Medical device for performing a liquid biopsy and related manufacturing method

Abstract

The present invention relates to a medical device (100) for liquid biopsy configured to assess a patient's health status and comprising: - a main body (1) constituting a physical support and comprising a channel (10) configured for the transit of a flow of bodily fluid of said patient; - an inlet duct (2) connected to said channel (10) to convey said flow of bodily fluid to said channel (10); - an outlet duct (3) connected to said channel (10) for a discharge of said flow of bodily fluid from said channel (10); wherein the main body (1) comprises a plurality of receptors operatively connected to said channel (10) and configured to detect a presence and / or a concentration of at least one substance in said flow of bodily fluid, said substance being representative of said patient's health status.

Description

[0001] “Medical device for performing a liquid biopsy and related manufacturing method”

[0002] DESCRIPTION

[0003] FIELD OF THE INVENTION

[0004] The present invention relates to a device, in particular a device for medical use, configured to perform a liquid biopsy. In particular, the present invention concerns a medical device configured to perform a liquid biopsy in order to obtain at least one piece of information regarding a patient’s health status. The present invention also relates to a device, in particular a device for medical use, configured for the administration of at least one substance into a patient’s bodily fluid. In particular, the present invention relates to a medical device configured for releasing and / or dosing at least one substance, for example a substance for medical treatment, into a patient’s bodily fluid.

[0005] Furthermore, the present invention relates to a method for manufacturing said device for medical use.

[0006] PRIOR ART

[0007] According to the Istituto Superiore di Sanita (Italian National Institute of Health), chronic non- communicable diseases, such as cardiovascular diseases, diabetes, cancer, chronic respiratory diseases, and mental health disorders, account for approximately 90% of deaths in Europe. Among these, neoplasms are characterized by uncontrolled proliferative processes which, in advanced stages of the disease, result in an involvement of other body regions (metastases), leading to the loss of function at the site of origin. Neoplastic processes are driven by both environmental components (lifestyle, dietary habits, etc.) and genetic / genomic factors which make tumor etiology ''multifactorial''. On a molecular level, multiple biological mechanisms trigger neoplastic transformation. Overall, alterations in the physiological mechanisms of tumor cells arises from the development of mutations in the DNA of somatic cells, driving neoplastic development. Mutations playing a key role in triggering the development of neoplasia are referred to as "drivers" and are typically observed in genes crucial for maintaining cellular physiological homeostasis. In particular, these alterations involve genes classified as "oncogenes" or "tumor suppressor". The first category includes genes that promote cell proliferation through their protein products (e.g., RAS, EGFR), while the second category includes genes that encode proteins responsible for regulating cell proliferation (e.g., CDK-cyclins) and preserving genomic stability (gatekeepers; e.g., p53, BRCA).

[0008] Lung cancer (commonly referred to as "LC") is currently one of the leading causes of death. In Italy, lung cancer is the second most common malignancy (over 40,000 new diagnoses annually), regardless of age and sex. Due to latent symptoms in early stages, diagnoses are often made late (stage IIIB-IV), by which point the disease is metastatic.

[0009] Currently, the diagnosis of solid tumors relies on the morphological evaluation of tissue samples representative of the neoplastic lesion and on diagnostic imaging procedures (CT scan, PET scan, ultrasound, MRI, X-ray, etc.) that allow to optimize the clinical-diagnostic assessment of the lesion. However, the technical time required for preparing and morphologically assessing histological samples, combined with interpretive challenges of instrumental investigation techniques, can prolong the time to definitive diagnosis, thereby increasing the challenges in detecting the lesion in the early stages of the disease.

[0010] Among known tumors, lung cancer is one of the most aggressive, as it progresses to cancer in an almost entirely asymptomatic manner. For this reason, the diagnosis is made in the advanced stages of the disease, at which point the disease has become metastatic. Surgery combined with adjuvant chemotherapy is the most commonly pursued therapeutic option for lung cancer patients.

[0011] In the last decade, international guidelines for clinically assessing patients with non-small cell lung carcinoma (NSCLC) have made molecular analysis mandatory for detecting specific mutations in nucleic acids. In line with precision medicine, the identification of these molecular alterations in advanced stages of the disease enables the selection of NSCLC patients who may benefit from targeted treatments based on the molecular characteristics of the disease. These treatments rely on the specific and selective recognition of tumor cells by molecularly targeted drugs, provided that these cells exhibit specific genomic fingerprints that render such biologic drugs effective in treating these patients.

[0012] However, the molecular analysis to be performed on patient samples for molecular diagnosis faces biological and technical challenges. From a biological perspective, samples obtained from patients with advanced-stage NSCLC are predominantly limited to small biopsies or cytological preparations. These types of samples are typically characterized by low cell ularity and a reduced quantity of extractable nucleic acids, regardless of the preparation method. Moreover, the use of cytological preparations obtained through fine-needle aspiration of the neoplastic lesion using negative-pressure needles introduces further challenges to the execution of molecular testing due to the heterogeneity of cytological preparations employed in clinical practice and the need to standardize the pre- analytical preparation steps for these samples.

[0013] For instance, the devices described in documents WO2016 / 164359A1 and US2008 / 0038738A1 provide for the collection, or sampling, of biological material from its natural site, i.e., the patient’s body, and the subsequent transfer of such biological material into a device for analysis, suitable for detecting the presence of one or more substances (markers) representative of the presence and / or progression of a pathology. In this regard, currently known technologies are characterized as ex vivo techniques, involving a spatial separation between the site of the biological material to be analyzed and the analysis device, which entails contamination risks during transport. Additionally, it should be emphasized that known methods, particularly biopsies, are highly invasive and carry the risk of compromising the patient’s health, for example due to infections resulting from the surgical procedures necessary to collect the biological material to be analyzed.

[0014] For the reasons outlined above, there is a particularly pressing need in the oncological medical field for the availability of investigative methodologies and corresponding devices capable of enabling early and "real-time" diagnosis, with significantly reduced waiting times compared to routine clinical- instrumental investigations, thereby allowing for the earliest possible management of the patient. Furthermore, the need to develop new diagnostic solutions that enable the dynamic evaluation of treatment effectiveness, promptly identifying patients experiencing recurrence, is equally evident. In particular, in the diagnosis and management of patients affected by non-small cell lung carcinoma (NSCLC), there is a strong need for reliable and user-friendly methodologies and devices.

[0015] In the medical field, and particularly in the evaluation of oncological patients, the Applicant has identified certain limitations and drawbacks. Specifically, the Applicant has observed that medical devices and related methodologies employed in the context of diagnostic procedures require excessive timeframes, often undermining the effectiveness of treatment aimed at restoring the patient’s health.

[0016] Moreover, traditional diagnostic methodologies are particularly complex and, consequently, excessively costly. These characteristics make them unsuitable for use as preventive measures within routine health check-ups aimed at monitoring an individual’s health status.

[0017] PURPOSE OF THE INVENTION

[0018] In this context, one of the objectives underlying the present invention, in its various aspects and / or embodiments, is to provide a medical device for performing a liquid biopsy capable of providing an assessment of a patient’s specific health status in a significantly short time, especially when compared to traditional diagnostic methodologies such as CT scans, PET scans, ultrasound, MRI, and X-ray.

[0019] In particular, the objective of the present invention is to provide a medical device for performing a liquid biopsy capable of delivering a diagnosis essentially in real time.

[0020] Another objective of the present invention is to provide a medical device for liquid biopsy capable of diagnosing a pathology, such as a tumor related disease, determining the prognosis and the potential recurrence of the disease, as well as monitoring minimal residual diseases after treatment and the development of resistance mechanisms following therapy.

[0021] A further objective of the present invention is to provide a medical device for liquid biopsy capable of providing an assessment of a patient’s specific health status at a particularly low cost, especially when compared to the per-diagnosis cost of traditional diagnostic methodologies, such as CT scans, PET scans, ultrasound, MRI, and X-ray.

[0022] Another objective of the present invention is to describe a medical device for liquid biopsy with a particularly low production cost. Specifically, the medical device for liquid biopsy as disclosed in this document has a sufficiently low cost to enable its use as a disposable product.

[0023] A further objective of the present invention is to provide a medical device for liquid biopsy that is highly versatile. In particular, the objective of the present invention is to propose a medical device that can be easily redesigned for any type of pathology intended to be assessed.

[0024] Another objective of the present invention is to propose a method for manufacturing the aforementioned medical device for a liquid biopsy. In particular, an objective of the present invention is to describe a method for manufacturing a medical device for liquid biopsy that is simple to implement.

[0025] Another objective of the present invention is to provide a method for manufacturing the aforementioned medical device for liquid biopsy whose implementation is particularly fast and cost- effective.

[0026] Another objective of the present invention is to describe a manufacturing method for the aforementioned medical device for liquid biopsy that is scalable for mass production, enabling industrial-scale manufacturing of the device.

[0027] Another objective of the present invention is to provide a medical device for the administration of at least one substance, such as a substance for medical treatment, into a patient’s bodily fluid. Specifically, the medical device described in the present invention allows for the efficient release of one or more substances into a bodily fluid, such as the bloodstream, of a patient while being minimally invasive for the patient.

[0028] A further objective of the present invention is to describe a medical device that allows for extremely controlled and adjustable dosing of at least one substance into a patient’s bodily fluid.

[0029] Another objective of the present invention is to illustrate a medical device that enables the administration of at least one substance into a patient’s bodily fluid in a substantially painless and non-invasive manner, particularly when compared to other methods such as oral capsule administration and / or direct injections into blood vessels via syringes.

[0030] Another objective of the present invention is to describe a medical device for administering at least one substance into a patient’s bodily fluid with particularly low production costs. Specifically, the medical device described in this document has a sufficiently low cost to ensure its use as disposable and / or personal product. A further objective of the present invention is to provide a medical device for administering at least one substance into a patient’s bodily fluid that is highly versatile. In particular, objective of the present invention is to propose a medical device that can be easily redesigned for any type of substance to be released into the specific bodily fluid and for the particular treatment intended for the patient. Another objective of the present invention is to provide a method for manufacturing the aforementioned medical device for administering at least one substance into a patient’s bodily fluid. In particular, one objective of the present invention is to describe a method for manufacturing the aforementioned medical device that is simple to implement.

[0031] Another objective of the present invention is to provide a method for manufacturing the aforementioned medical device for administering at least one substance into a patient’s bodily fluid whose implementation is particularly fast and cost-effective.

[0032] Another objective of the present invention is to describe a method for manufacturing the aforementioned medical device for administering at least one substance into a patient’s bodily fluid that is scalable for mass production, enabling industrial-scale manufacturing of the device.

[0033] These and other objectives, which that will become more apparent in the following description, are substantially achieved by a medical device for liquid biopsy, a method for manufacturing the aforementioned medical device for liquid biopsy, a medical device for administering at least one substance into a patient’s bodily fluid, and a method for manufacturing the aforementioned medical device, according to one or more of the appended claims and the following aspects and / or embodiments, which may be variously combined, possibly also with the aforementioned claims.

[0034] SUMMARY

[0035] In a first aspect, the invention relates to a device for medical use. In accordance with this aspect, the device for medical use of the present invention is configured to perform a liquid biopsy to obtain a piece of information relating to a patient’s health status. In the present document, the patient’s health status refers to a biological parameter, such as a biological parameter representative of the potential presence of at least one ongoing pathology.

[0036] In one aspect, in order to perform said liquid biopsy, said medical device is configured to be applied to said patient’s body. In accordance with this aspect, when said medical device is applied to said patient, at least one component of the medical device is in fluid communication with said patient’s body so as to receive the flow of fluid to be analyzed. Preferably, said medical device is configured to reintroduce said flow of fluid back into the patient’s body.

[0037] In one aspect, said medical device for a liquid biopsy comprises: - a main body constituting a physical support for the further components of said medical device;

[0038] - a channel configured to be supported by said main body and / or obtained within said main body and / or integrated into said main body.

[0039] In one aspect, said channel is configured for a transit of a flow of fluid, in particular a patient’s bodily fluid.

[0040] In one aspect, said medical device comprises at least one receptor operatively active on said fluid transiting said channel.

[0041] In one aspect, said medical device comprises a plurality of receptors operatively active on said fluid transiting the channel. In particular, said plurality of receptors is configured to detect a presence and / or a concentration of at least one substance in said bodily fluid circulating in said channel. In accordance with this aspect, said at least one substance is representative of the patient’s health status. In other words, said plurality of receptors is configured to detect, and thereby assess, the presence and / or concentration of at least one substance representative of the patient’s health status in said flow of fluid transiting said channel.

[0042] In one aspect, said plurality of receptors comprises at least a first receptor and a second receptor operatively active on the fluid transiting said channel. In accordance with this aspect, said first receptor is configured to detect a presence and / or a concentration of a first substance in said fluid, while said second receptor is configured to detect a presence and / or a concentration of a second substance in said fluid. Preferably, said first substance differs from said second substance.

[0043] In one aspect, said at least one substance detectable by said plurality of receptors in said bodily fluid enables at least one of the following assessments regarding the patient’s health status:

[0044] - diagnosis of at least one pathology;

[0045] - prognosis of at least one pathology;

[0046] - relapse of disease;

[0047] - presence of minimal residual disease after therapeutic treatment of a pathology;

[0048] - development of resistance mechanisms after therapeutic treatment.

[0049] In one aspect, said plurality of receptors comprises a plurality of biosensors. In accordance with this aspect, said plurality of biosensors comprises at least one of the following elements: oligonucleotide probes, pH meters, aptamers, and antibodies.

[0050] In one aspect, said plurality of biosensors is configured to detect mutations in nucleic acids circulating in said bodily fluid. In one aspect, said plurality of biosensors is configured to detect circulating free DNA (cfDNA) in said bodily fluid. Circulating free DNA (cfDNA) refers to DNA normally released by all cells as part of regular cellular renewal processes and can be isolated from various biological fluids, including, for example, blood.

[0051] In one aspect, said plurality of biosensors is configured to evaluate the levels of DNA fragments having specific mutations correlated with a specific pathology. Said free DNA fragments are present in the bodily fluid as they may have been released by cells undergoing apoptosis or necrosis.

[0052] In a further aspect, said plurality of biosensors is configured to detect circulating tumor DNA (ctDNA) released by tumor cells during their renewal and growth processes. In accordance with this aspect, said plurality of biosensors is configured to isolate said ctDNA from the bodily fluid circulating in the channel defined in the main body.

[0053] In accordance with the above, the terms cfDNA and ctDNA will be used in this document to refer to circulating free DNA and circulating tumor DNA, respectively, for descriptive convenience.

[0054] In one aspect, said plurality of biosensors is configured to detect a concentration of cfDNA fragments comprised between 0.001 ng and 100 ng throughout the entire operational range of the medical device.

[0055] In one aspect, said plurality of biosensors is configured to detect a specific protein concentration in said bodily fluid.

[0056] In a preferential aspect, said plurality of biosensors is configured to detect an altered concentration of proteins compared to a physiological condition. In the present document, the expression "altered protein concentration compared to a physiological condition" is intended to refer to a decreased or increased production of proteins with respect to a healthy physiological state, i.e., one where no particular pathology is present.

[0057] In one aspect, said oligonucleotide probes are synthetic oligonucleotide structures (20-25 base pairs) configured to recognize, through complementarity, specific coding and non-coding sequences of nucleic acids (DNA, RNA). It should be noted that the length of circulating free nucleic acids strictly depends on physiological conditions affecting the degree of DNA fragmentation. In this context, apoptosis (programmed cell death) generates DNA fragments whose lengths range from 185 to 200 base pairs (bp), which can consequently bind to said oligonucleotide probes.

[0058] In one aspect, said oligonucleotide probes comprise at least one of an oligonucleotide probe complementary to the ALU247 DNA interspersed sequence and an oligonucleotide probe complementary to the ALU115 DNA interspersed sequence. It should be noted that ALU {Arthrobacter luteus) sequences are highly repeated interspersed sequences in the human genome (1 .4x106copies). In one aspect, said plurality of biosensors comprises at least one oligonucleotide probe complementary to the ALU247 DNA interspersed sequence and at least one oligonucleotide probe complementary to the ALU115 DNA interspersed sequence. In accordance with this aspect, through the identification of a fragmentation index derived from the ratio between the ALU247 and the ALU115 sequences, the medical device enables prognostic stratification of patients affected by various solid tumors (thyroid, colon, lung, breast).

[0059] In one aspect, said pH meters are configured to detect variations in cellular or extracellular pH to highlight changes in the acid / base ratio.

[0060] In particular, the pH value quantifies the concentration of hydrogen ions in or on a substance. For this purpose, the hydrogen ion concentration is converted into electrical voltage, generating a digital signal interpretable by the user. The scales provided by these systems cover a range that spans from a value of 0 (extremely acidic pH) to a value of 14 (extremely alkaline pH). Examples of pH sensors that can be present on the main body of the medical device according to the present invention include copper circuits or silicon compounds that change color.

[0061] In one aspect, said aptamers are configured to detect specific molecular targets. Specifically, aptamers are oligonucleotide structures (DNA, RNA) of approximately 15-80 base pairs, selected through molecular biology processes, with the ability to bind with high specificity to specific molecular targets (DNA, RNA, proteins).

[0062] The oligonucleotide probes and / or aptamers operatively active on said channel of said medical device enable the selective identification and capture of genomic fragments exhibiting specific molecular characteristics.

[0063] In one aspect, said oligonucleotide probes and / or said aptamers are capable of detecting clinically relevant mutations in the DNA fragments of the following genes: RAS (e.g., point mutation p.G12C affecting exon 2), BRAF (e.g., point mutation p.V600E affecting exon 15), EGFR (e.g., deletion p.E746_A750del affecting exon 19), and HER2 (e.g., insertion p.G776insV_G / C affecting exon 20). In one aspect, said plurality of biosensors comprises one or more aptamers configured to bind aberrant fusion transcripts of the NRG1 gene. In particular, the identification of aberrant transcripts of the NRG1 gene by said plurality of biosensors enables the diagnosis of advanced-stage breast and / or lung cancer. In fact, detecting NRG1 gene rearrangements in oncological patients allows the molecular characterization of neoplasms, thereby enabling the optimization of the clinical pathway according to the biological and molecular aspects of each solid neoplasm.

[0064] In a further aspect, the oligonucleotide probes and / or aptamers operatively active on said channel of said medical device are capable of detecting aberrant fusion transcripts from RNA fragments of one or more of the following genes: ALK (e.g., ALK-EML4) ROS1 (e.g., ROS1-CD74), RET (e.g., RET- CCDC6), NTRK (e.g., NTRK-LMNA), NRG1 (e.g., NRG1-ATP1B1), as well as causative mutations leading to skipping of exon 14 of the MET gene (for example p.Y1003X).

[0065] The identification of gene rearrangements in one or more of the aforementioned genes in oncological patients falls within the composite and complex scenario of the molecular characterization of neoplasms aimed at defining an optimized clinical pathway based on the biological-molecular aspects of each solid neoplasm. The detection of these molecular events can be performed through the implementation of various technical-analytical procedures [RT-PCR, direct gene sequencing via Sanger method, and Next Generation Sequencing (NGS)]. However, these methodological approaches are affected by complex analytical operations, high turnaround time (TAT), and significant management costs. Advantageously, one or more aptamers capable of selectively capturing the aberrant fusion transcripts of the aforementioned genes allow overcoming the drawbacks of the techniques commonly used to identify one or more aberrant fusion transcripts in oncological patients within routine diagnostics.

[0066] In one aspect, said antibodies are configured to recognize and bind, with high specificity, to a specific antigen. Specifically, the antibodies are quaternary protein structures composed of two light chains and two heavy chains, which, through the hyper-variable region (HVR) consisting of 10-15 base pairs, enable the recognition and binding, with high specificity, to a particular antigen, i.e., a well- defined protein portion. In fact, the binding specificity characterizing the antibody-antigen interaction ensures the detection and isolation of biological markers associated with pathologies characterized by increased or decreased production of specific proteins.

[0067] In one aspect, said plurality of biosensors comprises one or more antibodies of the same type (i.e., antibodies capable of detecting and binding to the same target protein).

[0068] In an alternative aspect, said plurality of biosensors comprises one or more antibodies of different types (i.e., antibodies capable of detecting and binding to different target proteins). In one aspect, said plurality of biosensors comprises at least the antibody capable of binding the HER2 protein. In accordance with this aspect, the medical device allows for the diagnosis of breast cancer and, depending on the detected concentration of said HER2 protein, determines its prognosis.

