High throughput analysis unit

Abstract

The present disclosure relates to a screening system configured to identify biological agents, biological differences, pathogens and / or genetic differences. The screening system may include: a culture zone having a culture station for culturing a plurality of samples; and a detector for simultaneously or quasi-simultaneously detecting the electromagnetic radiation emitted by the plurality of samples. The screening system may include an optional replaceable incubator unit receivable in the culture station. The culture station may include a light-based fiducial system that is used as a reference point to locate images of the culture station captured by the detector, and optionally facilitate synchronous capture of spectral images corresponding to detected outputs of pathogen or gene differences.

Description

TECHNICAL FIELD

[0001] The present disclosure relates to a screening system for identifying pathogens or genetic differences, and in particular, but not exclusively, to a system for detecting genetic differences in DNA or RNA of a gene or in a gene expression profile. BACKGROUND

[0002] In particular, the COVID-19 pandemic, and other pandemics or infectious diseases, have required screening of large numbers of samples taken from symptomatic individuals expected to be carrying the virus, or routine monitoring screening of asymptomatic individuals in order to identify virus carriers. Different manual screening procedures are known, but in order to be able to test large numbers of samples for monitoring, screening systems capable of higher sample throughput are becoming increasingly important.

[0003] There are a variety of sensitive molecular diagnostic techniques for detecting pathogens such as SARS-coV2 using a range of nucleic acid amplification and detection systems, including polymerase chain reaction (PCR), isothermal amplification methods and CRISPR-based methods - review reference [Habli, Z., Saleh, S., Zaraket, H. & Khraiche, M. L. COVID-19 in-vitro Diagnostics: State-of-the-Art and Challenges for Rapid, Scalable, and High-Accuracy Screening. Frontiers in Bioengineering and Biotechnology 8, (2021)].

[0004] The skilled person will appreciate that the present disclosure can be applied to a range of newer molecular tests that utilise optical readouts for nucleic acid and protein targets that are emerging, including but not limited to the techniques disclosed in the following publications:

[0005] Zhang, X., Zhao, Y., Zeng, Y. & Zhang, C. Evolution of the Probe-Based Loop-Mediated Isothermal Amplification (LAMP) Assays in Pathogen Detection. Diagnostics 13, 1530 (2023).

[0006] 环介导等温扩增(LAMP)–在此进行全面综述如下:[Moehling,T.J.,Choi,G.,Dugan,L.C.,Salit,M.&Meagher,R.J.LAMP Diagnostics at the Point-of-Care:Emerging Trends and Perspectives for the Developer Community.Expert Rev MolDiagn21,1–19(2021)].

[0007] MD-LAMP[Becherer,L.et al.Simplified Real-Time Multiplex Detection ofLoop-Mediated Isothermal Amplification Using Novel Mediator DisplacementProbes with Universal Reporters.Anal Chem 90,4741–4748(2018)].

[0008] CRISPR

[0009] Liu,F.X.,Cui,J.Q.,Wu,Z.&Yao,S.Recent progress in nucleic aciddetection with CRISPR.Lab Chip 23,1467–1492(2023).

[0010] Pena,J.M.et al.Real-time,multiplexed SHERLOCK for in vitrodiagnostics.J.Mol.Diagn.25,428–437(2023).

[0011] Nguyen,L.T.et al.Engineering highly thermostable Cas12b via de novostructural analyses for one-pot detection of nucleic acids.Cell Rep.Med.4,101037(2023).

[0012] DETECTR[Broughton,J.P.et al.CRISPR–Cas12-based detection of SARS-CoV-2.Nat Biotechnol38,870–874(2020)]。

[0013] miSHERLOCK[Puig,H.de et al.Minimally instrumented SHERLOCK(miSHERLOCK)for CRISPR-based point-of-care diagnosis ofSARS-CoV-2and emergingvariants.Sci Adv 7,eabh2944(2021)]。

[0014] 自催化CRISPR

[0015] CONAN.[Shi,K.et al.A CRISPR-Cas autocatalysis-driven feedbackamplification network for supersensitive DNA diagnostics.Sci.Adv.7,eabc7802]。

[0016] Deng,F.,Sang,R.,Li,Y.,Deng,W.&Goldys,E.Bifunctional circular DNAamplifier transforms a classic CRISPR / Cas sensor into an ultrasensitiveautocatalytic sensor.(2023)doi:10.21203 / rs.3.rs-2626952 / v1。

[0017] Deng,F.,Li,Y.,Hall,T.,Vesey,G.&Goldys,E.M.Bi-functional antibody-CRISPR / Cas12a ribonucleoprotein conjugate for improved immunoassayperformance.Anal Chim Acta 1259,341211(2023)。

[0018] SPOT.[Xun,G.,Lane,S.T.,Petrov,V.A.,Pepa,B.E.&Zhao,H.A rapid,accurate,scalable,and portable testing system for COVID-19diagnosis.Nat Commun 12,2905(2021)]。

[0019] RTF-EXPAR[Carter,J.G.et al.Ultrarapid detection of SARS-CoV-2RNAusing a reverse transcription–free exponential amplification reaction,RTF-EXPAR.Proc National Acad Sci 118,(2021)]。

[0020] NACT[Moitra,P.,Alafeef,M.,Dighe,K.,Frieman,M.B.&Pan,D.SelectiveNaked-Eye Detection of SARS-CoV 2Mediated by N Gene Targeted AntisenseOligonucleotide Capped Plasmonic Nanoparticles.Acs Nano14,7617–7627(2020);Alafeef,M.,Moitra,P.,Dighe,K.&Pan,D.RNA-extraction-free nano-amplifiedcolorimetric test for point-of-care clinical diagnosis of COVID-19.NatProtoc16,3141–3162(2021)]。

[0021] Isothermal PCR[Gavrilov,M.et al.Engineered helicase replacesthermocycler in DNA amplification while retaining desired PCRcharacteristics.Nat Commun 13,6312(2022).]。

[0022] Those skilled in the art will recognize that the above list of nucleic acid amplification (NAAT) techniques is not exhaustive and does not explicitly mention other applicable techniques, including RPA, RCA, SPA, NASBA, see: [Wang, M. et al. Enzyme-Assisted Nucleic Acid Amplification in Molecular Diagnosis: A Review. Biosensors 13, 160 (2023)].

[0023] Those skilled in the art will appreciate that the products of the above molecular diagnostic assays (whether based on nucleic acid amplification assays, CRISPR, or protein or nanoparticle-based biosensors) can be detected by color change (detected by differences in absorbance, reflectance, or transmittance of irradiated light), luminescence, phosphorescence, or fluorescence. For example, the following review describes a series of nucleic acid aptamer, protein, and nanoparticle biosensors with optical output: [Singh, AK, Mittal, S., Das, M., Saharia, A. & Tiwari, M. Optical biosensors: a decade in review. Alex. Eng. J. 67, 673–691 (2023),

[0024] Xu,R.,Ouyang,L.,Chen,H.,Zhang,G.&Zhe,J.Recent Advances inBiomolecular Detection Based on Aptamers and Nanoparticles.Biosensors 13,474(2023),

[0025] Futane, A., Narayanamurthy, V., Jadhav, P. & Srinivasan, A. Aptamer-based rapid diagnosis for point-of-care application. Microfluid. Nanofluidics 27, 15 (2023)].

