled before implementation.

In that respect, the pricking member7and the collecting member8(carried by at least one connecting part10) are advantageously added on the cassette3containing said at least one immunochromatographic strip4.

The analysis module2is then handled in such a way as to generate a drop of capillary blood by means of the pricking member7that is arranged at a first end21of the analysis module2(item A. ofFIG.6).

A capillary blood sample is then collected by means of the collecting member8that is arranged at the second end22of this same analysis module2(item B. ofFIG.6).

The sample then automatically/naturally flows to the immunochromatographic strip4, via the duct81.

Thereafter, a suitable quantity of the buffer solution51is added through the through-hole82of the collecting member8that is provided for that purpose, by means of the container5that is separate from/independent of the analysis module2(item C. ofFIG.6).

Finally, after a suitable time for the migration of the buffer solution51, for example from 10 to 20 minutes, the reading of said at least one chromatographic strip4is made at the capture area43of said at least one immunochromatographic strip4, through the first through-hole241, to detect the potential presence of said at least one analyte A in said biological sample E (item D. ofFIG.6).

The reading may be made directly (with the naked eye) or through a reading apparatus.

Obviously, various other modifications may be made to the invention within the framework of the appended claims.