[0069] In one aspect, said bodily fluid corresponds to blood. In accordance with this aspect, said channel is configured for the circulation of blood, and said plurality of receptors is configured to detect, within said blood, the presence and / or concentration of at least said substance representative of the patient's health status.

[0070] In one aspect, the medical device for liquid biopsy is configured to detect cfDNA, preferably ctDNA, in the blood of a subject using said medical device or in a blood sample drawn and isolated from said subject. In one aspect, the medical device for liquid biopsy is configured to allow an enrichment of nucleic acids, specifically circulating free DNA, through a physicochemical selection process, by the adhesion of cfDNA to the plurality of receptors operatively active on the channel during the circulation of the flow of bodily fluid within said channel.

[0071] In one aspect, said medical device for a liquid biopsy is configured for short-term use, meaning it is intended to be used for a continuous duration ranging from 60 minutes to 30 days. Preferably, said medical device is configured for use over a duration ranging from 1 hour to 24 hours.

[0072] In one aspect, said medical device is configured to interact with whole blood. In accordance with this aspect, said channel is configured to be interact with whole blood drawn from said patient.

[0073] In one aspect, said channel is configured to interact with a bodily fluid, preferably blood, at a circulation speed ranging between 1 mm3 / s and 10 mm3 / s.

[0074] In one aspect, said channel extends between an inlet end and an outlet end.

[0075] In one aspect, said channel is configured to be traversed by said body fluid from the inlet end to the outlet end.

[0076] In one aspect, said channel defines an articulated path for the flow of bodily fluid within said main body. In accordance with this aspect, said channel has a length exceeding both the length and width of the main body.

[0077] In a preferential aspect, said channel defines a coil within said main body. In particular, said coil comprises a plurality of straight portions and a plurality of curved portions.

[0078] In one aspect, said plurality of straight portions and said plurality of curved portions are arranged in an alternating sequence. Specifically, each straight portion is interposed between two curved portions, and each curved portion is interposed between two straight portions, in a one-to-one alternation between straight and curved portions.

[0079] In one aspect, said plurality of straight portions comprises a number of straight portions comprised between 1 and 30, preferably comprised between 3 and 25, and even more preferably comprised between 5 and 20.

[0080] In one aspect, said plurality of curved portions comprises a number of curved portions comprised between 1 and 30, preferably comprised between 3 and 25, and more preferably comprised between 5 and 20.

[0081] In one aspect, said channel defined within the support of the main body has a diameter comprised between 1 mm and 3 mm, preferably equal to 2 mm. In other words, the cross-section through which the flow of bodily fluid flows in said channel has a width comprised between 1 mm and 3 mm, preferably equal to 2 mm.

[0082] In one aspect, said main body is made in a single body in which the channel is obtained. In other words, said main body is made in a single block in which said channel extends, the channel constituting a cavity formed within the main body itself.

[0083] In one aspect, said plurality of receptors is embedded within said main body, preferably in correspondence with said channel, so as to detect the presence of at least one substance of interest in the flow of flowing through said channel. In other words, said plurality of receptors is distributed within said main body, preferably in correspondence with the portions wherein the channel is obtained.

[0084] In one aspect, the main body has a substantially planar development, specifically of a rectangular shape. Preferably, said main body is a three-dimensional object with one dimension significantly smaller than the other two dimensions. In other words, said main body is shaped like a flat tablet, with a thickness considerably smaller than its length and width.

[0085] In one aspect, the main body is at least partially made of resin. In a preferential aspect, the main body is at least partially made of inert resin.

[0086] In one aspect, said channel is defined in said resin, and said plurality of receptors is fixed to said resin in correspondence with said channel so that it can be operationally active on the bodily fluid circulating in said channel. In accordance with a further aspect, said plurality of receptors is immobilized in said resin in correspondence with said channel.

[0087] In one aspect, said main body is made by means of a 3D printing process. In accordance with this aspect, said main body is obtained by overlapping multiple layers of specifically designed materials suited to concurrently form said channel during the printing process.

[0088] In an alternative aspect to the preceding one, said main body can be obtained from two semi-bodies permanently joined together to constitute the final configuration of said main body. Preferably, according to this aspect, said channel is created by removing material from both semi-bodies before their assembly.

[0089] In accordance with one aspect, said main body defines a physical support of a flexible type, meaning it can deform under the action of external forces.

[0090] In an alternative aspect, the main body defines a physical support of a rigid type.

[0091] In one aspect, said main body comprises multiple elements associated with each other.

[0092] In one aspect, said channel comprises a tubular duct, preferably with a circular cross-section. In accordance with this aspect, said channel is a stand-alone tubular element.

[0093] In one aspect, said main body comprises at least one capsule. Said at least one capsule is associated with said channel and is in fluid communication with said channel to allow the transit of said flow of fluid. Specifically, said at least one capsule serves as a reservoir in fluid communication with said channel, preferably associable laterally to the main development of the tubular duct that constitutes the channel itself.

[0094] In one aspect, said main body comprises a plurality of capsules.

[0095] In one aspect, said channel and said at least one capsule are made of resin, preferably inert resin. In one aspect, said at least one capsule is connected to said channel in correspondence with one of said curved portions.

[0096] In one aspect, said at least one capsule is configured to house said plurality of receptors. In particular, each capsule is configured to house at least a part of said plurality of receptors.

[0097] In one aspect, each capsule of said at least one capsule is configured to house a swab. Said swab comprises at least a part of said plurality of receptors. In accordance with this aspect, said fluid temporarily exits said channel and enters said at least one capsule, where it interacts with the corresponding swab enriched with at least part of said plurality of receptors suited to detect the presence and / or concentration of said at least one substance representative of the patient's health status. Subsequently, said fluid is reintroduced into said channel to continue its course toward said outlet end.

[0098] In one aspect, each swab comprises an absorbent element and an outer shell. Preferably, said absorbent element is made of absorbent material configured to allow the dispersion on its surface of at least part of said plurality of receptors capable of detecting the presence and / or concentration of said at least one substance of interest.

[0099] In one aspect, said outer shell is configured to provide shape stability to said absorbent element. In one aspect, said outer shell is permeable to said fluid. Preferably, at least part of said outer shell features a reticular structure, defining a plurality of openings to allow said fluid, present in the corresponding capsule, to interact with said absorbent element, specifically to imbue the absorbent element.

[0100] In one aspect, said outer shell comprises a first semi-shell and a second semi-shell which can be associated with each other to contain said absorbent element inside.

[0101] In one aspect, each swab is insertable and / or removable from its corresponding capsule.

[0102] In one aspect, each capsule comprises a central portion, which is associated with, preferably integral with, the channel. In accordance with this aspect, said central portion is configured to house a corresponding swab. In one embodiment, said central portion is configured as a tubular element overall shaped like a T, comprising a connecting section to said channel and a transverse section designed to define a housing seat for the corresponding swab.

[0103] In one aspect, each capsule comprises at least one closure element. In one embodiment, each capsule comprises a first closure element and a second closure element.

[0104] In one aspect, each closure element is selectively applicable to the central portion. Specifically, when said at least one closure element is disassociated from said central portion, the swab can be inserted into or removed from said capsule. Conversely, when said at least one closure element is associated with said central portion, the interior of said capsule is sealed from the outside, and said medical device is in the operational configuration, meaning that said at least one capsule can receive said fluid from said channel.

[0105] In one aspect, each capsule comprises at least one sealing gasket, operatively active between said central portion and said at least one closure element, to prevent fluid leakage between the capsule components during the use of the medical device.

[0106] In one aspect, said swab is, in use, free to rotate within the corresponding capsule. In accordance with this aspect, said at least one capsule has a substantially axially symmetric shape, and the swab can rotate about a rotation axis substantially coinciding with the longitudinal axis of the seat defined by said central portion.

[0107] In one aspect, said main body comprises a support at least for said channel. In embodiments where the device includes said at least one capsule, said support is configured to house both said at least one capsule and to said channel. Specifically, said support is configured to house said channel and said at least one capsule, if present.

[0108] In one aspect, said support is made of resin, preferably inert resin.

[0109] In one aspect, said main body comprises a support. In accordance with this aspect, said channel is obtained within a support. In accordance with said aspect, said channel is obtained in said support by means of a 3D printing process or by joining two semi-bodies suited to define the channel between them. Preferably, said support is made of resin, more preferably inert resin.

[0110] In one aspect, said main body comprises at least one swab containing said at least one receptor. According to this aspect, said at least one swab is selectively applicable to said support to interact with said flow of fluid.

[0111] In one aspect, said support comprises at least one installation seat configured to enable an installation of said swab.

[0112] In one aspect, said at least one swab is configured to be installed in said at least one installation seat with at least a portion exposed to facilitate installation and / or removal operations.

[0113] In one aspect, said at least one swab has a substantially planar configuration.

[0114] In one aspect, said at least one swab comprises an absorbent element and a gripping element, associated with each other. In accordance with this aspect, said absorbent element has a substantially planar shape and is made of absorbent material, configured to allow on its surface the dispersion of said at least one receptor capable of detecting at least one substance of interest, while said gripping element is configured to function as a support for said absorbent element and to facilitate the installation / removal of said swab in / from said support.

[0115] In one aspect, said at least one swab is configured as a self-supporting planar swab.

[0116] In one aspect, said at least one installation seat is shaped as a slot to enable an insertion of said absorbent element and its connection to said gripping element. In accordance with this aspect, said at least one installation seat and / or said gripping element comprise a sealing gasket, configured to prevent fluid leakage between the gripping element and the walls defining the installation seat.

[0117] In one aspect, said at least one installation seat is obtained in correspondence with said channel, optionally in correspondence with said straight portions, and said at least one swab is configured to be associated to said support with said absorbent element inserted in said channel and with said gripping element projecting from the support to facilitate convenient removal of the swab.

[0118] In one aspect, said support comprises at least one capsule associated, in use, with said channel, said at least one capsule being in fluid communication with said channel to be affected by said flow of fluid. In accordance with this aspect, said at least one installation seat is obtained at least in correspondence with said at least one capsule and said at least one swab is configured to be associated with said support, with said absorbent element inserted into said at least one capsule and with said gripping element projecting from said support.

[0119] In one aspect, said at least one swab comprises:

[0120] - an absorbent element made of absorbent material configured to allow a dispersion on its surface of said at least one receptor;

[0121] - a container element configured to define within itself a compartment suited for housing said absorbent element;

[0122] - a capping element selectively applicable to said container element to close said compartment.

[0123] In one aspect, said container element has an overall concave configuration, such that the compartment is open at the top to allow the insertion and removal of said absorbent element when said capping element is not applied to said container element.

[0124] In one aspect, said at least one swab is selectively configurable in the following configurations:

[0125] - a closed configuration, wherein said capping element is applied to said container element to retain the absorbent element within said compartment and prevent fluid leakage when said at least one swab is inserted into its corresponding installation seat; - an open configuration, wherein said capping element is disassociated from said container element so as to allow the insertion of said absorbent element into said compartment and / or removal of said absorbent element from said compartment.

[0126] In one aspect, said container element comprises:

[0127] - a coupling portion configured to enable an association between said at least one swab and a corresponding installation seat, and to allow a selective association of said capping element;

[0128] - a filtering portion configured to define the compartment suited to house said absorbent element.

[0129] In one aspect, said filtering portion has an overall reticular structure, defining a plurality of openings to allow said flow of fluid to interact with, i.e. to imbue, said absorbent element.

[0130] In one aspect, said channel comprises an initial portion, extending from said inlet end, and a final portion, extending from said outlet end. Preferably, said initial portion and said final portion are parallel to each other. In one embodiment, said initial portion and said final portion extend along the same axis. In an alternative embodiment, said initial portion and said final portion extend along distinct parallel axes.

[0131] In one aspect, said at least one installation seat is obtained in correspondence with said initial portion and / or said final portion. In a preferential aspect, said support comprises at least two installation seats, with at least one installation seat being positioned in correspondence with said initial portion and at least one other installation seat being positioned in correspondence with said final portion.

[0132] In one aspect, said at least one swab has, in use, at least the filtering portion inserted within said channel, while at least part of said coupling portion and / or said capping element is exposed from an external surface of said support. In accordance with this aspect, the reticular structure of the filtering portion allows the fluid circulating in the channel to imbue the absorbent element.

[0133] In one aspect, said coupling portion and the installation seat housing the corresponding swab are associable with one another by means of a coupling mechanism, said coupling mechanism optionally being a bayonet coupling mechanism. According to this aspect, the inner wall of said installation seat and the outer wall of said coupling portion feature a series of ribs shaped to enable stable installation of the swab within the corresponding installation seat.

[0134] In an alternative aspect, said coupling portion and said installation seat are associable with one another by means of alternative mechanisms, such as threaded connections or equivalent coupling mechanisms.

[0135] In one aspect, said coupling portion has a shape substantially mirrored to that of the corresponding installation seat. Preferably, said installation seat constitutes an opening with a substantially circular cross-section in said support, and, consequently, said coupling portion has a substantially circular cross-section, whose diameter substantially coincides with that of the installation seat.

[0136] In one aspect, said container element and said capping element are associable with each other by means of a coupling mechanism. Preferably, said container element and said capping element are associable to each other by means of a bayonet coupling mechanism. In accordance with this aspect, the inner wall of said coupling portion and the outer wall of said capping element feature a series of ribs shaped to allow stable installation of the capping element to close the compartment defined by the container element.

[0137] In an alternative aspect to the preceding one, said container element and said capping element are associable with each other by alternative mechanisms, such as threaded connections or equivalent coupling mechanisms.

[0138] In one aspect, said swab comprises at least one sealing gasket. In a preferential aspect, said swab comprises at least a first sealing gasket operatively active on said installation seat to prevent fluid leakage between said swab and the walls of the channel defining the respective installation seat. In another preferential aspect, said swab comprises at least a second sealing gasket operatively active between said container element and said capping element to prevent fluid leakage from said compartment.

[0139] In one aspect, said swab is made by means of a 3D printing process. In a preferential aspect, said container element and said capping element are separately manufactured by means of 3D printing processes.

[0140] In one aspect, said coupling portion of the container element and / or said capping element are shaped to define a gripping portion that extends from said support to facilitate convenient extraction of said swab.

[0141] In one aspect, said swabs are equal I to each other, meaning they substantially comprise the same amount of receptors of the same type.

[0142] In an alternative aspect, said swabs differ from each other. For instance, each swab may comprise different receptors and / or a different concentration of receptors compared to the other swabs.

[0143] In one aspect, said main body comprises an outer shell. Said outer shell is configured to house within it said channel, said at least one capsule, and said support. Specifically, said outer shell is configured to protect the components of said medical device from risks deriving from external contact, minimizing the risk of impacts and contamination from external agents.

[0144] In one aspect, said outer shell comprises a first protective element and a second protective element, which are associable with each other. According to this aspect, the possibility to disassociate said first protective element from said second protective element allows access to the interior of said outer shell, for example to insert or remove at least one swab from said at least one capsule or from said support.

[0145] In one aspect, said main body comprises an adhesive element. Said adhesive element is configured to secure said main body of said medical device to the patient’s body, thereby minimizing the risk of impacts and increasing comfort during use. Preferably, said adhesive element is associated with said outer shell, more preferably with said second protective element.

[0146] In one aspect, said adhesive element is a double-sided adhesive, configured to be applied to said outer shell on a first side and to the patient’s body on a second side.

[0147] In one aspect, said main body has a length comprised between 20 mm and 90 mm. In a preferential aspect, said main body has a length substantially equal to 60 mm.

[0148] In one aspect, said main body has a width comprised between 10 mm and 70 mm. In a preferential aspect, said main body has a width substantially equal to 40 mm.

[0149] In one aspect, said main body has a thickness comprised between 0.5 mm and 3 mm. In a preferential aspect, said main body has a thickness equal to 1 mm.

[0150] In one aspect, said medical device is configurable in different configurations depending on said patient’s health status. In other words, the medical device adopts different configurations based on the health status detected by the plurality of receptors operatively active on the channel.

[0151] In one aspect, at least part of said medical device is configured to take on different colourings depending on said patient’s health status.

[0152] In one aspect, at least part of said main body assumes a first colouring when said plurality of receptors detects the presence of said at least one substance and / or a concentration exceeding a specific threshold level. In accordance with this aspect, at least part of said main body assumes a second colouring when said plurality of receptors does not detect the presence of said at least one substance and / or detects a concentration below said specific threshold of said at least one substance.

[0153] In one aspect, said medical device comprises an electronic processing unit operatively connected to said plurality of receptors. Preferably, said processing unit is operatively connected, through appropriate circuitry, to said at least one capsule and to said at least one swab. Said electronic processing unit is configured to analyze, for example through optical techniques, said swab present in each of said at least one capsule and to verify whether said plurality of receptors has detected the presence and / or a specific concentration of said at least one substance in the bodily fluid.

[0154] In one aspect, said main body comprises an interface element, supported by said main body, particularly by said outer shell. In one embodiment, said interface element comprises a display. According to this aspect, said interface element is operatively connected to said electronic processing unit to make explicit, in particular to display, the results of the analysis performed by said processing unit.

[0155] In one aspect, said interface element may be configured to display other parameters related to the use of said medical device, such as total usage time and / or remaining time before completing the liquid biopsy.

[0156] In one aspect, said medical device does not require the assistance of external elements for assessing the patient’s health status. In other words, the medical device represents a stand-alone medical device for liquid biopsy for in situ and real-time assessment of the patient’s health status. In one aspect alternative to the previous one, said device is configured to be processed by an external reader device, in order to obtain, through said external reader device, at least one piece of information regarding said presence and / or said concentration of said at least one substance in said bodily fluid. According to this aspect, said medical device may require the use of additional instruments for health status evaluation. In this embodiment, evaluating said patient’s health status may require dedicated investigative equipment wherein the entire medical device, the main body alone, and / or only a single component of said main body, such as said at least one swab or the corresponding absorbent element, can be inserted.

[0157] In one aspect, said medical device comprises an inlet duct connected, in correspondence with a first inlet end, to said channel. In particular, said inlet duct is in fluid communication with said channel to convey said bodily fluid to said channel.

[0158] In one aspect, said inlet duct is configured to be applied, in correspondence with a second inlet end, to a portion of said patient’s body. In accordance with this aspect, said inlet duct is configured to receive, in correspondence with said second inlet end, a bodily fluid circulating in said portion of the patient’s body and to convey said bodily fluid to said channel through said first inlet end.

[0159] In one aspect, said inlet duct comprises an inlet cannula-needle in correspondence with said second inlet end. Said inlet cannula-needle is configured to be applied to said portion of the patient’s body to enable the collection of said bodily fluid.

[0160] In one aspect, said medical device comprises an outlet duct, connected, in correspondence with a first outlet end, to said channel. In particular, said outlet duct is in fluid communication with said channel for a discharge of said bodily fluid from said channel.

[0161] In one aspect, said outlet duct is configured to be applied, in correspondence with a second outlet end, to a portion of said patient’s body. According to this aspect, said outlet duct is configured to receive, in correspondence with said first outlet end, the flow of bodily fluid circulating in the channel and to deliver said bodily fluid back to said patient through said second outlet end. In one aspect, said outlet duct comprises an outlet cannula-needle in correspondence with said second outlet end. Said outlet cannula-needle is configured to be applied to said portion of the patient’s body to enable reinfusion of said bodily fluid into the patient’s body.

[0162] In a preferential aspect, said outlet duct is configured to be applied to a point on the patient’s body different from the point where said inlet duct is applied. According to a further aspect, said inlet duct and said outlet duct are configured to be connected to the same portion of the patient’s body but at two distinct points.

[0163] In one aspect, said inlet duct is configured to be applied to the patient’s body in correspondence with the patient’s arm. In a preferential aspect, said inlet duct is configured to be applied to the patient’s body in correspondence with the middle third of the arm.

[0164] In a further aspect, said inlet duct is configured to be applied to the patient’s body in correspondence with the basilic vein or the brachial veins of the patient.

[0165] In one aspect, said outlet duct is configured to be applied to the patient’s body in correspondence with the patient’s arm. In a preferential aspect, said outlet duct is configured to be applied to the patient’s body in correspondence with the middle third of the arm.