[0026] Those skilled in the art will recognize that the present disclosure can be applied to a range of homogeneous isothermal assays for nucleic acid, protein or small molecule targets - see: [Dekaliuk, M., Busson, P. & Hildebrandt, N. Isothermal Rolling Circle Amplification and Lanthanide-Based FRET for Femtomolar Quantification of MicroRNA. Anal. Sens. 2, (2022)] and [Fu, H.-J. et al. Rapid and Wash-Free Time-Gated FRET Histamine Assays Using Antibodies and Aptamers. ACS Sens. 7, 1113-1121 (2022), Li, Y., Liu, L., Qiao, L. & Deng, F. Universal CRISPR / Cas12a-associated aptasensor suitable for rapid detection of small proteins with a plate reader. Front. Bioeng. Biotechnol. 11, 1201175 (2023)] and [Kadam, U.S., Cho, Y., Park, T.Y. & Hong, J.C. Aptamer-based CRISPR-Cas powered diagnostics of diverse biomarkers and small molecule targets. Appl Biol Chem 66, 13 (2023)], for examples of applicable detections, respectively.

[0027] One promising technique for screening for molecular signatures in a sample is the so-called "Loop-mediated isothermal amplification ("LAMP") technique. The screening process involves collecting a biological sample (such as, but not limited to, saliva, sputum, anterior nasal swab, middle turbinate swab, or nasopharyngeal swab, and throat swab), and placing the sample in a test tube with chemicals used for the LAMP process. The sample is then incubated, and the results of the screening process can be determined using colorimetric or fluorescent detection techniques. The advantage of LAMP is that the incubation and detection process takes only 20 to 30 minutes. The screening system can be used for parallel processing and screening of samples, thereby increasing the throughput compared to manual LAMP procedures.

[0028] However, to date, the above-disclosed molecular diagnostic methods are currently implemented in low-throughput point-of-care or medium-throughput formats, lacking a viable and economic means to operate at ultra-high throughput scales. This means that the above-disclosed standard methods of molecular diagnostics are not suitable for ultra-high throughput screening methods, particularly those that support continuous operation of thousands of tests per hour. For example, even expensive high-throughput molecular diagnostic instruments such as Roche Cobas 6800, Abbott Alinity, Quiagen QIAstat-Dx, NeuMoDx or Hologic Panther, some of which support a more continuous flow loading mode, cannot be configured in a way that allows for economic scaling to continuous ultra-high throughput operation due to their inherent design limitations.

[0029] Point-of-care solutions connected to small molecule detection devices and / or smartphones also have their own limitations in terms of ID verifiability, integration, and affordable implementation costs for implementation in population scale or biosecurity monitoring applications.

[0030] Therefore, the ability to rapidly screen large numbers of samples associated with a pandemic, or to economically screen population-level genetic or phenotypic changes in the shortest time possible, requires not only the parallel processing of samples at ultra-high throughput, but also further technical solutions to increase throughput and versatility, allowing for flexible adaptation to fluctuations in test volume, such as but not limited to scalable random storage, continuous flow loading. This requires technical progress.

[0031] It will be appreciated that if any prior art publications are referred to herein, this does not constitute an admission that the publication forms part of the common general knowledge of the art in Australia or in any other country. SUMMARY

[0032] Embodiments relate to a screening system configured to identify biological agents, biological differences, pathogens and / or genetic differences at a continuous screening throughput rate of at least 2000 samples per hour. Such a system can be referred to as a continuous “ultra-high throughput” screening system.

[0033] Embodiments provide a screening system for identifying a pathogen or a genetic difference, the screening system comprising:

[0034] a culture zone having a culture station for culturing a plurality of samples;

[0035] an electromagnetic radiation source for irradiating the plurality of samples;

[0036] a detector for detecting electromagnetic radiation emitted by the plurality of samples; and

[0037] Reference System,The reference system is used to measure the position of the detector relative to the,cultivation station.

[0038] The reference system can include a light-based reference system. The reference system can include optical, acoustic and / or magnetic detectors configured to measure distance. The distance can be used to calculate the relative position of the detector and the cultivation station. The optical, acoustic and / or detectors can include ultrasonic detectors and / or lasers. The magnetic detector can include a detector capable of detecting changes in magnetic conditions. For example, the magnetic field conditions at a certain position of the cultivation station may change. The magnetic detector can also include a linear encoder using magnetic encoding on the stroke length.

[0039] The embodiment provides a screening system for identifying pathogens or genetic differences, the screening system comprising:

[0040] a culture area having culture stations for culturing a plurality of samples;

[0041] An incubator unit, the incubator unit being receivable in the incubation station, the incubator unit being replaceable and comprising:

[0042] a heating element or thermal regulator having a plurality of containers each capable of containing a sample, the heating element or thermal regulator being configured to heat or cool the plurality of containers; and

[0043] an electromagnetic radiation source for irradiating one or more of the containers; and

[0044] A detector is configured to detect electromagnetic radiation emitted by the plurality of samples.

[0045] In an embodiment, the screening system may include multiple culture stations that can each accommodate incubator units. Each incubator unit can be operated independently of one another. This can help the system analyze samples that require different culture conditions simultaneously. A thermal regulator can be located at the upper portion of the incubator unit in use or form the upper portion of the incubator unit in use. An electromagnetic radiation source can be located at the lower portion of the incubator unit in use or form the lower portion of the incubator unit in use. In an embodiment, each container is optically connected to the electromagnetic radiation source by a fiber optic cable. However, the present disclosure is not limited to the use of fiber optic cables, and alternative embodiments can be used to allow an electromagnetic radiation source to enter the container.

[0046] The incubator unit may include an identifier that can be read by the incubator station when the incubator unit is installed in the incubator station.The identifier may be used to identify a predefined operating condition of the incubator unit.

[0047] The incubator unit can include a light-based fiducial system capable of generating light that is used as a reference point to orient an image of the incubation station captured by the detector. The light-based fiducial system can include a laser source and a photodetector. The photodetector can detect the laser light to generate a signal to capture images of the plurality of samples.

[0048] Embodiments provide a screening system configured to identify biological agents, biological differences, pathogens, and / or genetic differences, the screening system comprising:

[0049] a culture area having a culture station for culturing a plurality of samples, the culture station having a light-based reference system;

[0050] an electromagnetic radiation source for irradiating the plurality of samples; and

[0051] a detector for detecting electromagnetic radiation emitted by the plurality of samples;

[0052] Therein, a light-based fiducial system is used as a reference point to orient the image of the cultivation station captured by the detector.

[0053] The reference system based on light can be considered to constitute a positioning system to help provide the position of the cultivation station. The light emitted from the reference system based on light can be detected by a detector. The screening system may include multiple cultivation stations. The cultivation station may include an incubator unit with a heating element or a thermal regulator, such as a magnetic induction or piezoelectric system, and the heating element or the thermal regulator is used to heat or cool multiple samples. The incubator system can be replaceable. The reference system based on light can be located on the thermal regulator. The incubator unit may include an electromagnetic radiation source for irradiating multiple samples.

[0054] In an embodiment, the electromagnetic radiation source is configured to illuminate the plurality of samples within a first wavelength range and the detector is configured to detect electromagnetic radiation emitted by the plurality of samples within a second wavelength range. The second wavelength range may be different from the first wavelength range. The light-based reference system may be visible within the second wavelength range.

[0055] The light-based fiducial system can include two light-based fiducials located at the incubation station. The light-based fiducial system can include a laser source that triggers a photodetector located at the incubation station. Triggering the photodetector can provide a signal to the detector to capture electromagnetic radiation emitted by multiple samples. This triggering can help ensure that the detector is in the same position each time an image is captured.

[0056] The system can be configured to simultaneously detect electromagnetic radiation emitted by multiple samples and light from a light-based fiducial system. The system can be configured to simultaneously detect electromagnetic radiation emitted by multiple samples, for example, with the aid of a multispectral detector and / or through a beam splitter or prism connected to multiple detectors. The system can be configured to at least quasi-simultaneously detect electromagnetic radiation emitted by multiple samples using synchronized detection of light emitted from the light-based fiducial positioning system, for example, with the aid of a multi-wheel filter and / or a narrow-band filter-based imager / camera.

