It is well known that biological samples from patients undergoing clinical tests are frequently taken at retrieval sites spread over the territory, near to the locality where the patients live or work, and transported - even for long distances - to an analysis site to be subject to pre-established clinical analysis. A plurality of biological samples acquired at a retrieval station is stored in respective collection units (for example, test tubes for blood samples), generally combined in certified containers for the safe transport of biological material relative to any risk of spreading, and transported from the retrieval station to an analysis station. The transport of samples is an important pre-analytical step, wherein the samples may be exposed to pre-analytical conditions defined by various transport parameters, including environmental parameters such as temperature, humidity and light conditions, and dynamic parameters, including handling and shocks, which can cause changes in certain physical, chemical or biological properties, which to some extent affect the results of the clinical analysis to which samples are finally subjected. This creates problems in that a sample that has not been transported in accordance with the necessary recommendations and guidelines may have suffered damage or major structural changes that may affect the quality of the biological samples themselves and the outcome of the relative clinical analysis, with the production of the results correct from an analytical point of view, but, being performed on altered samples, not representative of the in vivo condition, and therefore artifacts.

Below are some of the factors that, due to non-compliant pre-analytical conditions, can cause damage to the samples taken and their range of influence: Hemolysis: affects tests on potassium, glucose, LDH and in general all the tests affected by the rupture of red blood cells;

Formation of cellular aggregates: affects all hematological tests and coagulation studies;

- Exposure to light: in general, all substances suffer the effects of light exposure, in particular vitamins, bilirubin and the cell wall;

Vibrations: involve the rupture of the cell wall and chemical bonds;

Centrifugation speed: is a stage of processing the samples that occurs in the laboratory and during which cytolysis and sample heating take place;

- Heating by centrifugation: involves hemolysis and coagulation;

Heat: involves the activation of coagulation, agglutinins, and a change in state of protein molecules;

Time: each of the causes described above have different effects at different times of the pre-analytical step;

- Location of the collecting vessel: influences the amplitude of the surface of the biological material in contact with the air, which causes the activation of coagulation factors;

It is therefore necessary to define transport criteria in order not to expose biological samples to pre-analytical conditions that affect the reliability of the results of clinical analysis on these samples, and it is desirable to determine whether, and to what extent, these criteria are met.

WO 2004/108968 describes the execution of quality control on biological samples and a system for monitoring such pre-analytical variables.

The document describes a quality evaluation step for the samples taken that may take place before or at the same time as the clinical essay. The quality of a sample may be assessed before running a clinical test on the sample so that one may decide not to run the clinical test if the quality of the sample is not acceptable. This approach may provide significant savings of resources, and - with an independent quality evaluation step for each sample - a laboratory is able to monitor samples that usually do not have sufficient quality, and take remedial measures to obtain and preserve the sample in such cases.

It is, however, desirable also to be able to correlate the pre-analytical conditions, typically the transport conditions in a pre-analytical step, with the results of the clinical analysis of the biological samples.

One object of the present invention is therefore to propose a system and a method during the pre-analytical step for quality control of biological samples intended for clinical investigations.

More particularly, it is an object of the invention to assess the quality of the transport service, and the quality of the manipulation to which the biological samples are subjected, including separation and centrifugation, and relating the damage shown by the samples to the stresses undergone, i.e. to the pre-analytical conditions to which they have been subjected.

A further object of the invention is to propose a system and a method to evaluate the effects of the pre-analytical conditions that occur during the transport step of the biological samples.

These and other objects are achieved via a system for controlling biological samples having the features of claim 1. In this system, the sensor means for the acquisition of transport parameters are placed in the probe collection unit in an internal space corresponding to the inner space of a collection unit intended to receive a biological sample.

The sensor means for the acquisition of transport parameters include at least one among the following transport parameter sensors:

- a temperature sensor;

- a time sensor; - a light sensor;

- a three-axes acceleration sensor;

- a verticality condition sensor;

- a humidity sensor;

- for particular types of samples, at least one gas sensor.

Advantageously, the probe collection unit has a hole adapted to put the inner space of said probe collection unit in communication with the external environment. In a presently preferred embodiment of the invention, the identification data of at least one population of biological samples include at least one among the following data:

- an identifier code for the collection unit;

- the association with an identification datum of the retrieval station;

- an associated identification datum of an operator, and preferably of a retrieval operator and a transport operator.