[0166] In a further aspect, said outlet duct is configured to be applied to the patient’s body in correspondence with the basilic vein or the brachial veins of the patient.

[0167] In one aspect, said inlet duct and said outlet duct are positioned, respectively, upstream and downstream of said channel.

[0168] In this document, the terms "upstream" and "downstream" are to be interpreted with reference to the normal flow direction of the fluid within the medical device, i.e., a direction that flows from said inlet duet to said outlet duct.

[0169] In one aspect, said inlet duct is connected to said channel in correspondence with said inlet end to deliver said patient’s bodily fluid to said channel. Specifically, said first inlet end of the inlet duct is connected to the inlet end of the channel.

[0170] In one aspect, said outlet duct is connected to said main body in correspondence with said outlet end of the channel to receive said bodily fluid from said channel. Specifically, the first outlet end of the outlet duct is connected to the outlet end of the channel.

[0171] In one aspect, said medical device is a single-use device, meaning a device intended to be disposed of after its first and only use.

[0172] According to a further aspect, the present invention further relates to a method for manufacturing a medical device for a liquid biopsy.

[0173] In one aspect, said method of manufacturing is a method for manufacturing a medical device for a liquid biopsy in accordance with one or more of the preceding aspects. In one aspect, said method for manufacturing a medical device comprises a step of manufacturing a main body constituting the physical support of said medical device.

[0174] In one aspect, said step of manufacturing said main body involves arranging a channel which is configured, in use, to allow the flow of a patient’s bodily fluid.

[0175] In one aspect, said step of manufacturing said main body involves arranging a plurality of receptors operatively active on said channel. According to this aspect, said plurality of receptors is configured, in use, to detect a presence and / or concentration of at least one substance in said bodily fluid, representative of said patient’s health status.

[0176] In one aspect, said method for manufacturing a medical device includes a step of manufacturing an inlet duct.

[0177] In one aspect, said step of manufacturing an inlet duct involves equipping said inlet duct with an inlet cannula-needle.

[0178] In one aspect, said method for manufacturing a medical device comprises a step of associating said inlet duct with said main body so that said inlet duct and said channel are in fluid communication.

[0179] In one aspect, said method for manufacturing a medical device comprises a step of manufacturing an outlet duct.

[0180] In one aspect, said step of manufacturing an outlet duct involves providing said outlet duct with an outlet cannula-needle.

[0181] In one aspect, said method for manufacturing a medical device comprises a step of associating said outlet duct with said main body so that said outlet duct and said channel are in fluid communication. In one aspect, said step of manufacturing said main body provides that said main body is made in a single body wherein said channel is obtained. According to this aspect, said plurality of receptors is embedded within said main body, particularly in correspondence with said channel. Preferably, said main body is made by means of 3D printing processes.

[0182] In an alternative aspect to the preceding one, said step of manufacturing said main body provides that said main body comprises at least the following elements associated with each other:

[0183] - said channel configured like a tubular duct;

[0184] - at least one capsule, associated with said channel and in fluid communication with said channel for a transit of said flow of fluid;

[0185] - at least one swab per each capsule, configured to be removably inserted into the corresponding capsule, said at least one swab comprising at least a part of said plurality of receptors;

[0186] - a base for said channel and said at least one capsule. In an alternative aspect to the preceding one, said step of manufacturing said main body provides that said main body comprises at least the following elements:

[0187] - a support defining said channel, said support comprising at least one installation seat obtained in correspondence with said channel;

[0188] - at least one swab per each installation seat, configured to be removably inserted into a corresponding installation seat and comprising at least part of the plurality of receptors.

[0189] In an alternative aspect to the preceding one, said step of manufacturing said main body provides that said main body comprises at least the following elements:

[0190] - a support defining said channel and at least one capsule, associated with said channel and in fluid communication with said channel to allow a transit of the fluid, said support comprising at least one installation seat obtained in correspondence with said at least one capsule;

[0191] - at least one swab per each installation seat, configured to be removably inserted into a corresponding installation seat and comprising at least a part of the plurality of receptors.

[0192] In an alternative aspect to the preceding one, said step of manufacturing said main body provides that said main body comprises at least the following elements:

[0193] - a support defining said channel, said support comprising at least one installation seat obtained in correspondence with said channel;

[0194] - at least one swab per each installation seat, configured to be removably inserted into a corresponding installation seat and comprising at least a part of the plurality of receptors.

[0195] In accordance with the preceding aspect, said step of manufacturing said main body provides that each swab comprises a container element and a capping element, selectively associable with each other to contain an absorbent element.

[0196] The present description also concerns a method for assessing a patient’s health status through the use of a medical device for liquid biopsy in accordance with the foregoing description.

[0197] In one aspect, the evaluation method includes a step of providing a medical device for a liquid biopsy in accordance with one or more of the preceding aspects.

[0198] In one aspect, the analyzed bodily fluid is blood.

[0199] In one aspect, the substance representative of the patient’s health status is circulating free DNA.

[0200] In one aspect, the circulating free DNA detected is circulating tumor DNA, and the method is a method for diagnosing at least one tumor pathology, preferably lung cancer and / or breast cancer.

[0201] In one aspect, the plurality of biosensors included in the medical device comprises at least one aptamer configured to bind aberrant fusion transcripts of the NGR1 gene.

[0202] In one aspect, the plurality of biosensors included in the medical device comprises at least one antibody targeting the HER2 protein.

[0203] In one aspect, the plurality of biosensors included in the medical device comprises at least one oligonucleotide probe, preferably at least two oligonucleotide probes, more preferably at least one oligonucleotide probe complementary to the ALU247 DNA interspersed sequence and at least one oligonucleotide probe complementary to the ALU115 DNA interspersed sequence.

[0204] In one aspect, the plurality of biosensors included in the medical device comprises at least one aptamer configured to bind aberrant fusion transcripts of the NGR1 gene and / or at least one antibody targeting the HER2 protein and / or at least two oligonucleotide probes complementary to the ALU247 DNA interspersed sequence and the ALU115 DNA interspersed sequence.

[0205] In one aspect, the evaluation method includes a step of associating the inlet duct and the outlet duct with the patient’s body.

[0206] In one aspect, the evaluation method involves applying the inlet duet to a limb of the patient, more preferably the patient’s arm, and even more preferably the middle third of the patient’s arm, in correspondence with the basilic vein or the brachial veins of the patient.

[0207] In one aspect, the evaluation method provides for said outlet duct to be applied to a limb of the patient, more preferably to the patient’s arm, and even more preferably to the middle third of the arm in correspondence with the basilic vein or the brachial veins of the patient.

[0208] In one aspect, the evaluation method provides applying said inlet duct and said outlet duet to the same limb of the patient, for example both ducts applied to the right arm or the left arm.

[0209] In an alternative aspect, the evaluation method provides applying said inlet duct and said outlet duct to be applied to different limbs of the patient, for example, the inlet duct to the right arm and the outlet duct to the left arm, or vice versa.

[0210] In a preferential embodiment, the evaluation method provides temporally transferring blood to the medical device through the inlet cannula needle of the inlet duct, inserted via venipuncture of a vein at the middle third of the arm. Subsequently, the blood flows through the channel defined on the main body, where the plurality of biosensors actively detects the presence and / or concentration of the substance representative of the patient’s health status. Finally, the blood is reintroduced into the patient’s body through the outlet cannula needle of the outlet duct, also inserted via venipuncture of a vein in the middle third of the arm.

[0211] In one aspect, the evaluation method includes a step of analyzing the plurality of biosensors to estimate the patient’s health status.

[0212] In one aspect, said analysis step is performed directly by the medical device, which is equipped with a dedicated processing unit for analyzing the biosensors and an interface element for displaying the analysis results.

[0213] In an aspect alternative to the preceding one, said analysis step is performed by means of an external device configured to receive the entire medical device or only a part of it, such as only the plurality of biosensors, to perform said analysis and display its results.

[0214] In a further independent aspect, the invention relates to a medical device. In accordance with this aspect, the medical device of the present invention is configured to deliver at least one substance into a patient’s bodily fluid. As used therein, the expression "deliver at least one substance" refers to the release, preferably dosed, of a substance into a patient’s bodily fluid.

[0215] In one aspect, to administer the substance into said bodily fluid, said medical device is configured to be applied to the patient’s body. According to this aspect, when said medical device is applied to said patient, at least one component of the medical device is in fluid communication with the patient’s body to receive the flow of fluid to be analyzed. Preferably, said medical device is configured to reintroduce said flow of fluid into the patient’s body.

[0216] In one aspect, said medical device for administering a substance comprises:

[0217] - a main body constituting a physical support for the further components of said medical device;

[0218] - a channel configured to be supported by said main body and / or obtained in said main body and / or integrated into said main body.

[0219] In one aspect, said channel is configured for a transit of a fluid, in particular a patient’s bodily fluid.

[0220] In one aspect, said medical device comprises at least one dispenser operatively active on said bodily fluid transiting said channel to release said at least one substance into said bodily fluid. According to this aspect, said at least one substance is configured to be dispersed within the flow of fluid circulating in said channel.

[0221] In a preferential aspect, said medical device comprises a plurality of dispensers operatively active on said bodily fluid transiting said channel. In particular, said plurality of dispensers is configured to release said substance into said flow of bodily fluid in a dosed, i.e., gradual, manner. In accordance with this aspect, said plurality of dispensers is uniformly distributed along said channel.

[0222] In one aspect, said plurality of dispensers comprises at least a first dispenser and a second dispenser operatively active on the fluid transiting said channel. According to this aspect, said first dispenser is configured to release a first substance into said fluid, while said second dispenser is configured to release a second substance into said fluid. Preferably, said first substance differs from said second substance.

[0223] In one aspect, said at least one substance released by said plurality of dispensers into said bodily fluid allows performing at least one of the following operations:

[0224] - therapeutic treatment of said patient;

[0225] - cellular enrichment of said flow of bodily fluid;

[0226] - enrichment of nucleic acids of said flow of bodily fluid;

[0227] - administration of chemotherapeutic drugs;

[0228] - administration of antibodies conjugated with chemotherapeutics;

[0229] - administration of inhibitors for specific variants of proteins encoded by mutated genes, such as tyrosine kinase inhibitors;

[0230] - administration of drugs with inhibitory action.

[0231] In one aspect, said medical device is configured for short-term use, i.e. for a continuous use for a duration comprised between 60 minutes and 30 days.

[0232] Preferably, said medical device is configured to be used for a duration comprised between 1 hour and 24 hours.

[0233] In one aspect, said medical device is configured to interact with whole blood. In accordance with this aspect, said channel is configured to interact with whole blood drawn from said patient.

[0234] In one aspect, said channel is configured to interact with a bodily fluid, preferably blood, at a circulation speed comprised between 1 mm3 / s and 10 mm3 / s.

[0235] In one aspect, said channel extends between an inlet end and an outlet end.

[0236] In one aspect, said channel is configured to be traversed by said flow of bodily fluid from said inlet end to said outlet end.

[0237] In one aspect, said channel defines an articulated path for the flow of bodily fluid within said main body. In accordance with this aspect, said channel has a development greater than both the length and the width of said main body.

[0238] In a preferential aspect, said channel defines a coil within said main body. In particular, said coil comprises a plurality of straight portions and a plurality of curved portions.

[0239] In one aspect, said plurality of straight portions and said plurality of curved portions are arranged in an alternating sequence. Specifically, each straight portion is interposed between two curved portions and each curved portion is interposed between two straight portions, in a 1 -to-1 alternation between straight portions and curved portions.

[0240] In one aspect, said plurality of straight portions comprises a number of straight portions comprised between 1 and 30, preferably comprised between 3 and 25, even more preferably comprised between 5 and 20.

[0241] In one aspect, said plurality of curved portions comprises a number of portions comprised between 1 and 30, preferably comprised between 3 and 25, and even more preferably comprised between 5 and 20.

[0242] In one aspect, said channel defined within the main body’s support has a diameter comprised between 1 mm and 3 mm, preferably equal to 2 mm. In other words, the cross-section through which the bodily fluid flow passes within said channel has a width comprised between 1 mm and 3 mm, preferably equal to 2 mm.

[0243] In one aspect, said main body is made in a single body wherein said channel is obtained. In other words, said main body is composed of a single block in which said channel extends, the channel constituting a cavity formed within the main body itself.

[0244] In one aspect, said at least one dispenser is embedded in said main body, preferably in correspondence with said channel, so as to release said substance into the bodily fluid transiting within the channel itself.

[0245] In one aspect, the main body has a substantially planar configuration, specifically with a rectangular shape. Preferably, said main body is a three-dimensional object with one dimension significantly smaller than the other two dimensions.

[0246] In one aspect, said main body is at least partially made of resin. In a preferential aspect, said main body is at least partially made of inert resin.

[0247] In one aspect, said channel is defined within said resin and said plurality of dispensers is fixed to said resin in correspondence with said channel, so that it can be operatively active on the bodily fluid circulating within said channel. In accordance with an additional aspect, said plurality of dispensers is immobilized in said resin in correspondence with said channel.

[0248] In one aspect, said main body is made by means of 3D printing processes. In accordance with this aspect, said main body is created by overlapping multiple layers of specifically designed material suited to concurrently form said channel during the printing process.

[0249] In one aspect alternative to the previous one, said main body can be obtained from two semi-bodies, permanently joined together to form the final configuration of said main body. Preferably, according to this aspect, said channel is created by removing material from both semi-bodies before their assembly.

[0250] In accordance with one aspect, the main body provides a physical support of a flexible type, meaning it can deform under the action of external forces.

[0251] In an alternative aspect, the main body provides a rigid physical support. In one aspect, said main body comprises multiple elements associated with each other.

[0252] In one aspect, said channel comprises a tubular duct, preferably with a circular cross-section. In accordance with this aspect, said channel is a stand-alone tubular element.

[0253] In one aspect, said main body comprises at least one capsule. Said at least one capsule is associated with said channel and is in fluid communication with said channel, allowing the passage of said flow of fluid. Specifically, said at least one capsule represents a reservoir in fluid communication with said channel, preferably laterally attachable to the main development of the tubular duct constituting the channel itself.

[0254] In one aspect, said main body comprises a plurality of capsules.

[0255] In one aspect, said channel and said at least one capsule are made of resin, preferably inert resin.

[0256] In one aspect, said at least one capsule is connected to said channel in correspondence with one of said curved portions.

[0257] In one aspect, said at least one capsule is configured to house said plurality of dispensers. In particular, each capsule is configured to house at least a part of said plurality of dispensers.

[0258] In one aspect, each capsule of said at least one capsule is configured to house a doser. Said doser comprises at least part of said plurality of dispensers. In accordance with this aspect, said fluid temporarily exits said channel and enters said at least one capsule, where it interacts with the corresponding doser, which releases said at least one substance into the flow of bodily fluid, preferably in a gradual and controlled manner. Subsequently, said fluid is reintroduced into said channel to continue its course toward said outlet end.

[0259] In one aspect, each doser comprises a releasing element and an outer shell. Preferably, said releasing element comprises said at least one dispenser and is configured to release said at least one substance into said flow of bodily fluid.

[0260] In one aspect, said outer shell is configured to provide shape stability to said releasing element.

[0261] In one aspect, said outer shell is permeable to said fluid. Preferably, at least a part of said outer shell features a reticular structure, defining a plurality of openings to allow said fluid present in the corresponding capsule to interact with, specifically to flow over, said releasing element.

[0262] In one aspect, said outer shell comprises a first semi-shell and a second semi-shell, which can be joined to enclose said releasing element within them.

[0263] In one aspect, each doser is insertable and / or removable from the corresponding capsule.

[0264] In one aspect, each capsule comprises a central portion, associated to and preferably integral with, the channel. In accordance with this aspect, said central portion is configured to house a corresponding doser. In one embodiment, said central portion is configured as a tubular element overall shaped like a “T,” including a connecting section to said channel and a transverse section suited to define a housing seat for the corresponding doser.

[0265] In one aspect, each capsule comprises at least one closure element. In one embodiment, each capsule comprises a first closure element and a second closure element.

[0266] In one aspect, each closure element is selectively applicable to said central portion. Specifically, when said at least one closure element is detached from said central portion, it is possible to insert or remove said doser from said capsule. Conversely, when said at least one closure element is associated with said central portion, the interior of said capsule is isolated from the exterior, and said medical device is in its operational configuration, meaning said at least one capsule can receive said fluid from said channel.

[0267] In one aspect, each capsule comprises at least one sealing gasket, operatively active between said central portion and said at least one closure element to prevent fluid leakage between the components of the capsule during use of the medical device.

[0268] In one aspect, said doser is, in use, free to rotate within the corresponding capsule. In accordance with this aspect, said at least one capsule has a substantially axisymmetric shape, and the doser can rotate about a rotation axis substantially coinciding with the longitudinal axis of the housing seat defined by said central portion.

[0269] In one aspect, said main body comprises a base at least for said channel. In embodiments where the device comprises said at least one capsule, said base is configured to house also said at least one capsule in addition to said channel. Specifically, said base is configured to house said channel and said at least one capsule, if present.

[0270] In one aspect, said support is made of resin, preferably inert resin.

[0271] In one aspect, said main body comprises a support. In accordance with said aspect, said channel is formed within a support. In accordance with this aspect, said channel is formed within said support by means of 3D printing processes or by joining two semi-bodies configured to define the channel between them. Preferably, said support is made of resin, more preferably inert resin.

[0272] In one aspect, said main body comprises at least one doser comprising said at least one dispenser. In accordance with this aspect, said at least one doser is selectively applicable to said support to be affected by said flow of fluid.

[0273] In one aspect, said support comprises at least one installation seat configured to allow the installation of said doser.

[0274] In one aspect, said at least one doser is configured to be installed in said at least one installation seat with at least one portion being exposed to facilitate installation and / or removal operations.

[0275] In one aspect, said at least one doser has a substantially planar configuration.

[0276] In one aspect, said at least one doser comprises a releasing element and a gripping element, associated with each other. In accordance with this aspect, said releasing element has a substantially planar shape and comprises said at least one dispenser configured for dispersing said substance, while said gripping element is configured to act as a support for said releasing element and to allow installation / removal of said doser in / from said support.

[0277] In one aspect, said at least one doser is shaped as a self-supporting planar doser.

[0278] In one aspect, said at least one installation seat is shaped as a slot to allow an insertion of said releasing element and a coupling with said gripping element. In accordance with this aspect, said at least one installation seat and / or said gripping element comprises a sealing gasket, configured to prevent fluid leakage between the gripping element and the walls defining the installation seat itself. In one aspect, said at least one installation seat is provided in correspondence with said channel, optionally in correspondence with said straight portions, and said at least one doser is configured to be associated with said support with said releasing element inserted into said channel and with said gripping element emerging from the support to allow convenient removal of the doser.

[0279] In one aspect, said support comprises at least one capsule associated, in use, with said channel, said at least one capsule being in fluid communication with said channel to be affected by said flow of fluid. In accordance with this aspect, said at least one installation seat is provided at least in correspondence with said at least one capsule, and said at least one doser is configured to be associated with said support with said releasing element inserted into said at least one capsule and with said gripping element emerging from said support.

[0280] In one aspect, said at least one doser comprises:

[0281] - a releasing element comprising said at least one dispenser;

[0282] - a container element configured to define an internal compartment for housing said releasing element;

[0283] - a capping element selectively applicable to said container element to close said compartment.

[0284] In one aspect, said container element has an overall concave configuration such that the compartment is open at the top to allow the insertion and removal of said releasing element when said capping element is not applied to said container element.

[0285] In one aspect, said at least one doser is selectively configurable in the following configurations:

[0286] - a closed configuration, wherein said capping element is applied to said container element so as to retain said releasing element within said compartment and prevent fluid leakage when said at least one doser is inserted into its corresponding installation seat; - an open configuration, wherein said capping element is disassociated from said container element so as to allow insertion of said releasing element into said compartment and / or removal of said releasing element from said compartment.

[0287] In one aspect, said container element comprises:

[0288] - a coupling portion configured to allow an association between said at least one doser and a corresponding installation seat and to enable selective association of said capping element;

[0289] - a filtering portion configured to define the compartment suited to contain said releasing element.

[0290] In one aspect, said filtering portion features an overall reticular structure defining a plurality of openings to allow said flow of fluid to interact with, i.e., to flow over, said releasing element. In one aspect, said channel comprises an initial portion, extending from said inlet end, and a final portion, extending from said outlet end. Preferably, said initial portion and said final portion are parallel to each other. In one embodiment, said initial portion and said final portion extend along the same axis. In an alternative embodiment, said initial portion and said final portion extend along distinct parallel axes.