[0057] The light-based reference system can include a light source located at the culture station. In an embodiment of the screening system, the detector and the culture station can be capable of moving relative to each other. The embodiment of the screening system can also include a moving mechanism, which is configured to move the detector across the culture area. The screening system can be configured to allow the detector to continuously move across the culture area during use of the system. The detector can continuously move back and forth on the culture area. In an embodiment, the system can be configured to include at least quasi-simultaneous detection of electromagnetic radiation emitted by multiple samples: within a predefined interval immediately before or after detecting the electromagnetic radiation emitted by multiple samples, detecting light from the light-based reference system, and then performing time resolution to allow the positions of multiple samples to be calculated from the light-based reference system by interpolating the relative motion trajectory of the detector and the culture area.

[0058] In an embodiment of the screening system, the detector is a fixed detector and has a field of view that captures at least one culture station. An embodiment of the screening system may include a plurality of detectors. An embodiment of the screening system may include a plurality of culture stations. Each of the plurality of fixed detectors may be configured to record radiation emitted from some of the plurality of culture stations such that the plurality of fixed detectors in combination record radiation emitted from the plurality of culture stations. Each of the plurality of detectors may be configured to record radiation emitted by the plurality of samples at a predefined wavelength or one or more predefined wavelengths, which is different from the predefined wavelength or one or more predefined wavelengths of other detectors in the plurality of detectors. In an embodiment, at least one of the plurality of detectors is configured to record radiation emitted by the plurality of samples at a predefined wavelength, which is different from the predefined wavelength of at least one of the plurality of detectors, wherein at least one of the plurality of detectors is configured to record radiation at the same time as the other detectors, but is distinguished by time-resolved detection of asynchronous radiation in response to an excitation pulse provided from an electromagnetic radiation source.

[0059] The embodiment provides a screening system for identifying pathogens or genetic differences, the screening system comprising:

[0060] a culture area having culture stations for culturing a plurality of samples;

[0061] An incubator unit, the incubator unit being receivable in the incubation station, the incubator unit being replaceable and comprising:

[0062] a thermal regulator having a plurality of containers for holding samples, the thermal regulator being configured to heat or cool the plurality of containers;

[0063] an electromagnetic radiation source optically coupled to the container, the electromagnetic radiation source being configured to irradiate the plurality of samples; and

[0064] Light-based reference systems; and

[0065] a detector for detecting electromagnetic radiation emitted by the plurality of samples and light from the light-based reference system;

[0066] Therein, a light-based fiducial system is used as a reference point to orient the image of the cultivation station captured by the detector.

[0067] Embodiments of the screening system may further include a liquid handling system for transferring liquid reagents to the plurality of samples. The liquid handling system may include a pipette for transferring liquids and capable of receiving and dispensing pipette tips from a pipette tip box when in use. Embodiments of the screening system may further include a detector for visually detecting the presence or absence of one or more pipette tips in the pipette tip box.

[0068] Embodiments of the screening system may further include an airflow system. The airflow system may have an inlet, a filter, and an outlet, wherein the inlet is positioned to draw air from an environment external to the screening system, and the outlet is located in the chamber containing the liquid handling system. The airflow system may be configured to draw air through the inlet and filter it to form purified air, and then blow the purified air into the chamber containing the liquid handling system. The airflow system may be configured to maintain the chamber containing the liquid handling system at an elevated pressure compared to the environment external to the chamber containing the liquid handling system. The airflow system may include a conduit for directing the purified air to an upper portion of the chamber containing the liquid handling system.

[0069] The embodiment of this screening system can also include a robotic system, which is used to load and unload samples. The system for screening pathogens or genetic differences can be arranged to identify whether and when the screening and / or processing of each sample or sample group in the culture area is completed. In an embodiment, the robotic system can be arranged to remove each sample or sample group from the incubator, leaving an empty sample rack or sample group rack. The sample or sample group can be removed from the position or adjacent position surrounded by the sample or sample group that is being screened and / or processed incompletely. The robotic system can be arranged to obtain fresh samples or sample groups; and then fill the vacant position in the incubator with fresh samples. This system can be suitable for the continuous throughput of samples. For example, the embodiment of this screening system can be configured as continuous operation, wherein the sample cultivated is continuously removed and replaced with a new sample.

[0070] Embodiments of the screening system may include an ultrasonic detector for detecting one or more physical conditions of the system. The one or more physical conditions of the system may include the presence or absence of a sample at a predefined location in the culture area. For example, the sample may be a microplate with multiple samples. Embodiments may also include a trash can or waste container configured to receive waste generated by the screening system. The ultrasonic detector may be configured to measure the fill level of the trash can or waste container.

[0071] Embodiments provide a screening system configured to identify biological agents, biological differences, pathogens, and / or genetic differences, the screening system comprising:

[0072] The culture area has a culture station for culturing a plurality of samples, wherein an incubator unit can be accommodated in the culture station and can be replaced, and the incubator unit includes:

[0073] a thermal regulator having a plurality of containers each capable of accommodating a sample, the thermal regulator being configured to heat or cool the plurality of containers; and

[0074] an electromagnetic radiation source for irradiating one or more of the containers;

[0075] an electromagnetic radiation source, the electromagnetic radiation source being used to irradiate a plurality of samples;

[0076] a detector for detecting electromagnetic radiation emitted by the plurality of samples;

[0077] a chamber housing a liquid handling system for transferring liquid reagents to the plurality of samples; and

[0078] An airflow system having an inlet, a filter, and an outlet, the inlet being positioned to draw air from the environment external to the screening system, the outlet being located within the chamber, the airflow system being configured to:

[0079] drawing air in through the inlet and filtering it to form purified air and then blowing the purified air into the chamber; and

[0080] The chamber is maintained at an elevated pressure compared to the environment outside the chamber.

[0081] The culture station can have a light-based fiducial system. The light-based fiducial system can be used as a reference point to orient the image of the culture station captured by the detector. The detector can be in a fixed relationship to the culture area. The detector can be movable relative to the culture area.

[0082] Embodiments provide a screening system configured to identify biological agents, biological differences, pathogens, and / or genetic differences, the screening system comprising:

[0083] a culture area having culture stations for culturing a plurality of samples;

[0084] an electromagnetic radiation source, the electromagnetic radiation source being used to irradiate a plurality of samples;

[0085] a detector for detecting electromagnetic radiation emitted by the plurality of samples;

[0086] a chamber housing a liquid handling system for transferring liquid reagents to the plurality of samples; and

[0087] An airflow system having an inlet, a filter, and an outlet, wherein the inlet is positioned to draw air from the environment outside the screening system, and the outlet is located within the chamber, the airflow system being configured to: draw air through the inlet and filter it to form purified air and then blow the purified air into the chamber; and maintain the chamber at an elevated pressure compared to the environment outside the chamber.

[0088] The incubation station can include a light-based reference system. The light-based reference system can be used as a reference point to orient the image of the incubation station captured by the detector. The screening system can also include an incubator unit that can be accommodated in the incubation station and can be replaced. The incubator unit can include: a thermal regulator having a plurality of containers that can each accommodate a sample, the thermal regulator being configured to heat or cool the plurality of containers; and an electromagnetic radiation source for irradiating one or more of the containers.

[0089] Embodiments provide a screening system configured to identify biological agents, biological differences, pathogens, and / or genetic differences, the screening system comprising:

[0090] a culture area having culture stations for culturing a plurality of samples;

[0091] an electromagnetic radiation source for irradiating the plurality of samples; and

[0092] a detector for detecting electromagnetic radiation emitted by the plurality of samples;

[0093] Therein, the cultivation station and the detector can be movable relative to each other or be in a fixed relationship.