- a transport start time from a retrieval station and/or a transport end time at an analysis station.

In the presently preferred embodiment, the measurement data of transport parameters comprise at least one of:

- the instantaneous temperature to which said population of biological samples is subjected;

- the transport time;

- the total ambient light to which said population of biological samples is exposed; - the total accelerations along three axes to which said population of biological samples is subjected;

- the verticality condition of the collection units containing said population of biological samples;

- the humidity to which said population of biological samples is exposed to assess that no spillage or leakage has occurred within the containers;

- the average gas concentration to which said population of biological samples is exposed to assess the overall exposure of the sample to one or more specific gases. Conveniently, the system's probe collection unit is provided with an identification code and has a radio communication means adapted to transmit the measurement data of transport parameters remotely to the database system either directly or indirectly via an intermediate repeater device, together with the respective identification code.

In a particular embodiment, the radio communication means of the probe collection unit are adapted to transmit remotely the measurement data of transport parameters at the retrieval station, at least at one intermediate station between the retrieval station and the analysis station, and at the analysis station. Typically, an intermediate station is a station wherein the means and conditions of transport are changed, or it is a predetermined intermediate point on the route, identified by its position along the route, for example marked by GPS coordinates or a cell tower or a wi-fi hotspot. The database system is arranged to make available through a remote communications link the identification data of at least one population of biological samples, the measurement data of the transport parameters, and the result data from clinical analysis.

Advantageously, the population of biological samples is arranged in a transport container and an additional humidity sensor is coupled to said transport container to detect any spreading of the biological samples due to evaporation or rupture of the collection unit.

Another object of the invention is a method for controlling biological samples to be subjected to clinical analysis, as claimed.

The aforementioned method is furthermore characterized in that it comprises, in a first step, at the retrieval station, the transmission to the database system of the identification data together with an identification code of the probe collection unit associated with at least one population of biological samples; in a second step, at the analysis station or an intermediate station between the retrieval station and the analysis station, the transmission of the measurement data to the database system; and in a third step, at the analysis station, the transmission of the result data from clinical analysis. The acquisition of the measurement data of the transport parameters comprises at least one of:

- acquiring the instantaneous temperature to which the population of biological samples is subjected;

- acquiring the transport time;

- acquiring the total ambient light to which the population of biological samples is exposed;

- acquiring the total acceleration on three axes to which the population of biological samples is subject;

- acquiring the vertically condition of the collection unit containing the population of biological samples;

- acquiring the humidity to which the population of biological samples is exposed;

- acquiring the instantaneous gas concentration and calculating the average gas concentration to which the population of biological samples is exposed.

The set of measurement data of the acquired transport parameters, relative to a population of biological samples, defines a pre-analytical condition of the population of biological samples. The pre-analytical condition is a parameter vector, each parameter being a time- dependent parameter, or a parameter vector with constant values, e.g. representative of the averages of the parameters over time, or the maximum values of parameters or the summations of the relative maximum/minimum values of the parameters, or a vector of mixed parameters including time-dependent parameters and corresponding to derived constant values.

In a presently preferred embodiment, the method comprises generating a report indicative of at least one predetermined relationship between the identification data, the measurement data and the result data from clinical analysis. Further features and advantages of the present invention will become apparent from the detailed description that follows, provided by way of non-limiting example with reference to the accompanying drawings, wherein: Figure 1 schematically illustrates a system for the control of biological samples according to the present invention;

Figures 2a and 2b are perspective views of a probe collection unit used by the system for the control of biological samples according to the present invention; and - Figure 3 is a flowchart that shows the steps of the method for the control of biological samples according to the present invention.

Figure 1 schematically shows a system object of the invention for the control of biological samples acquired at least at one retrieval site 10 and intended to be subject to clinical analysis at an analysis site 12.

A population of said biological samples is placed in respective collection units PI, P2, Pn, in this embodiment described by way of example, represented in the form of test tubes, such as test tubes for the collection of blood samples marked with a respective identifier code, and transported from a retrieval station 20 to an analysis station 22. The transport takes place preferably by aggregating the collection units PI, P2, Pn in a transport container 24, possibly provided with environmental parameter sensors, and preferably a humidity sensor (not shown) adapted to detect any spreading of the biological samples, due to evaporation or rupture of the collection unit, and having safety functions to notify an operator at the time of the opening of the container.