[0291] In one aspect, said at least one installation seat is provided in correspondence with said initial portion and / or said final portion. In a preferential aspect, said support comprises at least two installation seats, with at least one installation seat positioned in correspondence with said initial portion and at least another installation seat positioned in correspondence with said final portion.

[0292] In one aspect, said at least one doser has, in use, at least the filtering portion inserted within said channel, while at least part of said coupling portion and / or said capping element is exposed from an external surface of said support. In accordance with this aspect, the reticular structure of the filtering portion allows the fluid circulating within the channel to imbue the releasing element.

[0293] In one aspect, said coupling portion and the installation seat housing the corresponding doser are associable with each other via a coupling mechanism, said coupling mechanism optionally being a bayonet coupling mechanism. In accordance with this aspect, the inner wall of said installation seat and the outer wall of said coupling portion comprise a series of ribs shaped to allow the stable installation of the doser within the corresponding installation seat.

[0294] In an alternative aspect to the previous one, said coupling portion and said installation seat are associable with each other via alternative mechanisms, such as threaded connections or equivalent coupling mechanisms.

[0295] In one aspect, said coupling portion has a shape substantially mirrored to that of the corresponding installation seat. Preferably, said installation seat constitutes an opening with a substantially circular cross-section in said support and, consequently, said coupling portion has a substantially circular cross-section, whose diameter substantially matches that of the installation seat.

[0296] In one aspect, said container element and said capping element are associable with each other via a coupling mechanism. Preferably, said container element and said capping element are associable with each other via a bayonet coupling mechanism. In accordance with this aspect, the inner wall of said coupling portion and the outer wall of said capping element comprise a series of ribs shaped to allow the stable installation of the capping element to close the compartment defined by the container element.

[0297] In an alternative aspect to the previous one, said container element and said capping element are associable with each other via alternative mechanisms, such as threaded connections or equivalent coupling mechanisms.

[0298] In one aspect, said doser comprises at least one sealing gasket. In a preferential aspect, said doser comprises at least a first sealing gasket operatively active on said installation seat to prevent fluid leakage between said doser and the walls of the channel defining the corresponding installation seat. In another preferential aspect, said doser comprises at least a second sealing gasket operatively active between said container element and said capping element to prevent fluid leakage from said compartment.

[0299] In one aspect, said doser is made by means of a 3D printing process. In a preferential aspect, said container element and said capping element are separately manufactured by means of 3D printing processes.

[0300] In one aspect, said coupling portion of the container element and / or said capping element are configured to define a gripping portion emerging from said support to facilitate convenient removal of said doser.

[0301] In one aspect, said dosers are equal to each other, meaning they substantially comprise the same number of dispensers of the same type.

[0302] In an alternative aspect, said dosers differ from each other. For instance, each doser may contain different dispensers and / or a different concentration of dispensers compared to the other dosers. In one aspect, said main body comprises an outer shell. Said outer shell is configured to house within itself said channel, said at least one capsule, and said support. Specifically, said outer shell is configured to protect the components of said medical device from risks deriving from external contact, minimizing the risk of impacts and contamination from external agents.

[0303] In one aspect, said outer shell comprises a first protective element and a second protective element, associable with each other. According to this aspect, the possibility to disassociate said first protective element from said second protective element allows access to the interior of said outer shell, for example to insert or remove at least one doser from said at least one capsule or from said support.

[0304] In one aspect, said main body comprises an adhesive element. Said adhesive element is configured to secure said main body of said medical device to the patient’s body, thereby minimizing the risk of impacts and increasing comfort during use. Preferably, said adhesive element is associated with said outer shell, more preferably with said second protective element.

[0305] In one aspect, said adhesive element is a double-sided adhesive element, configured to be applied to said outer shell, on a first side, and to the patient’s body, on the other side.

[0306] In one aspect, said main body has a length comprised between 20 mm and 90 mm. In a preferential aspect, said main body has a length substantially equal to 60 mm.

[0307] In one aspect, said main body has a width comprised between 10 mm and 70 mm. In a preferential aspect, said main body has a width substantially equal to 40 mm.

[0308] In one aspect, said main body has a thickness comprised between 0.5 mm and 3 mm. In a preferential aspect, said main body has a thickness equal to 1 mm.

[0309] In one aspect, said medical device comprises an inlet duct connected, in correspondence with a first inlet end, to said channel. Specifically, said inlet duct is in fluid communication with said channel to deliver said bodily fluid to said channel.

[0310] In one aspect, said inlet duct is configured to be applied, in correspondence with a second inlet end, to a portion of said patient's body. In accordance with this aspect, said inlet duct is configured to receive, in correspondence with said second inlet end, a bodily fluid circulating in said portion of the patient's body and to convey said bodily fluid to said channel through said first inlet end.

[0311] In one aspect, said inlet duct comprises an inlet cannula-needle in correspondence with said second inlet end. Said inlet cannula-needle is configured to be applied to said portion of the patient’s body to enable the withdrawal of said bodily fluid.

[0312] In one aspect, said medical device comprises an outlet duct, connected, in correspondence with a first outlet end, to said channel. Specifically, said outlet duct is in fluid communication with said channel for the discharge of said bodily fluid from said channel.

[0313] In one aspect, said outlet duct is configured to be applied, in correspondence with a second outlet end, to a portion of said patient’s body. According to this aspect, said outlet duct is configured to receive, in correspondence with said first outlet end, the bodily fluid circulating in the channel and to direct said bodily fluid back to said patient through said second outlet end.

[0314] In one aspect, said outlet duct comprises an outlet cannula-needle in correspondence with said second outlet end. Said outlet cannula-needle is configured to be applied to a portion of the patient’s body to allow a reinfusion of said bodily fluid into the patient’s body.

[0315] According to a preferential aspect, said outlet duct is configured to be applied to a point on the patient’s body different from the point where said inlet duct is applied. According to a further aspect, said inlet duct and said outlet duct are configured to be connected to the same portion of the patient’s body but at two distinct points.

[0316] In one aspect, said inlet duct is configured to be applied to the patient’s body in correspondence with the patient’s arm. In a preferential aspect, said inlet duct is configured to be applied to the patient’s body in correspondence with the middle third of the arm.

[0317] In a further aspect, said inlet duct is configured to be applied to the patient’s body in correspondence with the basilic vein or the brachial veins of the patient.

[0318] In one aspect, said outlet duct is configured to be applied to the patient’s body in correspondence with the patient’s arm. In a preferential aspect, said outlet duct is configured to be applied to the patient’s body in correspondence with the middle third of the arm.

[0319] In a further aspect, said outlet duct is configured to be applied to the patient’s body in correspondence with the basilic vein or the brachial veins of the patient.

[0320] In one aspect, said inlet duct and said outlet duct are positioned, respectively, upstream and downstream of said channel.

[0321] In this document, the terms "upstream" and "downstream" are to be interpreted with reference to the normal flow direction of the fluid within the medical device, meaning a direction that flows from said inlet duct to said outlet duct.

[0322] In one aspect, said inlet duct is connected to said channel in correspondence with said inlet end to deliver said patient’s bodily fluid to said channel. Specifically, said first inlet end of the inlet duct is connected to the inlet end of the channel.

[0323] In one aspect, said outlet duct is connected to said main body in correspondence with said outlet end of the channel to receive said bodily fluid from said channel. Specifically, the first outlet end of the outlet duct is connected to the outlet end of the channel.

[0324] According to a further aspect, the present invention also relates to a method for manufacturing a medical device for the administration of a substance in a bodily fluid of a patient.

[0325] In one aspect, said manufacturing method is a method for manufacturing a medical device for the administration of a substance in a bodily fluid of a patient in accordance with one or more of the preceding aspects.

[0326] In one aspect, said method for manufacturing a medical device comprises a step of manufacturing a main body constituting the physical support of said medical device.

[0327] In one aspect, said step of manufacturing said main body involves providing a channel configured, in use, for the passage of a patient’s bodily fluid.

[0328] In one aspect, said step of manufacturing said main body involves providing a plurality of dispensers operatively active on said channel. According to this aspect, said plurality of dispensers is configured, in use, to release said substance in said bodily fluid of said patient.

[0329] In one aspect, said method for manufacturing a medical device comprises a step of manufacturing an inlet duct.

[0330] In one aspect, said step of manufacturing an inlet duct involves equipping said inlet duct with an inlet cannula-needle.

[0331] In one aspect, said method for manufacturing a medical device comprises a step of associating said inlet duct with said main body so that said inlet duct and said channel are in fluid communication.

[0332] In one aspect, said method for manufacturing a medical device includes a step of manufacturing an outlet duct.

[0333] In one aspect, said step of manufacturing an outlet duct involves equipping said outlet duct with an outlet cannula-needle.

[0334] In one aspect, said method for manufacturing a medical device provides a step of associating said outlet duct with said main body so that said outlet duct and said channel are in fluid communication.

[0335] In one aspect, said step of manufacturing said main body provides that said main body is made in a single body wherein said channel is obtained. According to this aspect, said plurality of receptors is embedded within said main body, particularly in correspondence with said channel. Preferably, said main body is made by means of 3D printing processes.

[0336] In an alternative aspect to the preceding one, said step of manufacturing said main body provides that said main body comprises at least the following elements associated with each other:

[0337] - said channel configured as a tubular duct;

[0338] - at least one capsule, associated with said channel and in fluid communication with said channel for a transit of said flow of fluid;

[0339] - at least one doser per each capsule, configured to be removably inserted into the corresponding capsule, said at least one doser comprising said at least one dispenser;

[0340] - a support for said channel and said at least one capsule.

[0341] In an alternative aspect to the preceding one, said step of manufacturing said main body provides that said main body comprises at least the following elements:

[0342] - a support defining said channel, said support comprising at least one installation seat obtained in correspondence with said channel; - at least one doser per each installation seat, configured to be removably inserted into a corresponding installation seat and comprising said at least one dispenser.

[0343] In an alternative aspect to the preceding one, said step of manufacturing said main body provides that said main body comprises at least the following elements:

[0344] - a support defining said channel and at least one capsule, associated with said channel and in fluid communication with the channel for a transit of said fluid, said support comprising at least one installation seat formed in correspondence with said at least one capsule;

[0345] - at least one doser per each installation seat, configured to be removably inserted into a corresponding installation seat and comprising said at least one dispenser.

[0346] In an alternative aspect to the preceding one, said step of manufacturing said main body provides that said main body comprises at least the following elements:

[0347] - a support defining said channel, said support comprising at least one installation seat formed in correspondence with said channel;

[0348] - at least one doser per each installation seat, configured to be removably inserted into a corresponding installation seat and comprising said at least one dispenser.

[0349] In accordance with the preceding aspect, said step of manufacturing said main body provides that each doser comprises a container element and a capping element, selectively associable with each other to contain a releasing element. In accordance with this aspect, said releasing element comprises said at least one dispenser.

[0350] Further characteristics and advantages will become more apparent from the detailed description of a preferential, though not exclusive, embodiment of a medical device for liquid biopsy, a method of manufacturing said medical device, a medical device for the administration of at least one substance into a patient’s bloodstream, and a method of manufacturing said medical device for the administration of at least one substance into the bloodstream of a patient, in accordance with the present invention.

[0351] DESCRIPTION OF THE DRAWINGS

[0352] The following description is provided with reference to the accompanying drawings, which are presented for illustrative and non-limiting purposes, wherein:

[0353] - Figure 1 illustrates a perspective view of a first embodiment of a medical device according to the present invention; - Figure 2 illustrates a different perspective view, from below, of the medical device of Figure 1 ;

[0354] - Figure 3 illustrates a further perspective view of the medical device of Figure 1 in a different configuration;

[0355] - Figure 4 illustrates a perspective view of a second embodiment of the medical device according to the present invention;

[0356] - Figure 5 illustrates an exploded view of the medical device of Figure 4;

[0357] - Figures 6a-6d illustrate a sequence of operations required to configure the medical device for liquid biopsy as shown in Figures 4 and 5;

[0358] - Figure 7 illustrates a perspective view of a component of the medical device according to an alternative embodiment to the embodiment shown in Figures 4-6;

[0359] - Figure 8 illustrates a perspective view of a component of the medical device according to an alternative embodiment to those shown in Figures 4-7;

[0360] - Figure 9 illustrates an exploded view of the medical device comprising the component of Figure 7;

[0361] - Figure 10 illustrates an exploded view of the medical device comprising the component of Figure 8;

[0362] - Figures 11 a-11 b illustrate an element of the medical device component of Figures 6-10 according to two distinct configurations;

[0363] - Figure 12 illustrates a perspective view of a component of the medical device according to an alternative embodiment to the embodiments shown in Figures 4-10;

[0364] - Figure 13 illustrates an exploded view of the medical device comprising the component of Figure 12;

[0365] - Figure 14 illustrates a top plan view of the component of Figure 12 with some of the components removed for clarity of presentation;

[0366] - Figure 15 illustrates a side sectional view along plane XV-XV of the component of Figure 14;

[0367] - Figures 16a- 16d illustrate, respectively, a perspective view, an exploded view, a top plan view, and a perspective sectional view along plane XVI-XVI of an element of the medical device component shown in Figures 12-15 according to an exemplary embodiment.

[0368] DETAILED DESCRIPTION

[0369] With reference to the accompanying drawings, the reference number 100 refers to a device for medical use, hereinafter referred to simply as device 100 for the sake of brevity. As will become clear from the present description, the device 100 is configured to perform a liquid biopsy and / or to administer at least one substance into a patient’s bodily fluid. Generally, the same reference number is used for identical or similar elements, including their variations.

[0370] In the following description, the embodiments of the device 100 intended for performing a liquid biopsy will be detailed first and, subsequently, considerations will be presented regarding the modifications required to adapt the device 100 for administering at least one substance into a patient’s bodily fluid, highlighting the shared technical features while distinguishing the aspects that allow selective or combined use of the device 100 for medical applications that, at first glance, appear so different.

[0371] Given the above, the device 100 configured to perform a liquid biopsy in order to obtain a piece of information regarding a patient’s health status is now described. In the context of the present document, a patient’s health status refers to a biological parameter, such as one parameter representative of the possible presence of at least one ongoing pathology.

[0372] As will become clearer in the following description, to perform a liquid biopsy, the device 100 is configured to be applied to the patient’s body, where it interacts with a flow of fluid, specifically the patient’s bodily fluid. In particular, at least one component of the device 100 is in fluid communication with the patient’s body, allowing the fluid to be withdrawn for analysis. The device 100 is then configured to reintroduce the fluid into the patient’s body.

[0373] As shown in the accompanying drawings, the device 100 comprises a main body 1 , which serves as physical support for the further components of the device 100.

[0374] Furthermore, the device 100 comprises a channel 10, which, depending on the embodiment, is supported by the main body 1 and / or obtained within the main body 1 and / or integrated into said main body 1 . Specifically, the channel 10 is configured for the transit of a patient’s bodily fluid. In addition, the device 100 comprises at least one receptor, preferably a plurality of receptors, operatively active on the fluid transiting the channel 10. In particular, the plurality of receptors is configured to detect, in the bodily fluid circulating within the channel 10, a presence and / or concentration of at least one substance representative of the patient’s health status. In other words, the plurality of receptors is active on the channel 10 to analyze the circulating fluid and thus detect, and subsequently assess, the presence and / or concentration of at least one substance representative of the patient’s health status.

[0375] Preferably, said plurality of receptors comprises at least a first receptor and a second receptor, operatively active on the fluid transiting the channel 10. Specifically, the first receptor is configured to detect a presence and / or a concentration of a first substance in the fluid circulating within the channel 10, while the second receptor is configured to detect a presence and / or a concentration of a second substance, different from the first substance detectable by the first receptor.

[0376] Depending on the embodiment of the device 100, the substance or substances detectable by the plurality of receptors in the bodily fluid allow(s) for at least one of the following assessments regarding the patient's health status:

[0377] - diagnosis of at least one pathology;

[0378] - prognosis of at least one pathology;

[0379] - relapse of disease;

[0380] - presence of minimal residual disease after therapeutic treatment of a pathology;

[0381] - development of resistance mechanisms after therapeutic treatment.

[0382] In a preferential embodiment, the plurality of receptors comprises a plurality of biosensors. In particular, the plurality of biosensors comprises at least one of the following elements: oligonucleotide probes, pH meters, aptamers, and antibodies.

[0383] Preferably, the plurality of biosensors is configured to detect mutations in nucleic acids circulating within the bodily fluid.

[0384] In one embodiment, the plurality of biosensors is configured to detect circulating free DNA (cfDNA) in the bodily fluid. Circulating free DNA (cfDNA) refers to DNA typically released by all cells as part of normal cellular renewal processes and can be isolated from various biological fluids, including for example blood.

[0385] Preferably, the plurality of biosensors is configured to evaluate the levels of DNA fragments carrying specific mutations associated with a specific pathology. Free DNA fragments are present in the bodily fluid because they may have been released by cells undergoing apoptosis or necrosis.

[0386] Also preferably, the plurality of biosensors is configured to detect circulating tumor DNA (ctDNA) released by tumor cells during their renewal and growth processes. In particular, the plurality of biosensors is configured to isolate ctDNA from the bodily fluid circulating in the channel 10 defined in the main body 1.

[0387] In accordance with the definitions above, the terms cfDNA and ctDNA will be used interchangeably in the subsequent description to indicate circulating free DNA and circulating tumor DNA, respectively, for descriptive convenience.

[0388] Preferably, the plurality of biosensors is configured to detect a concentration of cfDNA fragments comprised between 0.001 ng and 100 ng over the entire operational range of the device 100.

[0389] In another embodiment, complementary but not necessarily alternative to the preceding embodiment, the plurality of biosensors is configured to detect a concentration of specific proteins in the bodily fluid.

[0390] In accordance with this latter embodiment, the plurality of biosensors is configured to detect an altered concentration of proteins compared to a physiological condition. In the present description, the expression "altered protein concentration compared to a physiological condition" is intended to refer to a decreased or increased production of proteins with respect to a healthy physiological state, i.e., one where no particular pathology is present.

[0391] Oligonucleotide probes are synthetic oligonucleotide structures (20-25 base pairs) configured to recognize, though complementarity, specific coding and non-coding sequences of nucleic acid (DNA, RNA). It should be noted that the length of circulating free nucleic acids strictly depends on physiological conditions affecting DNA fragmentation. In this context, apoptosis (programmed cell death) generates DNA fragments whose lengths range from 185 to 200 base pairs (bp), which can consequently bind to said oligonucleotide probes.

[0392] Preferably, oligonucleotide probes comprise at least one of an oligonucleotide probe complementary to the ALU247 DNA interspersed sequence and an oligonucleotide probe complementary to the ALU115 DNA interspersed sequence. It should be noted that ALU (Arthrobacter luteus) sequences are highly repeated interspersed sequences in the human genome (1 .4x106copies).

[0393] In one embodiment, the plurality of biosensors comprises at least one oligonucleotide probe complementary to the ALU247 DNA interspersed sequence and at least one oligonucleotide probe complementary to the ALU115 DNA interspersed sequence. In this embodiment, thanks to the identification of a fragmentation index derived from the ratio between ALU247 and ALU115 sequences, the medical device enables prognostic stratification of patients affected by various solid tumors (thyroid, colon, lung, breast).

[0394] PH meters are configured to detect variations in cellular or extracellular pH to highlight changes in the acid / base ratio.

[0395] In particular, the pH value quantifies the concentration of hydrogen ions in or on a substance. For this purpose, the hydrogen ion concentration is converted into electrical voltage, generating a digital signal interpretable by the user. The scales provided by these systems cover a range that spans from a value of 0 (extremely acidic pH) to a value of 14 (extremely alkaline pH). Examples of pH sensors that can be present on the main body of the medical device according to the present invention include copper circuits or silicon compounds that change color.

[0396] Aptamers are configured to detect specific molecular targets. Specifically, aptamers are oligonucleotide structures (DNA, RNA) of approximately 15-80 base pairs, selected through molecular biology processes, with the ability to bind with high specificity to specific molecular targets (DNA, RNA, proteins).