[0094] One or more embodiments of the screening system can be configured to continuously identify biological agents, biological differences, pathogens, and / or genetic differences. BRIEF DESCRIPTION OF THE DRAWINGS

[0095] Embodiments will now be described, by way of example only, with reference to the accompanying non-limiting drawings, in which:

[0096] Figure 1 is a perspective view of an embodiment of a screening system.

[0097] Figure 2 yes Figure 1 A magnified perspective view of area A in the middle.

[0098] Figure 3 Schematic diagram of an image captured by the detector at the first time point during the culture process.

[0099] Figure 4 Schematic diagram of an image captured by the detector at the second time point during the culture process.

[0100] Figure 5 is an implementation of a light-based reference system.

[0101] Figure 6 is an implementation of a light-based reference system.

[0102] Figure 7 is an implementation of a light-based reference system.

[0103] Figure 8 is a top perspective view of an embodiment of an incubator unit.

[0104] Figure 9 is a bottom perspective view of an embodiment of an incubator unit.

[0105] Figure 10 is a perspective view of an embodiment of a screening system.

[0106] Figure 11 It is along Figure 10 A cross-sectional view taken along line BB.

[0107] Figure 12 is an end view of an embodiment of a screening system.

[0108] Figure 13 is an end view of another embodiment of a screening system. DETAILED DESCRIPTION

[0109] Embodiments relate to a screening system configured to identify biological agents, biological differences, pathogens, and / or genetic differences. The screening system can have a continuous screening throughput rate of at least 2000 samples per hour. Such a system can be referred to as a continuous "ultra-high throughput" screening system. Biological agents can include molecules used, formed, and / or metabolized in a biological system, including small molecules such as drugs, hormones, and steroids, large molecules such as biopolymers (proteins and carbohydrates), biological substrates, and metabolites. Biological differences can include analyzing one or more markers of a biological system to assess or determine changes in the biological system.

[0110] From Figure 1 At the outset, the screening system 10 has a structure 12 that supports a culture area 14. The culture area 14 has a plurality of culture stations 16 each for culturing a plurality of samples. Only the upper portion of the screening system 10 is shown in the figures, and features such as feet are omitted for clarity, as will be readily understood by those skilled in the art.

[0111] In Figure 1 In the illustrated embodiment, there are 12 culture stations, consisting of three rows by four columns of culture stations 16 distributed across the width of the culture area 14. Although Figure 1 Although 12 culture stations 16 are shown in the figures, the number of culture stations can be arbitrary. For example, the culture area 14 can have one culture station 16 or can have two or more culture stations 16. In embodiments, there are nX culture stations 16, where n is the number of rows of culture stations 16 in the culture area 14 and X is the number of culture stations 16 in each row.

[0112] In use, the culture stations 16 hold samples, which are then cultured for a predefined period of time to induce changes in the fluorescent and / or optical properties of the samples depending on the properties of the pathogens or genetic differences of analytes in the sample. Each sample typically contains a fluorescent and / or colorimetric agent that will change the properties of fluorescent and / or transmitted electromagnetic radiation. In embodiments, each culture station 16 is capable of holding a well plate insert, such as a 96-well plate insert.

[0113] The screening system 10 has a source of electromagnetic radiation in the form of light for illuminating the plurality of samples Figure 1(not shown). The electromagnetic radiation source may include one or more of UV, visible light, IR, near IR and / or far IR light sources. Figure 1 The type of incubation area 14 and incubation station 16 in the apparatus is related, but their actual locations can vary depending on the illumination and / or excitation parameters required to analyze the analytes in each sample.

[0114] The screening system 10 has a detector 18 for detecting electromagnetic radiation emitted by or passing through the plurality of samples. For example, if a fluorescent agent is used in the sample, the detector can detect the emission of the fluorescent agent after being excited by the electromagnetic radiation source.

[0115] Detector 18 and culture station 16 can be movable relative to each other. For example, in an embodiment, detector 18 is mounted on gantry 22. Gantry 22 is connected to tracks 24 and 26 so that gantry 22 can move back and forth along the length of structure 12 in direction D, at least over culture area 14. In an embodiment, gantry 22 is connected to tracks 24 and 26 via linear bearings. In an embodiment, gantry 22 is provided with wheels that run along tracks 24 and 26. In an embodiment, detector 18 can move along gantry 22 between tracks 24 and 26.

[0116] In an embodiment, the detector 18 is in a fixed relationship relative to the culture stations 16 and / or the culture area 14 (not shown). For example, the gantry 22 can be fixed to the rails 24 and the rails 26. In such an embodiment, the fixed detector 18 has a field of view that captures at least one culture station 16. If the fixed detector 18 can only capture some of the culture stations 16, a plurality of fixed detectors 18 can be used, such that each fixed detector 18 is configured to record radiation emitted from some of the plurality of culture stations 16, so that the plurality of fixed detectors 18 are combined to image the plurality of culture stations. For example, the screening system 10 can include two fixed detectors, wherein the first detector is capable of detecting electromagnetic radiation from a first half of the culture area 14 and the second detector is capable of detecting electromagnetic radiation from a second half of the culture area 14. The data, such as images, collected by the first detector and the second detector can be combined so that the first detector and the second detector are capable of recording radiation emitted from all culture stations 16 in the culture area. The use of two detectors 18 is merely an example, and the screening system can use any number of fixed detectors 18. When the detector 18 is fixed relative to the culture station 16 and / or culture area 14 , the detector 18 may be provided with an optical system to reduce optical problems, such as parallax errors towards the edge of the field of view of the detector 18 .

[0117] exist Figure 1In the embodiment shown, the detector 18 includes a plurality of detectors. In an embodiment, the plurality of detectors include cameras 20a to 20d. In an embodiment, the number of cameras 20 is equal to the number of culture stations 16 in each row of culture stations 16 in the culture area 14. In this way, each camera 20a, camera 20b, camera 20c and camera 20d is responsible for detecting the "detection channel" extending in the direction of the structure 12 (i.e., direction D). When the detector 18 includes one or more cameras, the detection can be in the form of an image, which is processed by a processing unit to analyze the colorimetric and / or fluorescence properties of the sample captured in the image. However, a single camera can image two or more rows. For example, the first camera can image the first and second rows, while the second camera can image the third and fourth rows.

[0118] In an embodiment, the camera 20 may be one or more color and / or IR cameras. The one or more cameras may be monochrome or multicolor cameras. The camera 20 may be a multispectral camera. The camera 20 may be a mechanical multispectral camera. The cameras and fluorophores used in the screening system may be those described in International Patent Application No. PCT / AU2022 / 051036.

[0119] Screening system 10 can use multiple cameras, and wherein each camera detects the light (i.e. electromagnetic radiation) of a wavelength or one or more specific wavelengths.For example, the first detector can detect the wavelength of 400nm to 500nm, and the second detector can detect the wavelength of 500nm to 600nm.In embodiments, the control comprised in each sample in multiple samples can be with a wavelength emission, and this wavelength is separated (removed) or orthogonal with other wavelengths or channel for detecting the biological preparation, biological difference, pathogen and / or gene difference in multiple samples.For example, the control can be triggered by electromagnetic radiation source at the beginning or end of the incubation period, wherein the emission from the control is in being considered to noisy or undesirable wavelength for the probe etc. for detecting biological preparation difference, biological difference, pathogen and / or gene difference.In this example, the electromagnetic radiation source for activating or exciting the control can be activated at the beginning or end of cultivation, and simultaneously, the electromagnetic radiation for activating or exciting the probe for detecting biological preparation difference, biological difference, pathogen and / or gene difference is deactivated or suppressed. This arrangement can eliminate the need to use a dedicated channel to monitor the control, which would otherwise be required to detect electromagnetic radiation emitted from the probe.