In the present description, the population of biological samples means at least one biological sample and preferably a plurality of biological samples transferred simultaneously from the retrieval station to the analysis station and substantially subject to the same conditions of transport.

At least one probe collection unit S is associated with the collection units PI, P2, Pn in the transport from the retrieval station 20 to the analysis station 22, so as to be exposed substantially to the transport conditions to which the population of biological samples contained in the collecting unit PI, P2, Pn is subjected. The probe collection unit 52 is arranged to acquire the measurement data of transport parameters. A database system 30, residing on a remote server accessible in the cloud, includes at least one data memory module 32 and a first data processing unit 34 of the system for the control of biological samples object of the invention. The data memory module 32 includes:

a first submodule 32a adapted to store identification data of the population of biological samples associated with at least one retrieval site 10 of said samples and at least one respective retrieval time;

a second submodule 32b adapted to store the measurement data of transport parameters of the population of biological samples taken during transport from the retrieval station 20 to the analysis station 22; and

a third submodule 32c adapted to store the result data from clinical analysis performed on the population of biological samples at the analysis site 12. The data processing unit 34 is linked to the submodules 32a, 32b and 32c of the data memory module 32 and comprises a processor 40, adapted to read from and write to the memory submodules, as well as to determine at least one associative relationship between the identification data of the population of biological samples, the measurement data of the transport parameters, and the result data from clinical analysis.

The data processing unit 34 also comprises a data transmission/reception module 42, adapted to link bidirectionally the data processing unit 34 with the communication terminals T available from one or more operators, which are arranged to communicate with the probe collection unit S at the retrieval station 20, the analysis station 22, and possibly one or more intermediate stations. The intermediate stations may be sorting sites for the collection units and the associated probe collection unit or simply the locations of the collection units and the associated probe collection unit intermediate between the retrieval station and the analysis station, illustrated in the figure by the association of a terminal T to the transport vehicle. The terminals T represented in the figure may be the same terminal in possession of an operator who follows the retrieval, transport and analysis operations, in which case, these are mobile terminals such as tablets or smartphones; or different terminals in possession of different operators dedicated to each operation, in which case these may be a mobile terminal (tablet or smartphone) or a fixed terminal (PC) located at the relative station.

The link between the data processing unit 34 and the communication terminals T is a radio ¹ communications link, such as a link through a public communications network.

The probe collection unit S, shown in figures 2a and 2b, is identical to the collection units used for the storage of biological samples and comprises a body 50 of a generally cylindrical shape, open at one end, which is closed by a cap 52. The probe collection unit S may be advantageously provided with a hole 54 to allow the reduction of the moments of inertia between the surrounding environment and the inside of the test tube in the detection of environmental parameters.

Inside the probe collection unit S is arranged a printed circuit board 56 with a processor 58, a power supply battery (not shown) and a plurality of transport parameter acquisition sensors, including transport environmental conditions, arrangement and dynamics, i.e. the parameters necessary for the detection and logging of events that occur during the transport of biological samples from the retrieval station 20 to the analysis station 22. By way of example, the probe collection unit includes:

- a temperature sensor 60, adapted to detect the internal temperature of the probe collection unit, that for the purposes of the invention is considered to be approximately equal to the internal temperature of the collection unit PI, P2, Pn;

- a device for measuring the time 62, such as a clock or a stopwatch, adapted to measure the transport time between the retrieval station 20, any intermediate stations and the analysis station 22;

- a light sensor 64, advantageously positioned at the height of the dead space of the collection unit, namely the space immediately below the cap and above the surface of the biological sample, and adapted to detect the light condition to which the population of biological samples associated with the probe collection unit S is subject.