[0397] In one embodiment, the plurality of biosensors comprises one or more aptamers configured to bind aberrant fusion transcripts of the NRG1 gene. In particular, the identification of aberrant transcripts of the NRG1 gene by said plurality of biosensors enables the diagnosis of advanced-stage breast and / or lung cancer. In fact, detecting NRG1 gene rearrangements in oncological patients allows molecular characterization of neoplasms, optimizing the clinical pathway according to the biological and molecular aspects of each solid neoplasm.

[0398] Depending on the embodiments, the oligonucleotide probes and / or aptamers operatively active on the channel 10 of the device 100 enable the selective identification and capture of genomic fragments exhibiting specific molecular characteristics. By way of example and without limitation, the oligonucleotide probes and / or the aptamers are capable of detecting clinically relevant mutations in the DNA fragments of the following genes: RAS (e.g., point mutation p.G12C affecting exon 2), BRAF (e.g., point mutation p.V600E affecting exon 15), EGFR (e.g., deletion p.E746_A750del affecting exon 19), and HER2 (e.g., insertion p.G776insV_G / C affecting exon 20).

[0399] In further embodiments, compatible with the preceding ones, the oligonucleotide probes and / or the aptamers operatively active on the channel 10 are capable of detecting aberrant fusion transcripts from the RNA fragments of one or more of the following genes: ALK (e.g., ALK-EML4), ROS1 (e.g., ROS1-CD74), RET e.g., RET-CCDC6), NTRK (e.g., NTRK-LMNA), NRG1 (e.g., NRG1-ATP1B1), as well as causative mutations leading to skipping of exon 14 of the MET gene (for example p. Y1003X). The identification of gene rearrangements in one or more of the aforementioned genes in oncological patients falls within the composite and complex scenario of the molecular characterization of neoplasms aimed at defining an optimized clinical pathway based on the biological-molecular aspects of each solid neoplasm. The detection of these molecular events can be conducted through the implementation of various technical-analytical procedures [RT-PCR, direct Sanger gene sequencing, Next Generation Sequencing (NGS)]. However, these methodological approaches are affected by complex analytical operations, a high turnaround time (TAT), and significant management costs. Advantageously, the presence of oligonucleotide probes and / or aptamers capable of selectively capturing the aberrant fusion transcripts of the aforementioned genes allow overcoming the drawbacks of the techniques commonly used to identify one or more aberrant fusion transcripts in oncological patients within routine diagnostics.

[0400] Antibodies are configured to recognize and bind, with high specificity, to a specific antigen. Specifically, antibodies are quaternary protein structures composed of two light chains and two heavy chains, which, through the hyper-variable region (HVR), consisting of 10-15 base pairs, enable the recognition and binding, with high specificity, to a particular antigen, i.e., a well-defined protein portion. In fact, the binding specificity characterizing the antibody-antigen interaction ensures the detection and isolation of biological markers associated with pathologies characterized by increased or decreased production of specific proteins.

[0401] In one embodiment, said plurality of biosensors comprises one or more antibodies of the same type (i.e., antibodies capable of detecting and binding the same target protein).

[0402] In an alternative embodiment, the plurality of biosensors comprises one or more antibodies of different types (i.e., antibodies capable of detecting and binding different target proteins).

[0403] In one embodiment, the plurality of biosensors comprises at least the antibody capable of binding the HER2 protein. In accordance with this embodiment, the device 100 allows for the diagnosis of breast cancer and, depending on the detected concentration of the HER2 protein, determines its prognosis. In a preferential embodiment, said bodily fluid corresponds to blood. In this embodiment, the channel 10 is configured for the circulation of blood, and the plurality of receptors is configured to detect, within said blood, the presence and / or concentration of at least a substance representative of the patient's health status.

[0404] Depending on the embodiment, the device 100 is configured to detect cfDNA, preferably ctDNA, in the blood of a subject using the device 100 or in a blood sample drawn and isolated from the subject. In particular, the device 100 is configured to allow an enrichment of nucleic acids, specifically circulating free DNA, by means of a physicochemical selection due to the adhesion of cfDNA to the plurality of receptors operatively active on the channel during the circulation of bodily fluid within said channel.

[0405] The medical device 100 enables the selective capture of target molecules of interest by leveraging the interaction between the analyte of interest and the plurality of biosensors operatively active on the channel 10, where a flow of fluid circulates. The molecular targets isolated from the circulatory stream (cfDNA) undergo a series of standardized analytical procedures aimed at retrieving and analyzing the genomic characteristics of circulating nucleic acid fragments employing molecular biology technologies known in the field. Specifically, the nucleic acids and / or the proteins bound by one or more of the biosensors located on the main body of the medical device are purified using a dedicated extraction protocol, such as one based on porous membranes or magnetic beads, which maximize the recovery of the analyte of interest by exploiting physical (fragment size), chemical (fragment polarity), and physical (electrostatic interaction) properties.

[0406] Once the purification steps of the genetic material are completed, molecular biology technologies known in the field are applied to assess specific molecular alterations in the nucleic acids extracted from the main body of the device.

[0407] Preferably, the device 100 is configured for short-term use, meaning it is intended to be used for a continuous duration ranging from 60 minutes to 30 days. More preferably, the device 100 is configured for use over a period comprised between 1 hour and 24 hours. As a way of example, the device 100 is configured for use over a period comprised between 2 hours and 8 hours.

[0408] Preferably, the channel 10 of the device 100 is configured to process whole blood. Also preferably, the channel 10 is configured to interact with a bodily fluid, preferably blood, at a circulation speed comprised between 1 mm3 / s and 10 mm3 / s.

[0409] As shown in the accompanying figures, the channel 10 extends between an inlet end and an outlet end. Specifically, the channel 10 is configured to be traversed by said flow of bodily fluid from said inlet end 10a to said outlet end 10b.

[0410] Preferably, the channel 10 defines an articulated path for the flow of bodily fluid within the main body 1. Specifically, the channel 10 has a length greater than both the length and the width of the main body 1 .

[0411] In the shown embodiments, the channel 10 defines a coil within the main body 1 . These embodiments are to be understood as purely exemplary and not limiting, as the channel 10 may assume alternative shapes (spiral, zig-zag, etc.), which are considered within the scope of the present invention.

[0412] As shown in the accompanying figures, the coil defined by the channel 10 comprises a plurality of straight portions 10c and a plurality of curved portions 10d. Specifically, the plurality of straight portions 10c and the plurality of curved portions 10d are arranged in an alternating sequence. More specifically, each straight section 10c is interposed between two curved portions 10d, and each curved section 10d is interposed between two straight portions 10c, in a one-to-one alternation between straight and curved portions.

[0413] Depending on the embodiments, the plurality of straight portions 10c comprises a number of straight portions comprised between 1 and 30, preferably between 3 and 25, even more preferably between 5 and 20.

[0414] Similarly, the plurality of curved portions 10d comprises a number of curved portions comprised between 1 and 30, preferably comprised between 3 and 25, even more preferably comprised between 5 and 20.

[0415] Preferably, the channel 10 defined within the support of the main body 1 has a diameter comprised between 1 mm and 3 mm, preferably equal to 2 mm. In other words, the cross-section through which the flow of bodily fluids flows in the channel 10 has a width comprised between 1 mm and 3 mm, preferably equal 2 mm.

[0416] The accompanying figures illustrate various embodiments of the device 100, differing primarily in the number of components of the main body 1 , in the configuration of the channel 10, and / or in the arrangement of the plurality of receptors.

[0417] In a first embodiment, shown in Figures 1-3, the main body 1 is formed as a single piece in which the channel 10 is obtained. In other words, the main body 1 is composed of a single block in which the channel 10 extends, the channel constituting a tubular cavity formed within the same main body. In the first embodiment, the plurality of receptors is embedded within the main body 1, preferably in correspondence with the channel 10, so as to detect the presence of at least one substance of interest in the flow of fluid through the channel itself. In other words, the plurality of receptors is distributed within the main body 1, preferably in correspondence with the portions where the channel 10 is obtained.

[0418] In this first embodiment, the main body 1 has a substantially planar development. As shown in the accompanying figures, the main body 1 is a three-dimensional object with one dimension significantly smaller than the other two dimensions. In other words, the main body 1 is shaped like a flat tablet, with a significantly reduced thickness compared to its length and width.

[0419] Preferably, in the first embodiment, the main body 1 is made of resin. Preferably, in the first embodiment, the main body 1 is at least partially made of inert resin. More specifically, the channel 10 is defined in the resin and the plurality of receptors is fixed to the resin in correspondence with the channel 10 so that it can be operatively active on the bodily fluid circulating in the channel 10. Specifically, the plurality of receptors is immobilized within the resin in correspondence with the channel 10.

[0420] In this embodiment, the main body 1 can be made by means of 3D printing processes. Thus, the main body 1 is obtained by overlapping multiple layers of specifically designed materials suited to concurrently form said channel during the printing process.

[0421] Alternatively, the main body 1 can be obtained from two semi-bodies, permanently joined together to constitute the final configuration of said main body. Preferably, in this context, the channel 10 is created by removing material from both semi-bodies before their assembly.

[0422] In a preferential embodiment, as shown in figure 3, the main body 1 provides a physical support of a flexible type, meaning it can deform under the action of external forces.

[0423] In an alternative embodiment, the main body 1 provides a physical support of a rigid type, meaning it cannot deform under the action of external forces.

[0424] In other embodiments, shown in figures 4-16, the main body 1 comprises multiple elements associated with each other.

[0425] In a second embodiment, the channel 10 comprises a tubular duct, preferably with a circular crosssection. In particular, as shown in the exploded view of figure 5, the channel 10 is a stand-alone tubular element.

[0426] In accordance with the second embodiment, the main body 1 comprises at least one capsule 11 , associated with the channel 10 and in fluid communication with the channel 10 to allow the transit of the flow of fluid. Specifically, the at least one capsule 11 serves as a reservoir in fluid communication with the channel 10, preferably associable laterally to the main development of the tubular duct constituting the channel itself.

[0427] Preferably, as shown in Figures 4 and 5, the main body 1 comprises a plurality of capsules 11 . The description refers to the embodiment shown in Figures 4 and 5, wherein the main body 2 comprises multiple capsules 11. However, this description is intended to be purely exemplary and not limiting, as embodiments with only one capsule are within the scope of this description.

[0428] Preferably, each capsule 11 is positioned in correspondence with one of the curved portions 10d of the channel 10. In particular, when a plurality of capsules 11 is present, the capsules are arranged in correspondence with the curved portions 10d of the channel 10 in a predetermined sequence. For example, in the embodiment shown in Figure 5, the capsules 11 are arranged in correspondence with the curved portions 10d in a 2-by-2 sequence, meaning two curved portions 10d wherein two corresponding capsules are present, following two curved portions 10d without capsules, and so on throughout the entire length of the channel 10.

[0429] Preferably, in this second embodiment, the channel 10 and each capsule 11 are made of resin, more preferably inert resin. In accordance with the exploded view in Figure 5, the main body 1 also comprises a support B for the channel 10 and the capsules 11, when present.

[0430] Specifically, said base B is configured to accommodate the channel 10 and the capsules 11 , if present, serving as a housing for the channel and for any associated capsules.

[0431] Preferably, also the support B is also made of resin, more preferably inert resin.

[0432] The capsules 11 are configured to house the plurality of receptors. Specifically, each capsule 11 is configured to house at least a part of the plurality of receptors.

[0433] As shown in Figures 5 and 6, each capsule 11 is configured to house a corresponding swab 12. In particular, each swab 12 comprises at least a part of the plurality of receptors. Therefore, according to the second embodiment, the fluid temporarily exits the channel 10 and enters the capsule 11, or the capsules 11, where it interacts with the corresponding swab 12 enriched with at least a part of the plurality of receptors suited to detect the presence and / or concentration of at least one substance representative of the patient’s health status. Subsequently, the fluid is reintroduced into the channel 10 to continue its course toward the outlet duct 3.

[0434] In the embodiment shown in Figures 4-5 and more specifically in Figure 6, each swab 12 comprises an absorbent element 12a and an outer shell 12b, 12c. In particular, the absorbent element 12a is made of absorbent material configured to allow the dispersion on its surface of at least part of said plurality of receptors capable of detecting at least one substance of interest. The outer shell 12b, 12c is configured to provide shape stability to the absorbent element 12a.

[0435] Preferably, the outer shell 12b, 12c is permeable to bodily fluid. In the shown embodiment, at least part of the outer shell 12b, 12c features a reticular structure defining a plurality of openings that allow the fluid in the corresponding capsule 11 to interact with the absorbent element 12a. Specifically, the reticular structure of the outer shell allows the fluid to imbue the absorbent element 12a. More preferably, as shown for example in Figure 6a, the outer shell comprises a first semi-shell 12a and a second semi-shell 12b which can be joined together to contain absorbent element 12a inside. Preferably, as clearly shown in the sequence of Figures 6a-d, each swab 12 is insertable into and / or removable from the corresponding capsule 11 .

[0436] As detailed in Figures 6a and 6b, each capsule 11 comprises a central portion 11a, associated with, or preferably integral with, the channel 10. As shown in Figure 6c, the central portion 11a is configured to house a corresponding swab 12. In the shown embodiment, the central portion 11a is configured as a tubular element overall shaped like a "T", comprising a connecting section to the channel 10 and a transverse section designed to define a housing seat for the corresponding swab 12.

[0437] Additionally, each capsule 11 comprises at least one closure element 11 b, 11c. In the shown embodiment, each capsule 11 comprises a first closure element 11 b and a second closure element 11c. In particular, each closure element 11 b, 11c is selectively applicable to the central portion 11a, operating as a cap. As shown in Figures 6a-6c, when the closure element 11 b, 11c is disassociated from the central portion 11 a, it is possible to insert or remove the swab 12 from the capsule 11 . Conversely, as shown in Figure 6d, when the closure element 11 b, 11c is attached to the central portion 11 a, the interior of the capsule 11 is sealed from the outside, and the device 100 is in its operational configuration, meaning that the capsule 11 can receive fluid from the channel 10. Preferably, each capsule 11 comprises at least one sealing gasket, operatively active between the central portion 11 a and the at least one closure element 11 b, 11 c to prevent fluid leakage between the capsule components during the use of the device 100.

[0438] In the shown embodiment, the swab 12 is, in use, free to rotate within the capsule. Preferably, each capsule 11 has a substantially axially symmetric shape. Specifically, the swab 12 can rotate about a rotation axis substantially coinciding with the longitudinal axis of the housing defined by the central portion 11a of the capsule 11. In this configuration of the capsule 11 and the swab 12, the rotation of the swab within the capsule allows for an increase in the detection capabilities of the at least one substance by the plurality of receptors present in the absorbent element 12a.

[0439] A third embodiment and a fourth embodiment of the main body 1 of the device 100 are shown, respectively, in Figures 7 and 8. These embodiments differ from the previously described embodiments primarily in the configuration of the swabs 12, which will be described in greater detail below.

[0440] In accordance with Figures 7 and 8, the main body 1 comprises a support 13 in which channel 10 is obtained. In one embodiment, the support 13 is made by means of 3D printing processes, layering material specifically suited to concurrently form the channel 10 during the printing process. Alternatively, the support 13 is obtained by joining two semi-bodies to define the channel 10 between them. This configuration is purely illustrative and non-limiting, as embodiments wherein the channel 10 is separate from the support 13, operating as a base for the channel as in the embodiment shown in Figures 4 and 5, are also possible. Preferably, the support 13 is made of resin, more preferably inert resin.

[0441] As mentioned earlier, in the embodiments of Figures 7 and 8, the swabs 12 differ in configuration from the swabs 12 in the embodiment shown in Figures 4 and 5. Specifically, in these embodiments, the swabs 12 have a substantially planar shape and are configured to be associated with the support 13, with at least one portion exposed to facilitate installation and / or removal operations.

[0442] In the embodiment shown in Figure 7 (also shown in the exploded view in Figure 9 alongside other components of the device 100), the support 13 lacks capsules associated with the channel 10, and the swabs 12 are installed in correspondence with the straight portions 10c of the channel. Specifically, in the shown embodiment, the main body 1 comprises three swabs 12, installed in correspondence with three different straight portions of the channel 10. In this case, the channel 10 comprises nine straight portions, with the swabs 12 installed in correspondence with the second, fifth, and eighth straight portions.

[0443] Conversely, in the embodiment shown in Figure 8 (also shown in the exploded view in Figure 10 alongside other components of the device 100), the support 13 comprises a plurality of capsules 11 , in fluid communication with the channel 10 to interact with the flow of fluid transiting the channel itself. Additionally, the capsules 11 are configured for the installation of the swabs 12. Specifically, each capsule 11 is configured to at least partially house a swab 12. In this case, the support 13 comprises eight capsules 11 suited to house eight corresponding swabs 12.

[0444] The swabs 12 in accordance with these embodiments are shown in greater detail in Figures 12a— b. As shown, each swab 12 comprises an absorbent element 12a and a gripping element 12d. The absorbent element 12a has a substantially planar shape and is made of absorbent material configured to allow the dispersion on its surface of at least a part of the receptors capable of detecting at least one substance of interest. The gripping element 12d is configured to function as a support for the absorbent element 12a and facilitates the installation or removal of the swab 12 from the support 13. In other words, the swabs 12 are configured as self-supporting planar swabs. Preferably, each swab 12 is designed to be associated to the support 13 with the absorbent element 12a inserted into the channel 10 or its respective capsule 11 , and the gripping element 12d emerging from the support to facilitate convenient removal of the swab. To house at least partially the swabs 12, the support 13 comprises one or more installation seats 10e, 11e. Depending on the specific embodiment, each installation seat is located in correspondence with the channel 10, preferably in correspondence with the straight portions 10c of the channel 10, as shown for the three installation seats 10e in Figure 9, or in correspondence with a corresponding capsule 11, as shown for the eight installation seats 11 e in Figure 9. In these embodiments, the swab 12 remains, in use, rotationally fixed within channel 10 or within capsule 11 .

[0445] Preferably, each installation seat 10e, 11 e is slot-shaped to allow the insertion of the absorbent element 12a and the coupling with a terminal portion of the gripping element 12d. Even more preferably, the installation seat 10e, 11 e and / or the gripping element 12d comprise a sealing gasket, configured to prevent fluid leakage between the gripping element and the walls defining the installation seat.

[0446] Advantageously, the configuration of the swabs 12 as seen in the embodiments shown in Figures 7- 10, allows for easy handling of the swabs. Specifically, the presence of the gripping element 12d enables easy manipulation of the swab 12 during installation operations, namely the insertion of the absorbent element into the installation seats 10, 10e, and 11e, as well as during extraction operations, namely the removal of the absorbent element from the installation seats 10e and 11 e. Therefore, in the described embodiments, the swabs 12 are easily replaceable and transportable. A fifth embodiment of the main body 1 of the device 100 is shown in Figures 12-16. This embodiment also differs from the previously described ones primarily due to the configurations of the swabs 12. As shown in Figures 12-15, the main body 1 comprises a support 13, wherein the channel 10 is obtained. In one embodiment, the support 13 is made by means of 3D printing processes, layering materials specifically designed to form channel 10 during the printing process. In an alternative embodiment, the support 13 is obtained by joining two semi-bodies to define the channel 10. This configuration is merely illustrative and not restrictive, as embodiments wherein the channel 10 is separate from the support 13, which acts as a support for the channel as in the embodiment in Figures 4 and 5, are also possible. Preferably, the support 13 is made of resin, more preferably inert resin.

[0447] It should be noted that, in this embodiment, the channel 10 has a lower number of straight portions 10c and curved portions 10d compared to the previously described variants. Preferably, the channel 10 also comprises an initial portion 10’ that extends from the inlet end 10a along a direction substantially parallel to a longitudinal development direction of the support 13, i.e., parallel to the major development direction of the support 13. Also preferably, the channel 10 also comprises a final portion 10” that extends from the outlet end 10b along a direction substantially parallel to the longitudinal development direction of the support 13, i.e., parallel to the major development direction of the support 13. In a preferential embodiment, the initial portion 10’ and final portion 10” are parallel to each other, for example they may develop along the same axis (i.e., coaxial) or have distinct and parallel axes, as clearly shown in Figure 14.