[0120] A robotic system 28 is used to load and unload samples into the culture area 14. The structure 12 typically includes side walls and a hood to prevent unwanted light and foreign matter from interfering with the samples. To better illustrate the components of the screening system 10, Figure 1The front sidewall and cover are omitted. The sample enters the structure 12 through a window 30 via an actuator 32, where the robotic system 28 can move the sample from a pick-up area 31 to an empty incubation station 16. The actuator 32 may include a slidable plate that accommodates multiple samples, such as a microplate and a pipette tip.

[0121] The screening system 10 includes a liquid handling system. Figure 1 3. The pipetting system 34 is shown for pipetting a reagent such as a fluorescent agent into a sample. The pipetting system 34 includes a pipette 35 (see Figure 12 or Figure 13 ) and a pipette tip 42 located in a pipette tip box 44. The pipette tip box 44 can be provided as a cassette-style pipette tip 42, or the pipette tip 42 can be provided on the actuator 32 and moved through the window with the sample. In use, the pipette 35 is capable of receiving and dispensing a pipette tip 42 from the pipette tip box 44.

[0122] In use, a sample passes through window 30, then through pipetting system 34 to add reagents for incubation, and then is transferred to pick-up area 31, where robotic system 28 picks up the sample and moves it to an empty incubation station 16, where it undergoes incubation. After incubation, the sample is removed from incubation station 16 and discarded, leaving a new empty incubation station that can be filled with a fresh sample. This process of adding a new sample, incubating, and discarding the incubated sample can be continued, with random access to the next available incubation station 16.

[0123] In the embodiment, the screening system 10 is provided with a waste chute 36, through which waste samples generated by the screening system 10, such as used microplates, can be placed after incubation. A trash bin 50 is located below the waste chute, and the trash bin 50 can collect discarded samples (see Figure 12 ). The waste chute 36 can be equipped with a shield 38 to guide discarded samples such as microplates into the waste chute. Figure 1 In the embodiment shown, the waste chute 36 is positioned adjacent to the pick-up area 31. Typically, after a sample has been discarded, there will be a free incubation station 16 available for a new sample, which can be picked up in the pick-up area 31.

[0124] In an embodiment, the pipetting system 34 is provided with a detector in the form of a camera 46, which is used to visually detect the presence or absence of one or more pipette tips 42 in the pipette tip box 44. For example, during pipette pickup, the camera 46 can detect any missing or non-existent pipette tips 42 in the pipette tip box 44 before the pipette tip 42 is placed on the pipette and / or detect any remaining or unpicked pipette tips 42 that may remain in the pipette tip box 44 after pickup. Missing a pipette tip 42 before picking up and having a pipette tip 42 after picking up can cause one or more samples to not be properly prepared, thereby resulting in false positive or false negative results. During the liquid sample transfer process, using the camera 46 to detect the presence or absence of a pipette tip 42 can trigger the system controller to issue an error alert to the user. If necessary, such errors can be corrected before cultivation.

[0125] The screening system 10 is arranged to identify whether and when screening and / or processing of individual samples or groups of samples in the incubation area 14 is complete. For example, once the samples in one incubation station 16 have completed incubation, the robotic system 28 can remove the samples from the incubation station 16 to provide an empty incubation station 16, which can then be filled with a new sample. This allows the screening system 10 to be used for continuous throughput processing of samples. Each incubation station 16 can incubate samples independently of one another, thereby eliminating the need for batch processing.

[0126] In use, the detector 18 continuously scans the culture stations 16 in the culture area 14 to monitor the culture status of multiple samples. When the detector 18 includes a camera 20, the camera captures multiple images of the culture station 16 during a defined culture time period. Because the camera moves along the length of the structure 12 in the direction D via the gantry 22, the specific position of the camera relative to the culture station 16 can change when the image is captured. In order to ensure that the images captured by the camera are processed correctly, they should be aligned so that the position of each sample is consistent. Alignment can be achieved by using a reference locator or benchmark. However, for samples analyzed by fluorescence, during the initial stages of culture, the culture area 14 is typically dark and there is no light source that can be used to illuminate the culture station 16. Using a light source to illuminate the culture station 16 will result in a reduction in sensitivity because any fluorescent response in the sample will be drowned out by the light source used to illuminate the culture station 16 for reference.

[0127] Thus, in an embodiment, the screening system 10 includes a fiducial in the form of a light-based fiducial system 40 located in the culture area 14. The light-based fiducial system 40 uses a light source, such as an LED light, to provide a reference for aligning the image along the XY axis. In an embodiment, the light-based fiducial system 40 uses two separate point light sources 38a and 38b associated with each culture station 16, such as Figure 2The point light sources 38a and 38b are held in fixed positions relative to the culture station 16. In embodiments, the detector 18 is configured to detect light emitted from the light-based fiducial system 40. For example, the camera 20 can be used to detect light from the light-based fiducial system 40. The light-based fiducial system 40 can be held fixed to the culture area. To prevent any flooding of any emitted fluorescence or changes in optical properties, the point light sources 38a and 38b are, for example, of low intensity with a brightness just sufficient to be continuously recorded in the image, and are spaced apart from the microplate held in use in the culture station 16 to prevent light from the point light sources 38a and 38b from bleeding into the microplate.

[0128] The source of electromagnetic radiation used to illuminate the samples in each culture station 16 can have a first wavelength range. The detector 18 (e.g., the camera 20) is typically configured to detect electromagnetic radiation emitted by the plurality of samples in a second wavelength range. The first wavelength range is typically different from the second wavelength range. For example, the source of electromagnetic radiation can be UV light emitting light having a wavelength of 100 nm to 400 nm, and the camera 20 can be fitted with a UV filter to block the UV light and only detect visible light having a wavelength of > 400 nm. In embodiments, the light from the light-based fiducial system 40 is visible in the second wavelength range.

[0129] At the initial stage of the culture where none of the samples have yet exhibited a fluorescent response, the resulting image of the culture station 16 will have no signal because the filter or the like will block any light emitted by the source of electromagnetic radiation used to excite the fluorescent agent in the samples from reaching the detector 18. However, as Figure 3 shown, the point light sources 38a and 38b provide a light signal that is detected and captured by the camera (i.e., the detector 18) to provide the image 100 with a frame of reference, allowing for proper orientation and alignment of subsequent images. For ease of explanation, the position of the culture station 16 in the image 100 is indicated by a dashed line 104, but is not actually visible in the image 100.

[0130] During the culture, some of the samples in the culture station 16 will provide a fluorescent response, as indicated by the dots 106 in Figure 4 the image 102. Thus, electromagnetic radiation emitted by the plurality of samples can be detected simultaneously with the light from the point light sources 38a and 38b. Having the light sources 38a and 38b appear in the image 100 and the image 102 allows for proper orientation of the orientation of the image 100 and the image 102. The electromagnetic radiation emitted by the plurality of samples and the light from the point light sources 38a and 38b can be detected using, for example, a multi-sensor dichroic prism or a pixelated multi-spectral filter array camera, or by a CCD camera or CMOS camera or detector linked to a beam splitter.

[0131] In an embodiment, system 10 is configured to enable simultaneous detection of electromagnetic radiation emitted by multiple samples. In an embodiment, system 10 is configured to enable at least quasi-simultaneous detection of electromagnetic radiation emitted by multiple samples using synchronized detection of light emitted from a light-based fiducial positioning system. As used herein, the term "quasi-simultaneous" refers to two processes occurring sequentially, but at such a rate that the two processes are considered to occur substantially simultaneously.