- an accelerometer sensor 66, preferably a triaxial accelerometric sensor, adapted to detect accelerations and/or decelerations experienced by the probe collection unit, and therefore by the collection units PI, P2, Pn associated to it during transport, for example due to the handling and shocks experienced by the container 24;

- a humidity sensor 68, adapted to detect the internal humidity of the probe collection unit, that for the purposes of the invention is considered to be approximately equal to the internal humidity of the collection unit PI, P2, Pn;

- A location sensor 70, adapted to detect the geographical position of the probe collection unit;

- an alignment sensor 72, adapted to detect the spatial arrangement of the probe collection unit in order to determine, for example, the condition of verticality, closely related to the surface of the biological sample that will be exposed to the air inside the collection unit;

- at least one gas sensor 74, adapted to detect the percentage of oxygen, carbon dioxide and other gases within the container 24. The processor 58 forms a second data processing unit of the system for the control of biological samples object of the invention and is arranged to acquire the measurement data detected by the sensors and store it, at least temporarily, before transmitting it.

Inside of the probe collection unit, the printed circuit board 56 is stably fixed so as not to experience spurious vibrations to which it would be subjected during centrifugation or due to sudden movements.

Inside the cap 52, a transceiver module 76 is provided which allows, by means of a dedicated wireless link L, the transmission of the measurement data of transport parameters acquired by the sensors to a communication terminal T, for example according to an RFID communication protocol, and possibly the reception of data storage activation signals or data storage interruption signals, the programming of the activity and the download of stored data. The transceiver module 76 is positioned within the cap 52 in such a way that a relative antenna is oriented towards the outside. On the probe collection unit S is attached a label 80 on which an identification code 82 is provided, which allows, inter alia, to easily distinguish the probe collection unit S from the collection units PI, P2, Pn containing biological samples. In summary, the system according to the present invention allows the pre-analytical conditions of a population of biological samples to be detected with predetermined and possibly configurable periodicity. The pre-analytical conditions comprise the set of measurement data of the transport parameters acquired over time and are defined as a parameter vector, each of which is time-dependent, for example C _pre an = [T-T(t), u=u(t), a=a(t), ...] where T is the temperature, u is the humidity, a is the acceleration, or as a parameter vector with constant values, representative of the time averages of the parameters (Cprean = [T avg, Uavg, ¾vg, ··. ]) or the absolute maximum/minimum values of the parameters (C _pr ean = [T _ma x/min, Umax/min, a _m ax/min, ···]) or summations of the relative minimum/maximum values of the parameters (Cprean = [∑T _ma x/min,∑ Umax/min, ∑amax/min, ···]) or even as a mixed parameter vector including time-dependent parameters and the corresponding derived constant values.

An illustrative embodiment of the methos for the control of biological samples according to the invention is further described in the following with reference to figure 3.

The method comprises, in sequence, a step 100 of storing biological samples in respective collection units PI, P2, Pn, a step 200 of associating a probe collection unit S with the collection units PI, P2, Pn, a step 300 of activating the probe collection unit (activating the processor 58 and the sensors 60-74) and launching the monitoring of the pre-analytical conditions to which the biological samples are subjected.

In step 300, the transmission from the communication terminal T, associated with the retrieval site 10, to the database system 30 occurs for the identification data of the population of biological samples, including at least one identifier code of the collection units PI, P2,. .., Pn, an identification code of the probe collection unit S associated therewith, an identification datum of the retrieval station 20, an identification datum of a retrieval and/or transport operator, a retrieval time, and a transport start time from the retrieval station 20. These data can possibly also be stored in the probe unit.

The association between the collection unit (biological samples) and the probe collection unit can take place manually, e.g. by reading the identifier codes via printed bar code reader devices, or automatically, via query of the collection units and of the probe collection unit from the communication terminal T associated with the retrieval site 10, if the collection units and the probe collection unit are equipped with electronic identification devices, for example RFID labels.

Step 300 is initiated by an operator who transmits to the probe collection unit, via the communication terminal T, the identification datum of the retrieval station and synchronizes the date and time. During the transport of samples from the retrieval station 20 of a retrieval site 10 to the analysis station 22 of an analysis site 12, the transport parameters are acquired (detection and storage), identified by step 400.

During the pre-analytical step of transport, intermediate stations may be provided, e.g. dispatch stations, from which transmit, to the database system 30, the measurement data of the transport parameters in association with the location information of the intermediate station.

Once the collection units PI, P2, Pn and the associated probe collection unit S arrive at the analysis station 22, at step 500, the storage of the transport parameters from the sensors 60-74 of the probe collection unit S is stopped, and therefore the monitoring of the pre- analytical conditions to which the biological samples have been subjected is completed.