[0448] In the embodiment shown in Figures 11 -16, the swabs 12 are installed in correspondence with the initial portion 10’ and the final portion 10” of the channel 10. Specifically, in the shown embodiment, the main body 1 comprises two swabs 12, one installed in the initial portion 10’ and another installed in correspondence with the final portion 10” of the channel 10. In order to install the swabs 12, the channel 10 comprises two installation seats 10e, specifically obtained in correspondence with the initial portion 10’ and of the final portion 10”. Each installation seat 10e essentially forms an opening in the channel 10, allowing the swab 12 to be inserted into the channel 10. In the shown embodiment, each installation seat 10e has a substantially circular shape.

[0449] The swabs 12 according to the fifth embodiment are shown in detail in Figures 16-d. As shown, each swab 12 comprises an absorbent element 12a, a container element 12e, and a capping element 12f. Similar to the absorbent elements in other embodiments, the absorbent element 12a is made of absorbent material configured to allow the dispersion on its surface of at least a part of the receptors capable of detecting at least one substance of interest. The container element 12e is configured to define an internal compartment within itself apt to house the absorbent element 12a. Specifically, the container element 12e has an overall concave configuration, leaving the compartment open at the top to allow the insertion and removal of the absorbent element 12a. The capping element 12f is selectively applicable to the container element 12e to close the compartment. Specifically, the swab 12 can be selectively configured in the following configurations:

[0450] - a closed configuration (Fig. 16a), wherein the capping element 12f is associated to the container element 12e, retaining the absorbent element 12a within the compartment and preventing fluid leakage when the swab is inserted in its corresponding installation seat 10e in the channel 10;

[0451] - an open configuration (Fig. 16b), wherein the capping element 12f is disassociated from the container element 12e, allowing for the insertion and / or extraction of the absorbent element 12a into and / or from the compartment.

[0452] The absorbent element 12a has a shape configured to allow its insertion into the compartment of the container element 12e. In the shown embodiment, the absorbent element 12a has a predominantly cylindrical shape, for example created by stacking a plurality of planar discs, so it occupies at least part of the compartment defined by the container element.

[0453] Preferably, the container element 12e comprises a coupling portion 12e’ and a filtering portion 12e”. Specifically, the coupling portion 12e’ is configured to enable the association between the swab 12 and its corresponding installation seat 10e in the channel 10. Additionally, the coupling portion 12e’ is configured to allow the selective association of the capping element 12f. The filtering portion 12e” is configured to define the compartment apt to house the absorbent element 12a and features an overall reticulated structure with a plurality of openings to allow the fluid circulating in the channel 10 to interact with, ,i.e., to imbue, the absorbent element 12a. In use, the swab 12 has at least the filtering portion 12e” inserted into the channel 10, while at least part of the coupling portion 12e’ and / or of the capping element 12f remains exposed. In detail, the structure of the filtering portion 12e” allows the fluid circulating in the channel 10 to imbue the absorbent element 12a.

[0454] Also preferably, the coupling portion 12e’ and the installation seat 10e are associable to each other by means of a coupling mechanism. In the illustrated embodiment, the coupling portion 12e’ and the installation seat 10e are associable to each other via a bayonet coupling mechanism. Specifically, the inner wall of the installation seat 10e and the outer wall of the coupling portion 12e’ comprise a series of ribs shaped to enable stable the installation of the swab 12 within the corresponding installation seat. Hence, the installation operations involve inserting the swab 12 into the installation seat 10e until the filtering portion 12e” is at least partially housed within the channel 10, followed by the subsequent rotation of the swab 12 so as to enable the coupling between the ribs of the bayonet system, thereby preventing accidental dislodgment of the swab from its respective installation seat. Conversely, the extraction operations for the swab 12 from the installation seat 10e involve rotating the swab until the disconnection between the ribs of the bayonet system occurs, followed by the extraction of the filtering portion 12e” out of the channel 10 to allow for the detachment of the swab from the support 13. In other embodiments, the coupling portion 12e’ and the installation seat 10e are associable with each other by alternative mechanisms, such as threaded connections or equivalent coupling mechanisms. To enable the coupling with its corresponding installation seat 10e, the coupling portion 12e’ has a shape that is substantially mirrored to that of the installation seat. In the shown embodiment, the coupling portion 12e’ has a substantially circular cross-section.

[0455] Also preferably, the container element 12e and the capping element 12f can be connected to each other via a coupling system. In the shown embodiment, the container element 12e and the capping element 12f are associable to each other via a bayonet coupling mechanism. Specifically, the inner wall of the coupling portion 12e’ and the outer wall of the capping element 12f comprise a series of ribs shaped to allow for the stable installation of the capping element 12f onto the container element 12e. Hence, the installation operations of the capping element 12f involve inserting at least part of the capping element to close the compartment defined by the container element, followed by a subsequent rotation of the capping element to allow for the coupling between the ribs of the bayonet system, thereby preventing accidental dislodgment of the capping element. Conversely, the extraction operations of the capping element 12f from the container element 12e involve rotating the capping element until the disconnection between the ribs of the bayonet system occurs, followed by the extraction of the capping element in order to access the compartment defined by the container element 12e. In other embodiments, the container element 12e and the capping element 12f are associable with each other by means of alternative mechanisms, such as threaded connections or equivalent coupling mechanisms.

[0456] Also preferably, the swab 12 comprises at least one sealing gasket. In particular, the swab 12 comprises at least a first sealing gasket operatively active on the installation seat 10e to prevent fluid leakage between the swab and the walls of the channel defining the respective installation seat. Additionally, the swab 12 comprises at least one secondary gasket operatively active between the container element 12e and the capping element 12f to prevent fluid leakage. In a preferential embodiment, the coupling portion 12e’ of the swab 12 comprises at least one sealing gasket on the respective outer wall, i.e., the outer wall intended to allow association with the installation seat 10e, and at least one sealing gasket on the respective inner wall, i.e., the wall intended to allow association with the capping element 12f.

[0457] In one embodiment, the swab 12 is made by means of 3D printing processes. In particular, the container element 12e and the capping element 12f are separately manufactured by means of 3D printing processes.

[0458] Also preferably, the coupling portion 12e’ of the container element and / or the capping element 12f are shaped to define a gripping portion emerging from support 13 to facilitate convenient extraction of the swab 12. Advantageously, the presence of the gripping portion enables practical handling of the swabs. Specifically, the gripping portion facilitates convenient manipulation of the swab 12 during installation operations, i.e., insertion into the installation seats 10e, and during removal operations, i.e., detachment from the installation seats 10e. Therefore, in the described embodiment, the swabs 12 are easily replaceable and transportable.

[0459] In one embodiment, all the swabs 12 installed in the device 100 are equal to each other, meaning they substantially comprise the same number of receptors of the same type. In particular, all the absorbent elements 12a are enriched with the same receptors, which are present in substantially the same concentrations.

[0460] In an alternative embodiment, the swabs 12 differ from each other. Preferably, in this embodiment, each swab 12 comprises different receptors and / or different concentration of receptors compared to the other swabs. Specifically, the absorbent elements 12a are enriched with different receptors and / or have different concentrations of receptors. As shown in the exploded views of Figures 5, 9-10, and 13, the main body 1 comprises an outer shell 14. The outer shell 14 is designed to contain the channel 10, a plurality of capsules 11 , and the support 13. Furthermore, the outer shell 14 is configured to protect the components of the device 100 contained therein from external contact risks, minimizing the risk of impacts and contamination from external agents.

[0461] More preferably, the outer shell 14 comprises a first protective element 14a and a second protective element 14b, associable to each other. In particular, the possibility to disassociate the first protective element 14a from the second protective element 14b allows access to the interior of the outer shell 14, for example to insert or remove the swabs 12.

[0462] Preferably, the main body 1 comprises an adhesive element 15, configured to secure the main body 1 of the device 100 to the patient’s body, minimizing the risk of impacts and increasing comfort during use. Preferably, the adhesive element 15 is associated with the outer shell 14, more preferably with the second protective element 14b. In a preferential embodiment, the adhesive element 15 is a double-sided adhesive, configured to be applied to the outer shell 14, on a first side, and to the patient’s body, on the second side.

[0463] Preferably, the main body 1 has a length comprised between 20 mm and 90 mm. In a preferential embodiment, the main body 1 has a length substantially equal to 60 mm.

[0464] Preferably, the main body 1 has a width comprised between 10 mm and 70 mm. In a preferential embodiment, the main body 1 has a width substantially equal to 40 mm.

[0465] Preferably, the main body 1 has a thickness comprised between 0.5 mm and 3 mm. In a preferential embodiment, the main body 1 has a thickness substantially equal to 1 mm.

[0466] Preferably, the medical device 100 is configurable into different configurations depending on the patient’s health status. In other words, the medical device 100 adopts different configurations based on the health status detected by the plurality of receptors operatively active on the channel 10. In one embodiment, such as the first embodiment shown in Figures 1 -3, at least part of the main body 1 can take on different colorings depending on the patient’s health status. Preferably, the main body 1 takes on a first coloring when the plurality of receptors detects the presence of at least one substance and / or a concentration of at least one substance above a certain threshold level. Similarly, the main body 1 takes on a second coloring when the plurality of receptors does not detect the presence of the at least one substance in the bodily fluid and / or when the aforementioned concentration is below the determined threshold level.

[0467] In another embodiment, such as the embodiments shown in Figures 4-16, the device 1 comprises an electronic processing unit operatively connected to the plurality of receptors. In this embodiment, the electronic processing unit is operatively connected, through appropriate circuitry, to the swabs 12. The electronic processing unit is configured to analyze the swabs 12 present along the channel 10 and / or in the capsules 11 , for example by means of optical techniques, to verify whether the plurality of receptors has detected the presence and / or a certain concentration of at least one substance in the bodily fluid. According to this embodiment, the main body 1 of the device 100 preferably comprises an interface element 16, supported by said main body 1. In the embodiment shown in Figures 4-5, 9-10, and 13, the interface element 16 is a display supported by the outer shell 14. The interface element 16 is operatively connected to the electronic processing unit to make explicit, in particular to display, the results of the analysis performed by said processing unit. Additionally, the interface element 16 can be configured to display other parameters related to the use of the device 100, such as total usage time and / or remaining time before the completion of the liquid biopsy.

[0468] In accordance with the embodiments described in the previous two paragraphs, the device 100 does not require the assistance of external elements for assessing the patient’s health status. In other words, the medical device 100 represents a stand-alone medical device for liquid biopsy, enabling in- situ and real-time assessment of the patient’s health status.

[0469] Alternatively, the device 100 is configured to be processed by an external reader device to obtain at least one piece of information regarding said presence and / or said concentration of the at least one substance in said bodily fluid. In this embodiment, the device 100 requires the use of additional instruments for health status evaluation. For example, a dedicated investigative equipment (external reading device) may be necessary to evaluate the patient’s health status, wherein the entire device 100, the main body 1 alone, and / or only a single component of the main body 1 , such as the swabs 12 or the absorbent element 12a, can be inserted.

[0470] As shown in the accompanying figures, the device 100 comprises an inlet duct 2 and an outlet duct 3, fluid-dynamically connected to channel 10. In particular, the inlet duct 2 and the outlet duct 3 are positioned upstream and downstream of the channel 10, respectively.

[0471] The inlet duct 2 is connected, in correspondence with a first inlet end 2a, to the channel 10. In particular, the inlet duct 2 is in fluid communication with the channel 10 to convey said bodily fluid to the channel 10.

[0472] The outlet duct 3 is connected, in correspondence with a first outlet end 3a, to the channel 10. Specifically, the outlet duct 3 is in fluid communication with the channel 10 to allow the bodily fluid to exit the channel 10.

[0473] Preferably, the inlet duct 2 is configured to be applied, in correspondence with a second inlet end 2b, to a portion of the patient’s body. Specifically, the inlet duct 2 is configured to receive, in correspondence with the second inlet end 2b, a flow of bodily fluid circulating in the corresponding portion of the patient’s body and to convey that flow of bodily fluid to the channel 10 through the first inlet end 2a.

[0474] As shown in the accompanying figures, the inlet duct 2 preferably comprises an inlet cannula-needle 20 in correspondence with its second inlet end 2b. The inlet cannula-needle 20 is configured to be applied to the aforesaid portion of the patient’s body to enable the collection of said bodily fluid. Preferably, the outlet duct 3 is configured to be applied, in correspondence with a second outlet end 3b, to a portion of said patient’s body. In particular, the outlet duct 3 is configured to receive, in correspondence with the first outlet end 3a, the flow of bodily fluid circulating in channel 10 and to convey the bodily fluid back to the patient through the second outlet end 3b.

[0475] As shown in the accompanying figures, the outlet duct 3 preferably comprises an outlet cannulaneedle 30 in correspondence with the second outlet end 3b. The outlet cannula-needle 30 is configured to be applied to the aforesaid portion of the patient’s body to enable reinfusion of said bodily fluid into the patient’s body.

[0476] Preferably, the outlet duct 3 is configured to be applied to a point on the patient’s body that is different from the point where the inlet duct 2 is applied.

[0477] In one embodiment, the inlet duct 2 and the outlet duct 3 are configured to connect to the same portion of the patient’s body but at two distinct points.

[0478] Preferably, the inlet duct 2 is configured to be applied to the patient’s body in correspondence with the patient’s arm. More preferably, the inlet duct 2 is configured to be applied to the patient’s body in correspondence with the middle third of the arm. Even more preferably, the inlet duct 2 is configured to be applied to the patient’s body in correspondence with the basilic vein or brachial veins of the patient.

[0479] Preferably, the outlet duct 3 is configured to be applied to the patient’s body in correspondence with the patient’s arm. More preferably, the outlet duct 3 is configured to be applied to the patient’s body in correspondence with the middle third of the arm. Even more preferably, the outlet duct 3 is configured to be applied to the patient’s body in correspondence with the basilic vein or the brachial veins of the patient.

[0480] In one embodiment, the inlet duct 2 and the outlet duct 3 are configured to be applied to the same limb of the patient, for example both the inlet duct 2 and the outlet duct 3 are applied to the right arm or to the left arm.

[0481] In the shown embodiments, the inlet duct 2 is connected to the channel 10 in correspondence with the inlet end 10a to convey the patient’s bodily fluid to the channel. Specifically, the first inlet end 2a of the inlet duct 2 is connected to the inlet end 10a of the channel 10. Similarly, the outlet duct 3 is connected to the channel 10 in correspondence with the outlet end 10b to receive the bodily fluid from the channel itself. In particular, the first outlet end 3a of the outlet duct 3 is connected to the outlet end 10b of the channel 10.

[0482] Preferably, the device 100 is a single-use device, meaning a device intended to be disposed of after its first and only use. Accordingly, it is necessary for the device 100 to have a sufficiently low unit production cost to make its use sustainable.

[0483] The present description also relates to a method of manufacturing the device 100 in accordance with the details outlined above.

[0484] The method of manufacturing a medical device comprises a step of manufacturing the main body 1 , which constitutes the physical support of the device 100.

[0485] In particular, the step of manufacturing the main body 1 involves providing the channel 10, which is configured, in use, for a transit of a flow of a patient’s bodily fluid.

[0486] Furthermore, the step of manufacturing the main body 1 involves providing a plurality of receptors operatively active on the channel 10. As previously described, the plurality of receptors is configured, in use, to detect the presence and / or concentration of at least one substance in the bodily fluid, representative of the patient’s health status.

[0487] The method of manufacturing the device 100 comprises a step of manufacturing the inlet duct 2. Preferably, the step of manufacturing the inlet duct 2 involves equipping the inlet duct with an inlet cannula-needle 20.

[0488] Additionally, the method of manufacturing the device 100 comprises a step of associating the inlet duct 2 with the main body 1 so that the inlet duct 2 and the channel 10 are in fluid communication. The method of manufacturing the device 100 also comprises a step of manufacturing the outlet duct 3. Preferably, the step of manufacturing the outlet duct 3 involves equipping the outlet duct 3 with an outlet cannula-needle 30.

[0489] Subsequently, the method of manufacturing the device 100 comprises a step of associating the outlet duct 3 with the main body 1 so that the outlet duct 3 and the channel 10 are in fluid communication. In one embodiment of the manufacturing method, in accordance with, for example, the first embodiment of the device 100 (Figures 1-3), the step of manufacturing the main body 1 provides that the main body 1 is made in a single body wherein the channel 10 is obtained. In this embodiment, the plurality of receptors is embedded within said main body 1 and is preferably positioned in correspondence with the channel 10. Also preferably, in this embodiment, the main body 1 is made by means of 3D printing processes.

[0490] In another embodiment of the manufacturing method, in accordance with, for example, the second embodiment of the device 100 (Figures 4-6), the step of manufacturing the main body 1 provides that the main body 1 comprises at least the following elements associated with each other:

[0491] - the channel 10 configured as a tubular duct; - at least one capsule 11, associated with the channel 10 and in fluid communication with the channel 10 for a transit of said fluid;

[0492] - at least one swab 12 per each capsule 11, configured to be removably inserted into the corresponding capsule and comprising at least a part of the plurality of receptors;

[0493] - a support 13 for the channel 10 and for the at least one capsule 11 .

[0494] In a further embodiment of the manufacturing method, in accordance for example with the third embodiment of the device 100 (Figures 7 and 9), the step of manufacturing the main body 1 provides that the main body 1 comprises at least the following elements:

[0495] - a support 13 defining the channel 10, said support 13 comprising at least one installation seat 10e obtained in correspondence with the channel 10;

[0496] - at least one swab 12 per each installation seat 10e, configured to be removably inserted into the corresponding installation seat and comprising at least a part of the plurality of receptors.

[0497] In another embodiment of the manufacturing method, in accordance for example with the fourth embodiment of the device 100 (Figures 8 and 10), the step of manufacturing the main body provides that the main body 1 comprises at least the following elements:

[0498] - a support 13 defining the channel 10 and at least one capsule 11, associated to the channel 10 and in fluid communication with the channel 10 for a transit of the fluid, said support 13 comprising at least one installation seat 11e obtained in correspondence with at least one capsule 11;

[0499] - at least one swab 12 per each installation seat 11 e, configured for removable insertion into the corresponding installation seat and comprising at least a part of the plurality of receptors.

[0500] In another embodiment of the manufacturing method, in accordance for example with the fifth embodiment of the device 100 (Figures 12-15), the step of manufacturing the main body provides that the main body 1 comprises at least the following elements:

[0501] - a support 13 defining the channel 10, said support 13 comprising at least one installation seat 10e obtained in correspondence with the channel 10;

[0502] - at least one swab 12 per each installation seat 10e, configured for removable insertion into the corresponding seat and containing at least a part of the plurality of receptors.

[0503] In accordance with the preceding embodiment, the step of manufacturing the main body provides that each swab 12 comprises a container element 12e and a capping element 12f, selectively associable with each other to contain an absorbent element 12a.

[0504] It should be noted that a skilled technician can easily adapt the device 100, previously described for performing a liquid biopsy, for a different uses. In particular, the device 100 can be suitable for the administration of at least one substance into the flow of a patient’s bodily fluid. In this description, the expression “administration of at least one substance” refers to the release, preferably in a dosed manner, of a substance into the flow of a patient’s bodily fluid. Specifically, to enable the administration of the aforementioned substance(s), a skilled technician can adapt the previously described device 100 while leaving the overall structure of its components largely unchanged across its various embodiments, only replacing at least some of the receptors configured to detect the presence and / or concentration of at least one substance in said fluid. in detail, the device 100 can be employed to administer at least one substance by replacing at least a part of the receptors with at least one dispenser element that is operatively active along channel 10 and configured to release said substance into the fluid circulating within the channel itself. Depending on whether all receptors or only some of them are replaced with appropriate dispensing elements, the device 100 can be used exclusively or also for administering at least one substance into a flow of a patient’s bodily fluid.

[0505] With reference to the previously described embodiments concerning the use of the device 100 for a liquid biopsy, the changes needed to adapt the same device for administering a substance into a flow of a patient’s bodily fluid will now be described. It should be noted that the changes described below do not impact, except in an extremely marginal way, the overall structure of the device 100 and are therefore fully within the capabilities of a skilled technician based on the preceding description. For simplicity of description, the modifications aimed at adapting the device 100 for exclusive use as a substance administrator will be outlined. The skilled technician will certainly understand that if the described changes are executed only partially, the device 100 could have a mixed function of performing a liquid biopsy and administering at least one substance.

[0506] With reference to the first embodiment illustrated in Figures 1-3, the device 100 can be employed as a substance administrator by replacing the receptors dispersed within the main body 1 with just as many dispensers, operatively active on the channel 10 to release the substance to be dispersed in the fluid circulating within that channel.