[0132] In an embodiment, synchronous detection of light emitted from a light-based fiducial system (e.g., from point light sources 38a and 38b) can be used to at least quasi-simultaneously detect electromagnetic radiation emitted by a plurality of samples. When the detector 20 and the culture area 14 are movable relative to each other, the system 10 can be configured such that at least quasi-simultaneous detection of electromagnetic radiation emitted by the plurality of samples includes detecting light from the light-based fiducial system (e.g., point light sources 38a and 38b) within a predefined interval immediately before or after detecting electromagnetic radiation emitted by the plurality of samples, and then performing time resolution to allow calculation of the positions of the plurality of samples from the light-based fiducial system by interpolating the relative motion trajectory of the detector and the culture area.

[0133] An advantage of using a light-based fiducial system 40 to provide a reference for orienting images of samples in each incubation station 16 is that it eliminates the need for mechanical position measurements. For example, encoders and stepper motors can be used to monitor the position of one object relative to another, but achieving the measurement accuracy required to orient subsequent images requires fine tolerances and expensive electrical equipment. Such mechanical position measurement devices also limit the speed at which the detector 18 can move across the incubation area 14, thereby reducing sample throughput and / or result accuracy. In contrast, the light-based fiducial system 40 is able to achieve pixel-level resolution image alignment using high detector movement speeds. Mechanical position measurements must also be performed for pre-imaging / detection alignment, while the light-based fiducial system 40 allows for post-imaging / detection alignment, which means that imaging / detection capture is not a rate-limiting step during analysis of samples in the screening system 10.

[0134] Point light sources 38a and 38b (such as Figure 5 ) describes a light-based reference system 40, but the light-based reference system 40 can also be embodied in other forms. For example, Figure 6 As shown, the light-based fiducial system 40 may use a single light source 38c having an asymmetric profile. In another embodiment, as shown Figure 7As best shown in FIG, 4 , the light-based fiducial system 40 includes a photodetector 39 and a laser source mounted on the gantry 22 and directed downwardly toward the culture area 14. As the gantry 22 moves across the culture area 14 during the culture process to inspect and monitor the culture conditions at the culture stations 16, laser light from the laser source on the gantry 22 sweeps across the photodetector 39. When the photodetector 39 detects the laser light, this event is used by the screening system 10 as a trigger to inspect / image the sample in the culture station 16. In this way, the use of the laser and photodetector 39 ensures that the inspection / imaging is performed at the same position relative to the photodetector 39, thereby ensuring that any resulting images are correctly oriented.

[0135] In another embodiment, the light-based fiducial system 40 may include an ultrasonic detector or laser to reflect light from one end of the culture area 14 or another fixed location on the structure 12, thereby providing a distance reference along the length of the culture area 14. The predefined location measured by the ultrasonic detector or reflected laser light can be used by the screening system 10 as a trigger to detect / image the sample in the culture station 16.

[0136] In an embodiment, the culture station 16 is fixed within the culture area. However, in another embodiment and as Figure 8 and Figure 9 As best shown in FIG, each of the culture stations 16 is in the form of an incubator unit 200 that can be individually removed from the culture area 14. When each of the culture stations 16 is in the form of an incubator unit 200, the culture area 14 includes one or more wells in which one or more incubator units 200 can be received. Thus, the terms "culture station" and "culture well" can be used interchangeably.

[0137] The incubator unit 200 has a thermal regulator or heating element in the form of a container plate 210. The container plate 210 is positioned or located in the upper part of the incubator unit 200 in use and has a plurality of containers 212 that can each hold a sample. Figure 8In the illustrated embodiment, the container plate 210 has 96 containers 212 that can accommodate 96-well plate inserts. A thermostatically controlled heating element is thermally connected to the container plate 210 for heating or cooling the container plate 210. Typically, the incubator unit 200 will heat the samples contained in the containers 212. However, in some cases, the incubator unit 200 will need to cool the samples contained in the containers 212. For example, if the incubator unit 200 is used in a hot climate and the culture conditions require the culture temperature to be lower than the ambient temperature for culture conditions close to 20°C, for example, the incubator unit 200 is configured to cool the samples contained in the plurality of containers 212. In an embodiment, the incubator unit 200 includes a piezoelectric or thermoelectric (Peltier) unit to heat or cool the container plate 210. Therefore, the term "heating element" used throughout this disclosure is not limited to heating, but can also provide cooling. Thus, the term "heating element" can be used interchangeably with the term "thermal regulator".

[0138] The cultivation unit 200 also has a source of electromagnetic radiation in the form of a light source 214, which is positioned or located in the lower part of the cultivation unit 200 in use. Each container 212 is optically connected to the light source 214. Figure 1 and Figure 9 In the embodiment shown, each container 212 is optically connected to a light source 214 via a fiber optic cable 216. However, the use of fiber optic cables is merely an example and other optical coupling means may be used, such as by direct illumination.

[0139] In the case where each culture unit 200 has its own heating element and light source, the culture conditions for each culture unit 200 can be specific and independent of each other. Referring to the screening system 10 only as an example, each of the 12 culture stations 16 (i.e., wells) can accommodate a culture unit 200, and each of the culture units 200 can have its own culture conditions. Alternatively, some of the culture units 200 can be grouped together according to culture conditions. For example, a first group of culture units 200 can have a first culture condition, and a second group of culture units 200 can have a second culture condition. Cultivation can be isothermal. Each incubator unit 200 can operate independently of each other.

[0140] In embodiments, the incubator units 200 are replaceable, such that each incubator unit 200 can be installed or removed in a manner independent of one another. The incubator units 200 can be pre-configured to perform a particular type of incubation. For example, a first incubator unit 200 can be configured with a first incubation condition to identify a first pathogen or genetic difference, and a second incubator unit 200 can be configured with a second incubation condition to identify a second pathogen or genetic difference. If the screening system (e.g., 10) is equipped with both the first and second incubator units, the screening system can simultaneously identify two or more groups of pathogen or genetic differences according to different incubation conditions. Incubation conditions include heating characteristics such as isothermal and non-isothermal heating, and illumination characteristics such as driving a single light source or alternating a plurality of light sources.

[0141] The advantage of pre-configuring the incubator units 200 is that it allows a user to more easily change the type of pathogen or genetic difference to be identified by the screening system and the type of incubation required. For example, if the screening system 10 is equipped with a first type of incubator unit 200 having a first incubation condition, the user can simply replace one or more of the first type of incubator units 200 with a second type of incubator unit 200 having a second incubation condition.

[0142] In embodiments, the incubator units 200 include an identifier that can be read by the incubator stations 16 or the screening system 10, e.g., by the central processing unit, when the incubator units are installed to the incubator stations 16. For example, each incubator unit 200 can be provided with a unique code or the like that allows the incubator stations 16 or the screening system 10 to identify the type of incubator unit 200 and the associated pre-defined incubation condition. The identifier can be transmitted to the incubator stations 16 or the screening system 10 by a transmission means such as RFID, CAN Bus, Ethernet connection, optical scanning, bar code, or QR Code. Using a wired connection to transmit the identifier can also provide power to the incubator units 200. However, power can be delivered independently of the means to transmit the identifier using a specific interface such as a receptacle and plug.

[0143] Using the identifier to tell the incubator stations 16 or the screening system 10 what type of incubator unit 200 is placed in the incubator station 16 helps to remove user input and any associated user error when installing the incubator units 200. This can be beneficial when a user needs to perform maintenance or update the incubation zones 14, e.g., by replacing the incubator units 200 from one type to another. Embodiments in which the incubator stations 16 are each in the form of an incubator unit 200 that can be individually removed from the incubation zones 14 can help the screening system 10 to provide greater flexibility in the types of pathogen or genetic difference and the identification methods associated therewith that can be identified by the screening system 10.

[0144] In an embodiment, the culture unit 200 includes a light-based reference system. Figure 8 As shown, the culture unit 200 can include point light sources 28a and 38b. Including a light-based fiducial system in the culture unit 200 means that the fiducials always remain in a fixed position relative to the container 212, which helps improve accuracy when aligning images of the sample contained in the container 212.