In the context of the invention, the pre-analytical step must be understood as the step that precedes the clinical analysis, regardless of the place or places where it takes place. Generally, the pre-analytical step concerns the transport conditions of the biological samples, i.e. the environmental and dynamic conditions to which the samples are exposed in the transport step between a retrieval station and an analysis station and possibly in the step of handling the samples at an analysis site before reaching the analysis station.

Subsequently, in step 600 the measurement data of the transport parameters are sent from the probe collection unit to the communication terminal T associated with the analysis site

12, which in turn sends the data to the database system 30.

Simultaneously or subsequently, in step 700, the result data are obtained from the clinical analysis conducted on the biological samples of the collection units PI, P2, Pn, and these data are transmitted from the communication terminal T to the database system 30.

At a subsequent step 800, the database system 30 is arranged to generate one or more reports indicative of predetermined relationships between the identification data, the measurement data and the result data from clinical analysis.

In a first example, the report is a comparison report between the result data from clinical analysis of a single analysis station and all the result data from clinical analysis for each pre-analytical condition stored in the database system. In a second example, the report is a comparison report between the result data from clinical analysis of a single analysis station and all the result data from clinical analysis for homogeneous pre-analytical conditions, i.e. which present measurement values between pairs of maximum and minimum thresholds, stored in the database system. In a third example, the report is a comparison report between the result data from clinical analysis from a single analysis station and all the result data from clinical analysis for at least one predetermined pre-analytical condition, for example, a selected pre-analytical condition wherein one or more parameters exceed a predetermined threshold, stored in the database system. In a fourth example, the report is a comparison report between result data from clinical analysis of a single analysis station over time for each pre-analytical condition stored in the database system. In a fifth example, the report is a comparison report between the result data from clinical analysis of a single analysis station over time, for homogeneous pre-analytical conditions, stored in the database system.

In a sixth example, the report is a comparison report between result data from clinical analysis of a single analysis station over time for at least one predetermined pre-analytic condition stored in the database system.

Advantageously, the method further comprises, at step 900, the generation of a quality control report indicative of at least one predetermined relationship between the measurement data and respective predetermined thresholds.

More specifically, the system object of the invention allows the identification data, the measurement data and the result data from clinical analysis to be processed with mathematical statistical methods to produce reports on the quality of the pre-analytical conditions related to the analyses performed on the samples. The system makes available an on-line consultation service for the traceability of the transport conditions and evaluation of the transport parameters based on the type of clinical analysis requested both in interactive format and for communication to the analysis site management software. Overall, the system and method described above allow the effects of physical stress to which the organic materials are subjected to be assessed.

The data collected make possible the evaluation of the quality of the pre-analytical step, both as a whole and in a finer detail: for example, being able to assess particularly critical steps in the preparation of the samples, such as centrifugation characteristics. In one fully automated embodiment, the intermediate stations and the analysis station do not require any intervention by the operators for the transmission of data to the database system. Advantageously, the use of the system and the method according to the invention described above, allow the following results to be obtained.

On specific topics, with the joint participation of several laboratories of microbiological and clinical chemical analysis, it will be possible to evaluate the effects of transport parameters measured, or mathematically processed, using very large reference populations.

This is made possible by the association between a probe collection unit and the collection units of real samples, all while ensuring the anonymity of the data source. The control of biological samples according to the system object of the invention allows mappings of the effects on specific tests both for clinical criticality and for the onerousness of one or more tests, possibly correlating them to pathologies or suspected pathologies.

In this way, it is possible to decide when to intervene on the entire system, at what level and with what type of intervention.

It is also possible to avoid processing samples that arrived for analysis in improper conditions for the purpose for which they were collected or retrieved. The areas of diagnostic doubt defined for example by using simple Gaussian distributions of analytical results of single test coming from different populations may be interpreted by better distinguishing between samples transported so as to ensure their representativeness and samples which have undergone stress during transport. Using a system according to the invention, it is possible to certify that a whole production chain from a retrieval station to an analysis station is able to trace events that occurred during the transport and better ensure the representativeness of the samples collected, transported and analyzed, relative to the observed variables.

Naturally, without altering the principle of the invention, the embodiments and the details of implementation may vary widely with respect to those described and illustrated purely by way of non-limiting example, without thereby departing from the scope of the invention as defined in the appended claims.