[0507] With reference to the second embodiment illustrated in figures 4-6, the device 100 can also be employed as a substance administrator by replacing the swabs with as many dosers. Specifically, the swab illustrated in Figures 6a-d can be easily transformed into a doser by replacing the absorbent element with a releasing element comprising at least said dispenser. In one embodiment, the releasing element is configured as a soluble tablet in the fluid circulating within capsules 11. With reference to the third and fourth embodiments illustrated in Figures 7-11, the device 100 can be employed as a substance administrator by replacing the swabs with as many dosers. Specifically, the swab illustrated in figures 11 a-b can be easily transformed into a doser by replacing the absorbent element with a releasing element comprising at least said dispenser. In one embodiment, the releasing element is configured as a planar element soluble in the fluid circulating within the channel 10 (third embodiment in Figure 7) or within the capsules 11 (fourth embodiment in Figure 8).

[0508] With reference to the fifth embodiment illustrated in Figures 12-16, the device 100 can be employed as a substance administrator by replacing the swabs with as many dosers. Specifically, the swab illustrated in Figures 16a-d can be easily transformed into a doser by replacing the absorbent element with a releasing element comprising at least said dispenser. In one embodiment, the releasing element is configured as a disc-shaped or cylindrical element (e.g. , a tablet) soluble in the fluid circulating within the channel 10.

[0509] In light of the above, depending on whether the device 100 is employed to perform a liquid biopsy or to administer a substance into a patient's bodily fluid, the numerical references "12" and "12a" in the appended figures may refer respectively to a swab and to an absorbent element or to a doser and to a releasing element. Similarly, the preceding detailed description can be adapted for the use of the device 100 for the administration of a substance by replacing the terms "receptor / s," "swab / s," and "absorbent element / s" with the terms "dispenser / s," "doser / s," and "releasing element / s," and applying the necessary changes.

[0510] ADVANTAGES OF THE INVENTION

[0511] The present invention achieves significant advantages.

[0512] First, the medical device described herein enables the evaluation of a specific health status of a patient in remarkably short times, especially when compared to traditional diagnostic methodologies such as CT scans, PET scans, ultrasound, MRI, and X-rays. Specifically, the medical device 100 is capable of providing a diagnosis substantially in real time.

[0513] In the previously described embodiment, the medical device enables the detection of the presence of cfDNA and / or proteins in a bodily fluid, preferably blood, and optionally allows for the diagnosis of a pathology, such as a tumor pathology, the determination of prognosis and the identification of disease recurrence, as well as monitoring minimal residual disease after treatment and the development of resistance mechanisms following therapy.

[0514] It should be emphasized that the device 100 allows for the detection of circulating free DNA fragments with greater efficiency than routinely employed procedures (blood sampling, plasma separation, purification of circulating free nucleic acids). In particular, the device 100 employs highly sensitive analytical methodologies for the real-time evaluation of the presence of circulating free DNA (cfDNA) and / or specific proteins in a flow of bodily fluid, preferably blood.

[0515] Additionally, the device 100 is capable of providing an evaluation of a particular health status of a patient at a particularly low cost, especially when compared to the unit cost of traditional diagnostic methodologies such as CT scans, PET scans, ultrasound, MRI , and X-rays. Moreover, the device 100 features a sufficiently low production cost so as to make it suitable for single-use applications.

[0516] The various embodiments illustrated in the present document demonstrate the exceptional versatility of the device 100 and its ability to be easily reconfigured for any type of pathology to be evaluated. Furthermore, it has been demonstrated that the device is easily adaptable to perform, either in combination or exclusively, the administration of a substance into a bodily fluid, for example in the bloodstream of a patient. Specifically, the adaptation of the device 100 for medical applications that appear to be so different requires only the practical replacement of a component.

[0517] It should also be noted that the use of inert materials, such as the resins employed in manufacturing the main body of the device 100, significantly reduces the risk of bacterial contamination and makes the device highly biocompatible. In other words, the device offers the advantage of not requiring patient hospitalization during operation, thereby reducing the costs of managing oncological patients and alleviating the financial burden on national healthcare systems.

Claims

CLAIMS1. Device (100), in particular device for medical use, more particularly device for medical use configured to perform a liquid biopsy in order to obtain at least one piece of information regarding a health status of a patient, said device (100) comprising:- a main body (1),- a channel (10) supported by said main body (1 ) and / or formed within said main body (1 ) and / or integrated into said main body (1), said channel (10) being configured for a transit of a flow of a fluid, in particular of a bodily fluid of said patient; characterized by comprising at least one receptor operatively active on the fluid transiting said channel (10), said at least one receptor being configured to detect a presence and / or a concentration of at least one substance in said fluid, in particular configured to detect a presence and / or a concentration of at least one substance in said bodily fluid representative of said health status of said patient, optionally wherein said device (100) comprises a plurality of receptors operatively active on the fluid transiting said channel (10) and configured to detect a presence and / or a concentration of at least one substance in said fluid and wherein the receptors of said plurality of receptors are distributed, in particular uniformly distributed, along said channel (10).

2. Device (100) according to the preceding claim, wherein said at least one substance in said flow of bodily fluid is configured to enable at least one of the following assessments regarding the health status of the patient:- diagnosis of at least one pathology;- prognosis of at least one pathology;- relapse of disease;- presence of minimal residual disease after a therapeutic treatment of a pathology;- development of resistance mechanisms after a therapeutic treatment.

3. Device (100) according to claim 1 or 2, wherein said bodily fluid corresponds to blood.

4. Device (100) according to any one of the preceding claims, wherein said device (100) is configured to be involved by said bodily fluid through said channel (10) at a circulation speed comprised between 1 mm! / s and 10 mm3 / s.

5. Device (100) according to any one of the preceding claims, wherein said device (100) is configured for a short-term use, i.e., for a continuous duration comprised between 60 minutes and 30 days.

6. Device (100) according to any one of the preceding claims, wherein said device (100) comprises at least a first receptor and a second receptor operatively active on the fluid transiting said channel (10), said first receptor being configured to detect a presence and / or a concentration of a first substance insaid fluid, said second receptor being configured to detect a presence and / or a concentration of a second substance in said fluid, said first substance differing from said second substance.

7. Device (100) according to any one of the preceding claims, wherein said at least one receptor comprises at least one biosensor, said at least one biosensor comprising at least one of an oligonucleotide probe and / or a pH meter and / or an aptamer and / or an antibody.

8. Device (100) according to any one of the preceding claims, wherein said at least one biosensor is configured to detect circulating free DNA (cfDNA), preferably to detect circulating tumor DNA (ctDNA), in said bodily fluid and / or to detect a concentration of specific proteins in said bodily fluid.

9. Device (100) according to any one of the preceding claims, wherein said at least one biosensor comprises at least one between an oligonucleotide probe complementary to the ALU247 DNA interspersed sequence and one oligonucleotide probe complementary to the ALLI115 DNA interspersed sequence.

10. Device (100) according to any one of the preceding claims, wherein said at least one biosensor comprises at least one or more aptamers configured to bind aberrant transcripts of the NGR1 gene fusion.

11. Device (100) according to any one of the preceding claims, wherein said at least one biosensor comprises at least one antibody capable of binding the HER2 protein.

12. Device (100) according to any one of the preceding claims, wherein said channel (10) extends in said main body between an inlet end (10a) and an outlet end (10b), said channel (10) being configured to be traversed by said flow of bodily fluid from said inlet end (10a) to said outlet end (10b).

13. Device (100) according to any one of the preceding claims, wherein said channel (10) defines an articulated path for the flow of bodily fluid, said channel (10) having a development greater than both the length and the width of said main body (1).

14. Device (100) according to any one of the preceding claims, wherein said channel (10) defines a coil comprising a plurality of straight portions (10c) and a plurality of curved portions (1 Od).

15. Device (100) according to the preceding claim, wherein said plurality of straight portions (10c) and said plurality of curved portions (1 Od) are arranged among themselves in an alternating sequence, preferably in a 1-to-1 alternation between straight portions (10c) and curved portions (1 Od).

16. Device (100) according to claim 14 or 15, wherein said plurality of straight portions (10c) comprises a number of straight portions comprised between 1 and 30, preferably comprised between 3 and 25, even more preferably comprises 5 and 20 straight portions.

17. Device (100) according to the preceding claim, wherein said plurality of curved portions (10c) comprises a number of curved portions comprised between 1 and 30, preferably comprised between 3 and 25, even more preferably comprises 5 and 20 straight portions.

18. Device (100) according to any one of the preceding claims, wherein said channel (10) has a diameter comprised between 1 mm and 3 mm, preferably equal to 2 mm.

19. Device (100) according to any one of the preceding claims, wherein said main body (1) is made in a single body, said channel (10) being obtained in said main body (1).

20. Device (100) according to the preceding claim, wherein said at least one receptor is embedded in said main body (1).

21. Device (100) according to the preceding claim, wherein said at least one receptor is positioned in correspondence with said channel (10).

22. Device (100) according to the preceding claim, wherein said main body (1) is at least partially made of resin, preferably of inert resin.

23. Device (100) according to any one of claims 19 to 22, wherein said main body (1 ) defines a physical support of flexible type.

24. Device (100) according to anyone of claims 19 to 23, wherein said main body (1) has a substantially planar development, preferably of a substantially rectangular shape.

25. Device (100) according to any one of claims 19 to 24, wherein said main body (1 ) is made by means of a 3D printing process.

26. Device (100) according to any one of claims 1 to 18, wherein said main body (1) comprises multiple elements associated with each other and said channel (10) comprises a tubular duct, preferably with a circular cross-section.

27. Device (100) according to the preceding claim, wherein said device (100) comprises at least one capsule (11) associated, in use, with said channel (10), said at least one capsule (11) being in fluid communication with said channel (10) to be involved in said flow of fluid.

28. Device (100) according to the preceding claim, wherein said at least one capsule (11) is configured to house at least one swab (12), said at least one swab (12) comprising said at least one receptor.

29. Device (100) according to the preceding claim, wherein said at least one swab (12) is insertable and / or removable from said at least one capsule (11).

30. Device (100) according to claim 28 or 29, wherein said at least one swab (12) comprises an absorbent element (12a) and an outer shell (12b, 12c), said absorbent element (12a) being configured to allow a dispersion on it of said at least one receptor, said outer shell (12b, 12c) being configured to provide shape stability to said absorbent element (12a) and / or to allow the passage of said fluid through it.

31. Device (100) according to the preceding claim, wherein at least part of said outer shell (12b, 12c) has a reticular structure, defining a plurality of openings to allow said fluid, present in the corresponding capsule (11), to involve, in particular to imbue, said absorbent element (12a).

32. Device (100) according to claim 30 or 31 , wherein at least part of said outer shell (12b, 12c) comprises a first semi-shell (12b) and a second semi-shell (12c), associable with each other to contain said absorbent element (12a) inside them.

33. Device (100) according to any one of claims 28 to 32, wherein said at least one swab (12) is free to rotate in said at least one capsule (11), said at least one capsule (11) having a substantially axisymmetric shape and the rotation of said at least one swab (12) occurring about the axis of said at least one capsule (11).

34. Device (100) according to any one of claims 27 to 33, wherein said main body (1 ) comprises a base (B) for said channel (10) and said at least one capsule (11).

35. Device (100) according to the preceding claim, wherein said channel (10), said at least one capsule(11) and said base (B) are at least partially made of resin, preferably inert resin.

36. Device (100) according to claim 26, wherein said main body (1) comprises:- a support (13), said channel (10) being obtained in said support (13);- at least one swab (12) comprising said at least one receptor, said at least one swab (12) being selectively applicable to said support (13) to be involved in said flow of fluid.

37. Device (100) according to the preceding claim, wherein said support (13) comprises at least one installation seat (1 Oe, 11e) configured to allow an installation of said swab (12), said at least one swab(12) being configured to be installed in said at least one installation seat (1 Oe, 11e) with at least one portion exposed to allow an installation and / or removal operation.

38. Device (100) according to the preceding claim, wherein said at least one swab (12) has a substantially planar configuration.

39. Device (100) according to the preceding claim, wherein said at least one swab (12) comprises an absorbent element (12a) and a gripping element (12d) associated with each other, said absorbent element (12a) having a substantially planar shape and being made in absorbent material configured to allow a dispersion on it of said at least one receptor, said gripping element (12d) being configured to act as a support for said absorbent element (12a) and to allow the installation / removal of said swab (12) in / from said support (13).

40. Device (100) according to the preceding claim, wherein said at least one installation seat (1 Oe, 11e) is shaped as a slot to allow an insertion of said absorbent element (12a) and a coupling with said gripping element (12d).

41. Device (100) according to claim 39 or 40, wherein said at least one installation seat (10e) is formed at least in correspondence with said channel (10) and said at least one swab (12) is configured to be associated with said support (13) with said absorbent element (12a) inserted in said channel (10) and with said gripping element (12d) which emerges from said support (13).

42. Device (100) according to any one of claims 39 to 41, wherein said support (13) comprises at least one capsule (11) associated, in use, with said channel (10), said at least one capsule (11) being in fluid communication with said channel (10) to be involved in said flow of fluid, said at least one installation seat (11e) being obtained at least in correspondence with said at least one capsule (11), said at least one swab (12) being configured to be associated with said support (13) with said absorbent element (12a) inserted in said at least one capsule (11) and with said gripping element (12d) which emerges from said support (13).

43. Device (100) according to claim 37, wherein said at least one swab (12) comprises:- an absorbent element (12a) made of absorbent material configured to allow dispersion on its surface of said at least one receptor;- a container element (12e) configured to define within itself a compartment apt to house said absorbent element (12a);- a capping element (12f) selectively applicable to said container element (12e) to close said compartment.

44. Device (100) according to the preceding claim, wherein said at least one swab (12) is selectively configurable in the following configurations:- a closed configuration, wherein said capping element (12f) is applied to said container element (12e) so as to retain said absorbent element (12a) inside said compartment and prevent fluid leakage when said at least one swab (12) is inserted in the corresponding installation seat (10e);- an open configuration, wherein said capping element (12f) is disassociated from the container element (12e) so as to allow an insertion of said absorbent element (12a) into said compartment and / or a removal of said absorbent element (12a) from said compartment.

45. Device (100) according to claim 43 or 44, wherein said container element (12e) comprises:- a coupling portion (12e') configured to enable an association between said at least one swab (12) and a corresponding installation seat (1 Oe) and to enable a selective association of said capping element (12f);- a filtering portion (12e") configured to define the compartment apt to contain said absorbent element (12a); optionally said filtering portion (12e") having an overall reticular structure, defining a plurality of openings to allow said flow of fluid to involve said absorbent element (12a).

46. Device (100) according to any one of claims 43 to 45 and to claim 12, wherein said channel (10) comprises an initial portion (1 O'), extending from said inlet end (10a), and a final portion (10"), extendingfrom said outlet end (10b), optionally said initial portion (10') and said final portion (10") being parallel to each other; and wherein said at least one installation seat (1 Oe) is obtained in correspondence with said initial portion (10') and / or said final portion (10"), preferably said support (13) comprising at least two installation seats (1 Oe), at least one installation seat being positioned in correspondence with said initial portion (1 O') and at least one other installation seat being positioned in correspondence with said final portion (10").

47. Device (100) according to claim 45 and to claim 46, wherein, in use, said at least one swab (12) has at least the filtering portion (12e") inserted inside said channel (10), while at least part of said coupling portion (12e') and / or said capping element (12f) is exposed from an outer surface of said support (13).

48. Device (100) according to the preceding claim, wherein said coupling portion (12e') and the installation seat (1 Oe) housing the respective swab (12) are associable with each other by means of a coupling mechanism, said coupling mechanism optionally being a bayonet coupling mechanism.

49. Device (100) according to any one of claims 45 to 48, wherein said container element (12e) and said capping element (12f) are associable with each other by means of a coupling mechanism, said coupling mechanism optionally being a bayonet coupling mechanism.

50. Device (100) according to any one of claims 45 to 49, wherein said swab (12) is made by means of 3D printing techniques, optionally said container element (12e) and said capping element (12f) being made separately by means of respective 3D printing processes.

51. Device (100) according to any one of claims 36 to 50, wherein said support (13) is made by means of 3D printing techniques, by overlapping multiple layers of material apt to concurrently form said channel (10).

52. Device (100) according to any one of claims 36 to 50, wherein said support (13) is made by joining two semi-bodies apt to define said channel (10) between them.

53. Device (100) according to any one of claims 36 to 52, wherein said support (13) is made of resin, preferably of inert resin.

54. Device (100) according to any one of claims 36 to 53, wherein said main body (1) comprises an outer shell (14) configured to contain at least said channel (10), said at least one capsule (11 ) and said support (13).

55. Device (100) according to the preceding claim, wherein said outer shell (14) comprises a first protective element (14a) and a second protective element (14b) associable with each other.

56. Device (100) according to any one of claims 36 to 55, wherein said main body (1) comprises an adhesive element (15) configured to secure said device (100) to the body of the patient.

57. Device (100) according to any one of the preceding claims, wherein said device (100) is configurable in different configurations depending on said health status of the patient.

58. Device (100) according to the preceding claim, wherein at least part of said device (100) is configured to take on different colorings depending on said health status of the patient.

59. Device (100) according to the preceding claim, wherein said main body (1) takes on a first coloring when said at least one receptor detects said presence and / or said concentration of said at least one substance in said bodily fluid is above a certain threshold level and a second coloring when said at least one receptor does not detect said presence and / or when said concentration is below said certain threshold level.

60. Device (100) according to any one of the preceding claims comprising an electronic processing unit operatively connected to said at least one receptor to analyze the presence and / or a certain concentration of said at least one substance in the bodily fluid.

61. Device (100) according to the preceding claim comprising an interface element, such as, for example, a display (16), said interface element being supported by said main body (1), in particular by said outer shell (14), and being operatively connected to the electronic processing unit to make explicit, in particular to display, the results of the analysis performed by the electronic processing unit.

62. Device (100) according to any one of the preceding claims, wherein at least part of said device (100) is configured to be processed by an external reading device, in order to obtain, by means of said external reading device, at least one piece of information relating to said presence and / or said concentration of said at least one substance in said bodily fluid.

63. Device (100) according to any one of the preceding claims, said device (100) further comprising an inlet duct (2) and an outlet duct (3) fluidically connected to said channel (10), said inlet duct (2) and said outlet duct (3) being in particular arranged respectively upstream and downstream of said channel (10).

64. Device (100) according to the preceding claim, wherein said inlet duct (2) is connected, in correspondence with a first inlet end (2a), to said channel (10) to convey said flow of bodily fluid.

65. Device (100) according to claim 63 or 64, wherein said outlet duct (3) is connected, in correspondence with a first outlet end (3a), to said channel (10) for a discharge of said bodily fluid.

66. Device (100) according to any one of claims 63 to 65, wherein said inlet duct (2) is configured to be applied, in correspondence with a second inlet end (2b), to a portion of the body of aforesaid patient, said inlet duct (2) being configured to receive, in correspondence with said second inlet end (2b), said flow of bodily fluid circulating in said body portion of the patient and to convey said flow of bodily fluid to said channel (10) through said first inlet end (2a);and wherein said outlet duct (3) is configured to be applied, in correspondence with a second outlet end (3b), to a portion of the body of aforesaid patient, said outlet duct (3) being configured to receive, in correspondence with said first outlet end (3a), the flow of bodily fluid circulating in said channel (10) and to send said flow of bodily fluid to said patient through said second outlet end (3b).

67. Device (100) according to the preceding claim, wherein said inlet duct (2) comprises an inlet cannula-needle (20) in correspondence with said second inlet end (2b).

68. Device (100) according to claim 66 or to claim 67, wherein said outlet duct (3) comprises an outlet cannula-needle (30) in correspondence with said second outlet end (3b).

69. Device (100) according to any one of claims 63 to 68, wherein said inlet duct (2) is configured to be applied to the body of the patient in correspondence with the arm of the patient, preferably in correspondence with the middle third of the arm, even more preferably in correspondence with the basilic vein or the brachial veins of the patient.

70. Device (100) according to any one of claims 63 to 69, wherein said outlet duct (3) is configured to be applied to the body of the patient in correspondence with the arm of the patient, preferably in correspondence with the middle third of the arm, even more preferably in correspondence with the basilic vein or the brachial veins of the patient.