[0145] Embodiments of the screening system 10 include an airflow system 300, such as Figure 10 、 Figure 11 and Figure 12 Please note that for ease of reference, the Figure 10 、 Figure 11 and Figure 12 Not all features of the screening system 10 are identified by reference numerals. The airflow system 300 has an inlet 314 located outside the structure 12, so that the inlet 314 can draw air from the environment outside the screening system 10. A filter, such as a HEPA filter, is provided in the inlet 314. The filter is accessible by a user from outside the inlet 314. The inlet 314 is also provided with a motor group 316, which has a fan 318 capable of drawing air through the filter. The filter removes particulate matter from the air drawn in through the inlet 314, thereby forming purified air. The purified air is then blown through the duct 320, where the purified air exits through the outlet 310.

[0146] A housing 312 is positioned above the pipetting system 34 to form a pipetting chamber 322. The pipetting chamber 322 can be considered a liquid handling chamber. An outlet 310 is located within the pipetting chamber 322, allowing purified air to exit the outlet 310 and enter the pipetting chamber 322. In an embodiment, the airflow system 300 is configured to maintain the pressure inside the pipetting chamber 322 at an elevated pressure compared to the environment outside the pipetting chamber 322. The window 30 allows air at a relative pressure to exit the pipetting chamber 322. This elevated pressure means that purified air exits the pipetting chamber 322 via the window 30, as indicated by the path of the dashed line 324. Purified air can continuously exit through the window 30. Continuous exit of purified air from the pipetting chamber 322 helps reduce the possibility of foreign matter, particulate matter, or aerosolized matter entering the pipetting chamber 322 through the window 30 and contaminating the sample being analyzed by the screening system 10. Purified air can also exit the pipetting chamber 322 on the side of the pickup area 31 of the pipetting system 34 and be directed to the incubation area 14.

[0147] In the embodiment, Figure 13As best shown, the airflow system 300 provides a conduit 326 defined between the side wall 328 and the wall of the housing 312. The conduit 326 has an opening 310a positioned towards the top or upper portion of the pipetting chamber 322. The conduit 326 directs the purified air through the opening 310a to the top of the pipetting chamber 322 such that the purified air flows down over and / or through the components of the pipetting system 34 and out through the window 30 or to the culture area 14. The flow of the purified air is represented by arrows 330 in Figure 13 The conduit 326 can assist in reducing the circulation of the purified air within the pipetting chamber 322.

[0148] Now referring back to Figure 1 In embodiments, the screening system 10 includes a detector for detecting one or more physical conditions of the screening system 10 in the form of an ultrasonic detector 48. The ultrasonic detector 48 is mounted to the robotic system 28 and is capable of detecting one or more physical conditions of the screening system 10 at one or more predefined locations in the area below the robotic system 28. In embodiments, the ultrasonic detector 48 is capable of detecting a height-based condition of a component of the screening system 10 at one or more predefined locations, for example, along the Z direction. For example, certain actions result in the presence or absence of a component. Take the example of placing a new set of samples in the culture station 16, there is a difference in height along the z direction between the presence of a sample in the culture station 16 and the absence of a sample.

[0149] If the ultrasonic detector detects that the height of a component is outside of a predefined condition, a trigger can be tipped to alert a user that an error has occurred in the screening system 10. For example, if the screening system 10 calculates that a sample should be at a particular culture station 16, which would be associated with a physical condition of a culture station 16 of a known height, but the ultrasonic detector 48 detects that the detected height is outside of the physical condition of a sample in the culture station 16, the trigger will be tipped. Thus, the ultrasonic detector 48 can be used to detect the presence or absence of an object at one or more locations in the screening system 10. The physical condition can also include whether the gripper 52 of the robotic system 28 correctly picks up a microplate. The physical condition can also include the presence or absence of a microplate in the pick-up area 31 and / or the culture station 16. In embodiments, the robotic system 28 is configured to remove individual samples or sets of samples from the culture station 16, leaving an empty sample rack or set of sample racks. The robotic system 28 can be the robotic system outlined in International Application Patent PCT / AU2021 / 051209 or PCT / AU2022 / 051036.

[0150] The ultrasonic detector 48 can also be used to detect the fill level of the bin 50. In use, waste samples, such as waste microplate wells, are discarded in the bin as described above. As more samples are placed into the bin 50, the fill level of the bin 50 increases. This increase in fill level is associated with a change in height in the Z direction. Thus, the ultrasonic detector 48 can be used to detect when the waste level in the bin reaches a maximum level. The fill level of the bin 50 can be staged. For example, a user signal can be triggered when the bin reaches a first fill threshold, such as 80% full. A second or more fill thresholds, such as 90% full, can then be triggered. A final maximum fill level, such as 100% full, can be triggered such that the screening system 10 stops loading new samples until the user empties the bin 50. Thus, the ultrasonic detector 48 can be used to prevent clogging and / or damage of the screening system 10 and can help improve accuracy or at least detect sources of error during culturing and analysis.

[0151] The above-described embodiments relate to screening systems 10 having multiple culture stations 16. However, the principles of the present disclosure also relate to screening systems having one or two culture stations. For example, in such embodiments, the detector can be fixed and movement of the detector (e.g., 18) relative to the culture station can be achieved by manually moving the culture station relative to the detector. Other principles of the present disclosure, such as embodiments relating to use of a light-based fiducial system, removable culture units, use of an air flow system, etc., are also applicable to screening systems having one or two culture stations.

[0152] Although the detailed description refers to 96-well plates, the present disclosure is not limited to 96-well plates and can include any type of microplate, such as 6, 24, 48, 96, 384, and 1536-well plates, etc.

[0153] In the appended claims and present description, the word "comprise" or variations such as "comprises" or "comprising" are used in an inclusive sense, that is to say, specifying the presence of the stated features but not precluding the presence or addition of further features in various embodiments of the present disclosure. Modifications and alterations to this disclosure that are obvious or apparent to a person skilled in the art are deemed to be within the scope of the present disclosure.

Claims

1. A screening system configured to identify biological agents, biological differences, pathogens, and / or genetic differences, the screening system comprising: a culture area having culture stations for culturing a plurality of samples; an incubator unit, which is receivable in the incubation station, the incubator unit being replaceable and comprising: a thermal regulator having a plurality of containers each capable of containing a sample, the thermal regulator being configured to heat or cool the plurality of containers; and an electromagnetic radiation source for irradiating one or more of the containers; and a detector for detecting electromagnetic radiation emitted by the plurality of samples.

2. The screening system according to claim 1, wherein: The screening system includes a plurality of incubation stations each capable of accommodating an incubator unit.

3. The screening system according to claim 2, wherein: Each incubator unit can be operated independently of the others.

4. The screening system according to any one of claims 1 to 3, wherein: The thermal regulator is located in or forms an upper part of the incubator unit when in use, and the electromagnetic radiation source is located in or forms a lower part of the incubator unit when in use.

5. The screening system according to any one of claims 1 to 4, wherein: Each container is optically connected to the electromagnetic radiation source via a fiber optic cable.

6. The screening system according to any one of claims 1 to 5, wherein: The incubator unit comprises an identifier which can be read by the cultivation station after the incubator unit is installed in the cultivation station, wherein the identifier is used to identify a predefined operating condition of the incubator unit.

7. The screening system according to any one of claims 1 to 6, wherein: The incubator unit includes a light-based fiducial system capable of generating light that is used as a reference point to orient images of the incubation station captured by the detector.

8. A screening system configured to identify biological agents, biological differences, bioactive agents, pathogens, and / or genetic differences, the screening system comprising: a culture area having a culture station for culturing a plurality of samples, the culture station having a light-based reference system; an electromagnetic radiation source for irradiating the plurality of samples; and a detector for detecting electromagnetic radiation emitted by the plurality of samples; Therein, the light-based fiducial system is used as a reference point to orient the image of the cultivation station captured by the detector.

9. The screening system according to claim 8, wherein: The screening system includes a plurality of incubation stations.

10. The screening system according to claim 8 or 9, wherein: The incubation station includes an incubator unit having a thermal regulator for heating or cooling a sample contained in the incubator unit, The incubator system is replaceable, and The light-based reference system is located on the thermal regulator.

11. The screening system according to claim 10, wherein: The incubator unit comprises the electromagnetic radiation source for irradiating the plurality of samples.

12. The screening system according to any one of claims 7 to 11, wherein The electromagnetic radiation source is configured to illuminate the plurality of samples within a first wavelength range and the detector is configured to detect electromagnetic radiation emitted by the plurality of samples within a second wavelength range, and wherein the second wavelength range is different from the first wavelength range and the light-based fiducial system is visible within the second wavelength range.

13. The screening system according to any one of claims 7 to 12, wherein: The detector is configured to detect light emitted from the light-based reference system.

14. The screening system according to any one of claims 7 to 13, wherein: The light-based fiducial system includes two light-based fiducials located at the culture station.

15. The screening system according to any one of claims 7 to 14, wherein The screening system is configured to enable simultaneous detection of the electromagnetic radiation emitted by the plurality of samples and the light from the light-based reference system.

16. The screening system according to any one of claims 7 to 14, wherein The screening system is configured to enable simultaneous detection of the electromagnetic radiation emitted by the plurality of samples.

17. A screening system according to any one of claims 7 to 14, wherein: The screening system is configured to enable at least quasi-simultaneous detection of the electromagnetic radiation emitted by the plurality of samples using synchronized detection of the light emitted from the light-based fiducial positioning system.

18. A screening system according to any one of claims 7 to 17, wherein The light-based fiducial system includes a light source located at the culture station.

19. The screening system according to any one of claims 1 to 18, wherein The detector and the cultivation station are movable relative to each other.

20. The screening system of claim 19, wherein: The screening system further includes a movement mechanism configured to move the detector across the culture area.

21. The screening system of claim 20, wherein: The screening system is configured such that the detector is continuously moved across the culture area during use of the system.

22. A screening system according to any one of claims 19 to 21 when dependent on claim 17, wherein The screening system is configured such that the at least quasi-simultaneous detection of the electromagnetic radiation emitted by the plurality of samples comprises detecting light from the light-based reference system within a predefined interval immediately before or after the detection of the electromagnetic radiation emitted by the plurality of samples, and then performing time resolution to allow calculation of the positions of the plurality of samples relative to the light-based reference system by interpolating the relative motion trajectories of the detector and the culture area.

23. The screening system according to any one of claims 1 to 18, wherein The detector is a fixed detector and has a field of view that captures at least one culture station.

24. The screening system according to any one of claims 1 to 23, wherein The screening system includes a plurality of detectors.

25. A screening system according to claim 24 when dependent on claim 23, wherein The screening system comprises a plurality of culture stations, wherein each of the plurality of fixed detectors is configured to record radiation emitted from some of the plurality of culture stations such that the plurality of fixed detectors in combination record radiation emitted by the plurality of culture stations.

26. The screening system according to claim 24 or 25, wherein: Each detector of the plurality of detectors is configured to record radiation emitted by the plurality of samples at a predefined wavelength or at one or more predefined wavelengths, the predefined wavelength or one or more predefined wavelengths being different from the predefined wavelength or one or more predefined wavelengths of other detectors of the plurality of detectors.

27. The screening system according to claim 24 or 25, wherein: At least one of the plurality of detectors is configured to record radiation emitted by the plurality of samples at a predefined wavelength that is different from a predefined wavelength of at least one of the plurality of detectors, the at least one of the plurality of detectors being configured to record radiation at a similar time as the other detectors but distinguished by means of time-resolved detection of asynchronous radiation in response to the excitation pulse.

28. A screening system according to any one of claims 1 to 27, wherein The screening system further comprises a liquid handling system for transferring liquid reagents to the plurality of samples, wherein the liquid handling system comprises a pipette for transferring liquid and capable of receiving and dispensing pipette tips from a pipette tip box when in use.

29. The screening system of claim 28, wherein: The screening system further includes a detector for visually detecting the presence or absence of one or more pipette tips in the pipette tip magazine.

30. The screening system according to claim 28 or 29, wherein The screening system further includes an airflow system having an inlet positioned to draw air from an environment external to the screening system, a filter, and an outlet located in the chamber housing the liquid handling system, the airflow system being configured to: drawing air in through the inlet and filtering it to form purified air, and then blowing the purified air into the chamber containing the liquid handling system; and The chamber containing the liquid handling system is maintained at an elevated pressure compared to an environment external to the chamber containing the liquid handling system.

31. The screening system according to any one of claims 1 to 30, wherein The screening system further comprises a robotic system for loading and unloading samples, wherein the system for screening for pathogens or genetic differences is arranged to identify whether and when screening and / or processing of each sample or group of samples in the culture area is complete, wherein the robotic system is arranged to: removing the individual samples or the sample groups from the incubation station to leave an empty sample rack or sample group rack, wherein the samples or sample groups are being removed at locations surrounding or adjacent to samples or sample groups that have not yet completed screening and / or processing; thereafter: Obtain a fresh sample or set of samples; and then filling the empty positions in the incubator with the fresh sample; The system is thus suitable for continuous throughput of samples.

32. A screening system according to any one of claims 1 to 31, wherein The screening system also includes an ultrasonic detector for detecting one or more physical conditions of the system.

33. The screening system of claim 32, wherein: The one or more physical conditions of the system include the presence or absence of a sample at a predefined location in the culture area.

34. A screening system according to any one of claims 1 to 33, wherein The screening system also includes a waste bin configured to receive waste generated by the screening system.

35. The screening system of claim 34 when dependent on claim 32, wherein: The ultrasonic detector is configured to measure a fill level of the waste bin.

36. A screening system configured to identify biological agents, biological differences, pathogens, and / or genetic differences, the screening system comprising: a culture area having culture stations for culturing a plurality of samples; an electromagnetic radiation source for irradiating the plurality of samples; a detector for detecting electromagnetic radiation emitted by the plurality of samples; a chamber housing a liquid handling system for transferring liquid reagents to the plurality of samples; and an airflow system having an inlet positioned to draw air from the environment external to the screening system, a filter, and an outlet positioned within the chamber, the airflow system being configured to: drawing air in through the inlet and filtering it to form purified air and then blowing the purified air into the chamber; and The chamber is maintained at an elevated pressure compared to the environment outside the chamber.

37. The screening system of claim 36, wherein: The culture station comprises a light-based fiducial system, wherein the light-based fiducial system is used as a reference point to orient an image of the culture station captured by the detector.

38. The screening system of claim 36 or 37, wherein: The screening system further comprises an incubator unit receivable in the incubation station, the incubator unit being replaceable and comprising: a thermal regulator having a plurality of containers each capable of containing a sample, the thermal regulator being configured to heat or cool the plurality of containers; and A source of electromagnetic radiation for irradiating one or more of the containers.

39. A screening system configured to identify biological agents, biological differences, pathogens, and / or genetic differences, the screening system comprising: a culture area having culture stations for culturing a plurality of samples; an electromagnetic radiation source for irradiating the plurality of samples; and a detector for detecting electromagnetic radiation emitted by the plurality of samples; Therein, the cultivation station and the detector are movable relative to each other or are in a fixed relationship.

40. A screening system according to any one of claims 36 to 39, wherein The screening system is as defined in any one of claims 1 to 35.

Images