71. Method of manufacturing a medical device (100) for a liquid biopsy, said method of manufacturing comprising at least the following steps:- manufacturing a main body (1) constituting the physical support of said medical device (100), said step of manufacturing said main body (1) providing for the arrangement of a channel (10) configured, in use, for the transit of a flow of bodily fluid of a patient;- manufacturing an inlet duct (2);- associating said inlet duct (2) with said main body (1 ) so that said inlet duct (2) and said channel (10) are in fluid communication;- manufacturing an outlet duct (3);- associating said outlet duct (3) with said main body (1) so that said outlet duct (3) and said channel (10) are in fluid communication; said manufacturing method being characterized in that said step of manufacturing said main body (1) provides for arranging a plurality of receptors operatively active on said channel (10), said plurality of receptors being configured, in use, to detect a presence and / or a concentration of at least one substance in said bodily fluid representative of a health status of said patient.

72. Method of manufacturing according to the preceding claim, wherein said step of manufacturing said main body (1) provides that said main body (1) consists of a single piece wherein said channel (10) isobtained and said plurality of receptors is embedded in said main body (1), said main body (1) being preferably made by means of 3D printing techniques.

73. Method of manufacturing according to claim 71, wherein said step of manufacturing said main body (1) provides that said main body (1) comprises at least the following elements associated with each other:- said channel (10) configured as a tubular duct;- at least one capsule (11), associated with said channel (10) and in fluid communication with said channel (10) for a transit of said flow of fluid;- at least one swab (12) per each capsule (11), configured to be removably inserted into the corresponding capsule, said at least one swab (12) comprising at least a part of said plurality of receptors;- a base (B) for said channel (10) and said at least one capsule (11).

74. Method of manufacturing according to claim 71, wherein said step of manufacturing said main body (1) provides that said main body (1) comprises at least the following elements:- a support (13) defining said channel (10), said support comprising at least one installation seat (1 Oe) obtained in correspondence with said channel (10);- at least one swab (12) per each installation seat (1 Oe), configured to be removably inserted into a corresponding installation seat (1 Oe) and comprising at least a part of the plurality of receptors.

75. Method of manufacturing according to claim 71, wherein said step of manufacturing said main body (1) provides that said main body (1) comprises at least the following elements:- a support (13) defining said channel (10) and at least one capsule (11) associated with said channel (10) and in fluid communication with said channel for a transit of said flow of bodily fluid, said support comprising at least one installation seat (11 e) obtained in correspondence with said at least one capsule (11);- at least one swab (12) for each installation seat (11e) configured for removable insertion into a corresponding installation seat and comprising at least a part of the plurality of receptors.

76. Method of manufacturing according to claim 71, wherein said step of manufacturing said main body (1) provides that said main body (1) comprises at least the following elements:- a support (13) defining said channel (10), said support (10) comprising at least one installation seat (1 Oe) obtained in correspondence with said channel (10);- at least one swab (12) per each installation seat (1 Oe), configured to be removably inserted into a corresponding installation seat and comprising at least a part of the plurality of receptors;wherein said step of manufacturing said main body (1) provides that each swab (12) comprises a container element (12e) and a capping element (12f), selectively associable with each other to contain an absorbent element (12a).

77. Method of manufacturing according to any one of claims 71 to 76, wherein said step of manufacturing an inlet duct (2) provides equipping said inlet duct (2) with an inlet cannula needle (20) and wherein said step of manufacturing an outlet duct (3) provides equipping said outlet duct (3) with an outlet cannula needle (30).

78. Device (100), in particular device for medical use, more particularly device for medical use configured to administer at least one substance into a bodily fluid of a patient, said device (100) comprising:- a main body (1),- a channel (10) supported by said main body (1) and / or obtained in said main body (1) and / or integrated into said main body (1), said channel (10) being configured for a transit of a flow of fluid, in particular of a bodily fluid of said patient; characterized by comprising at least one dispenser element operatively active on the fluid transiting said channel (10), said at least one dispenser element being configured to release a substance into said bodily fluid, in particular configured to dose said substance into said bodily fluid, optionally wherein said device (100) comprises a plurality of dispenser elements operatively active on the fluid transiting said channel (10) and configured to release a substance into said bodily fluid and wherein the dispenser elements of said plurality of dispenser elements are distributed, in particular uniformly distributed, along said channel (10).

79. Device (100) according to the preceding claim, wherein said at least one substance released by said at least one dispenser element into said flow of bodily fluid is configured to enable at least one of the following operations:- therapeutic treatment;- cellular enrichment of said flow of bodily fluid;- a nucleic acid enrichment of said flow of bodily fluid;- administration of chemotherapeutic drugs;- administration of antibodies conjugated with chemotherapeutics;- administration of inhibitors for specific variants of proteins encoded by mutated genes;- administration of drugs with inhibitory action.

80. Device (100) according to claim 78 or 79, wherein said bodily fluid corresponds to blood.

81. Device (100) according to any one of claims 78 to 80, wherein said device (100) is configured to be involved by said bodily fluid through said channel (10) at a circulation speed comprised between 1 mm3 / s and 10 mm3 / s.

82. Device (100) according to any one of claims 78 to 81 , wherein said device (100) is configured for a short-term use, i.e. for a continuous duration comprised between 60 minutes and 30 days.

83. Device (100) according to any one of claims 78 to 82, wherein said device (100) comprises at least a first dispenser element and a second dispenser element operatively active on the fluid transiting said channel (10), said first dispenser element being configured to release a first substance into said fluid, said second dispenser element being configured to release a second substance into said fluid, said first substance differing from said second substance.

84. Device (100) according to any one of claims 78 to 83, wherein said channel (10) extends within said main body between an inlet end (10a) and an outlet end (10b), said channel (10) being configured to be traversed by said flow of bodily fluid from said inlet end (10a) to said outlet end (10b).

85. Device (100) according to any one of claims 78 to 84, wherein said channel (10) defines an articulated path for the flow of bodily fluid, said channel (10) having a development greater than both the length and the width of said main body (1).

86. Device (100) according to any one of claims 78 to 85, wherein said channel (10) defines a coil comprising a plurality of straight portions (10c) and a plurality of curved portions (1 Od).

87. Device (100) according to the preceding claim, wherein said plurality of straight portions (10c) and said plurality of curved portions (1 Od) are arranged among themselves in an alternating sequence, preferably in a 1 -to-1 alternation between straight portions (10c) and curved portions (1 Od).

88. Device (100) according to claim 76 or 77, wherein said plurality of straight portions (10c) comprises a number of straight portions comprised between 1 and 30, preferably between 3 and 25, even more preferably comprises 5 and 20 straight portions.

89. Device (100) according to the preceding claim, wherein said plurality of curved portions (10c) comprises a number of curved portions comprised between 1 and 30, preferably comprised between 3 and 25, even more preferably comprises 5 and 20 straight portions.

90. Device (100) according to any one of claims 78 to 89, wherein said channel (10) has a diameter comprised between 1 mm and 3 mm, preferably equal to 2 mm.

91. Device (100) according to any one of claims 78 to 90, wherein said main body (1) is made in a single body, said channel (10) being obtained in said main body (1).

92. Device (100) according to the preceding claim, wherein said at least one dispenser element is embedded in said main body (1).

93. Device (100) according to the preceding claim, wherein said at least one dispenser element is positioned in correspondence with said channel (10).

94. Device (100) according to the preceding claim, wherein said main body (1) is at least partially made of resin, preferably of inert resin.

95. Device (100) according to any one of claims 81 to 94, wherein said main body (1 ) defines a physical support of a flexible type.

96. Device (100) according to any one of claims 81 to 95, wherein said main body (1) has a substantially planar development, preferably of a substantially rectangular shape.

97. Device (100) according to any one of claims 81 to 96, wherein said main body (1 ) is made by means of a 3D printing process.

98. Device (100) according to any one of claims 77 to 90, wherein said main body (1 ) comprises multiple elements associated with each other and said channel (10) comprises a tubular duct, preferably with a circular cross-section.

99. Device (100) according to the preceding claim, wherein said device (100) comprises at least one capsule (11) associated, in use, with said channel (10), said at least one capsule (11) being in fluid communication with said channel (10) to be involved by said flow of fluid.

100. Device (100) according to the preceding claim, wherein said at least one capsule (11) is configured to house at least one doser (12), said at least one doser (12) comprising said at least one dispenser element.

101. Device (100) according to the preceding claim, wherein said at least one doser (12) is insertable and / or removable from said at least one capsule (11).

102. Device (100) according to claim 100 or 101, wherein said at least one swab (12) comprises a releasing element (12a) and an outer shell (12b, 12c), said releasing element (12a) comprising said at least one dispenser and being configured to release said at least one substance into said flow of bodily fluid, said outer shell (12b, 12c) being configured to provide shape stability to said releasing element (12a) and / or to allow the passage of said fluid through it.

103. Device (100) according to the preceding claim, wherein at least part of said outer shell (12b, 12c) features a reticular structure, defining a plurality of openings to allow said fluid, present in the corresponding capsule (11 ) to involve, specifically to imbue, said releasing element (12a).

104. Device (100) according to claim 102 or 103, wherein at least part of said outer shell (12b, 12c) comprises a first semi-shell (12b) and a second semi-shell (12c), associable with each other to contain said releasing element (12a) within them.

105. Device (100) according to any one of claims 100 to 104, wherein said at least one doser (12) is free to rotate within said at least one capsule (11 ), said at least one capsule (11 ) having a substantiallyaxially symmetric shape, and the rotation of said at least one doser (12) occurring about the axis of said at least one capsule (11 ).

106. Device (100) according to any one of claims 99 to 105, wherein said main body (1) comprises a base (B) for said channel (10) and said at least one capsule (11).

107. Device (100) according to the preceding claim, wherein said channel (10), said at least one capsule (11), and said base (B) are at least partially made of resin, preferably inert resin.

108. Device (100) according to claim 98, wherein said main body (1) comprises:- a support (13), said channel (10) being obtained in said support (13);- at least one doser (12) comprising said at least one dispenser, said at least one doser (12) being selectively applicable to said support (13) to be involved by said flow of fluid.

109. Device (100) according to the preceding claim, wherein said support (13) comprises at least one installation seat (1 Oe, 11e) configured to enable an installation of said doser (12), said at least one doser (12) being configured to be installed in said at least one installation seat (1 Oe, 11e) with at least one portion exposed to allow an installation and / or removal operation.

110. Device (100) according to the preceding claim, wherein said at least one doser (12) has a substantially planar configuration.

111. Device (100) according to the preceding claim, wherein said at least one doser (12) comprises a releasing element (12a) and a gripping element (12d) associated with each other, said releasing element (12a) having a substantially planar shape and comprising said at least one dispenser, said gripping element (12d) being configured to act as a support for said releasing element (12a) and to enable an installation / removal of said doser (12) into / from said support (13).

112. Device (100) according to the preceding claim, wherein said at least one installation seat (1 Oe, 11e) is shaped as a slot to allow an insertion of said releasing element (12a) and a coupling with said gripping element (12d).

113. Device (100) according to claim 111 or 112, wherein said at least one installation seat (1 Oe) is obtained at least in correspondence with said channel (10) and said at least one doser (12) is configured to be associated to said support (13) with said releasing element (12a) inserted into said channel (10) and with said gripping element (12d) which emerges from said support (13).

114. Device (100) according to any one of claims 111 to 113, wherein said support (13) comprises at least one capsule (11) associated, in use, with said channel (10), said at least one capsule (11) being in fluid communication with said channel (10) to be involved by said flow of fluid, said at least one installation seat (11e) being obtained at least in correspondence with said at least one capsule (11), said at least one doser (12) being configured to be associated to said support (13) with said releasingelement (12a) inserted into said at least one capsule (11) and with said gripping element (12d) which emerges from said support (13).

115. Device (100) according to claim 109, wherein said at least one doser (12) comprises:- a releasing element (12a) comprising said at least one dispenser;- a container element (12e) configured to define within itself a compartment suitable for housing said releasing element (12a);- a capping element (12f) selectively applicable to said container element (12e) to close said compartment.

116. Device (100) according to the preceding claim, wherein said at least one doser (12) is selectively configurable in the following configurations:- a closed configuration, wherein said capping element (12f) is applied to said container element (12e) so as to retain said releasing element (12a) within said compartment and to prevent a fluid leakage when said at least one doser (12) is inserted into the respective installation seat (10e);- an open configuration, wherein said capping element (12f) is disassociated from the container element (12e) so as to allow an insertion of said releasing element (12a) into said compartment and / or a removal of said releasing element (12a) from said compartment.

117. Device (100) according to claim 115 or 116, wherein said container element (12e) comprises:- a coupling portion (12e') configured to allow an association between said at least one doser (12) and a corresponding installation seat (1 Oe) and to allow a selective association of said capping element (12f);- a filtering portion (12e") configured to define the compartment apt to house said releasing element (12a); optionally said filtering portion (12e") having an overall reticular structure, defining a plurality of openings to allow said flow of fluid to interact with said releasing element (12a).

118. Device (100) according to any one of claims 115 to 117 and to claim 84, wherein said channel (10) comprises an initial portion (10'), extending from said inlet end (10a), and a final portion (10"), extending from said outlet end (10b), optionally said initial portion (10') and said final portion (10") being parallel to each other; and wherein said at least one installation seat (1 Oe) is obtained in correspondence with said initial portion (10') and / or said final portion (10"), preferably said support (13) comprising at least two installation seats (1 Oe), at least one installation seat being positioned in correspondence with said initial portion (101) and at least another installation seat being positioned in correspondence with said final portion (10").

119. Device (100) according to claim 117 and to claim 118, wherein, in use, said at least one doser (12) has at least the filtering portion (12e") inserted within said channel (10), while at least part of said coupling portion (12e') and / or of said capping element (12f) is exposed from an outer surface of said support (13).

120. Device (100) according to the preceding claim, wherein said coupling portion (12e') and the installation seat (1 Oe) housing the corresponding doser (12) are associable to each other by means of a coupling mechanism, said coupling mechanism being optionally a bayonet coupling mechanism.

121. Device (100) according to any one of claims 117 to 120, wherein said container element (12e) and said capping element (12f) are associable to each other by means of a coupling mechanism, said coupling mechanism being optionally a bayonet coupling mechanism.

122. Device (100) according to any one of claims 117 to 121, wherein said doser (12) is made by means of a 3D printing process, optionally said container element (12e) and said capping element (12f) being made separately by means of respective 3D printing processes.

123. Device (100) according to any one of claims 108 to 122, wherein said support (13) is made by means of 3D printing techniques, by overlapping multiple layers of material apt to concurrently form said channel (10).

124. Device (100) according to any one of claims 108 to 122, wherein said support (13) is made by joining two semi-bodies configured to define said channel (10) between them.

125. Device (100) according to any one of claims 108 to 124, wherein said support (13) is made of resin, preferably of inert resin.

126. Device (100) according to any one of claims 108 to 125, wherein said main body (1) comprises an outer shell (14) configured to contain at least said channel (10), said at least one capsule (11 ), and said support (13).

127. Device (100) according to the preceding claim, wherein said outer shell (14) comprises a first protective element (14a) and a second protective element (14b) associable with each other.

128. Device (100) according to any one of claims 108 to 127, wherein said main body (1) comprises an adhesive element (15) configured to secure said device (100) to the body of the patient.

129. Device (100) according to any one of claims 78 to 129, said device (100) further comprising an inlet duct (2) and an outlet duct (3) fluidically connected to said channel (10), said inlet duct (2) and said outlet duct (3) being in particular arranged respectively upstream and downstream of said channel (10).

130. Device (100) according to the preceding claim, wherein said inlet duct (2) is connected, in correspondence with a first inlet end (2a), to said channel (10) to send said flow of bodily fluid.

131. Device (100) according to claim 129 or to claim 130, wherein said outlet duct (3) is connected, in correspondence with a first outlet end (3a), to said channel (10) for a discharge of said bodily fluid.

132. Device (100) according to any one of claims 129 to 131, wherein said inlet duct (2) is configured to be applied, in correspondence with a second inlet end (2b), to a portion of the body of the aforesaid patient, said inlet duct (2) being configured to receive, in correspondence with said second inlet end (2b), said flow of bodily fluid circulating in said portion of the body of the patient and to convey said flow of bodily fluid to said channel (10) through said first inlet end (2a); and wherein said outlet duct (3) is configured to be applied, in correspondence with a second outlet end (3b), to a portion of the body of the aforesaid patient, said outlet duct (3) being configured to receive, in correspondence with said first outlet end (3a), the flow of bodily fluid circulating in said channel (10) and to send said flow of bodily fluid to said patient through said second outlet end (3b).

133. Device (100) according to the preceding claim, wherein said inlet duct (2) comprises an inlet cannula needle (20) in correspondence with said second inlet end (2b).

134. Device (100) according to claim 132 or to claim 133, wherein said outlet duct (3) comprises an outlet cannula needle (30) in correspondence with said second outlet end (3b).

135. Device (100) according to any one of claims 129 to 134, wherein said inlet duct (2) is configured to be applied to the body of the patient in correspondence with the arm of the patient, preferably in correspondence with the middle third of the arm, even more preferably in correspondence with the basilic vein or with the brachial veins of the patient.

136. Device (100) according to any one of claims 129 to 135, wherein said outlet duct (3) is configured to be applied to the body of the patient in correspondence with the arm of the patient, preferably in correspondence with the middle third of the arm, even more preferably in correspondence with the basilic vein or with the brachial veins of the patient.

137. Method of manufacturing a medical device (100) for the administration of at least one substance into a bodily fluid of a patient, said manufacturing method comprising at least the following steps:- manufacturing a main body (1) constituting the physical support of said medical device (100), said step of manufacturing said main body (1) providing for the arrangementof a channel (10) configured, in use, for the transit of a flow of bodily fluid of a patient;- manufacturing an inlet duct (2);- associating said inlet duct (2) with said main body (1) so that said inlet duct (2) and said channel (10) are in fluid communication;- manufacturing an outlet duct (3);- associating said outlet duct (3) with said main body (1) so that said outlet duct (3) and said channel (10) are in fluid communication;said manufacturing method being characterized in that said step of manufacturing said main body (1) provides for the arrangement of a plurality of dispensers operatively active on said channel (10), said plurality of dispensers being configured, in use, to release said at least one substance into said bodily fluid.

138. Manufacturing method according to the preceding claim, wherein said step of manufacturing said main body (1) provides that said main body (1) consists of a single piece wherein said channel (10) is obtained and said plurality of dispensers is embedded in said main body (1), said main body (1) being preferably made by means of 3D printing techniques.

139. Manufacturing method according to claim 137, wherein said step of manufacturing said main body (1) provides that said main body (1) comprises at least the following elements associated with each other:- said channel (10) configured as a tubular duct;- at least one capsule (11), associated with said channel (10) and in fluid communication with said channel (10) for a transit of said flow of fluid;- at least one doser (12) per each capsule (12), configured to be removably inserted into the corresponding capsule, said at least one doser (12) comprising said at least one dispenser;- a base (B) for said channel (10) and said at least one capsule (11).

140. Manufacturing method according to claim 137, wherein said step of manufacturing said main body (1) provides that said main body (1) comprises at least the following elements:- a support (13) defining said channel (10), said support (13) comprising at least one installation seat (1 Oe) obtained in correspondence with said channel (10);- at least one doser (12) per each installation seat (1 Oe), configured to be removably inserted into a corresponding installation seat (1 Oe) and comprising said at least one dispenser.

141. Manufacturing method according to claim 137, wherein said step of manufacturing said main body (1) provides that said main body (1) comprises at least the following elements:- a support (13) defining said channel (10) and at least one capsule (11), associated with the channel (10) and in fluid communication with said channel for a transit of said flow of bodily fluid, said support (13) comprising at least one installation seat (11e) obtained in correspondence with said at least one capsule (11);- at least one doser (12) for each installation seat (11e), configured to be removably inserted into a corresponding installation seat and comprising said at least one dispenser.

142. Manufacturing method according to claim 137, wherein said step of manufacturing said main body (1) provides that said main body (1) comprises at least the following elements:- a support (13) defining said channel (10), said support (13) comprising at least one installation seat (1 Oe) obtained in correspondence with said channel (10);- at least one swab (12) for each installation seat (1 Oe), configured to be removably inserted in a corresponding installation seat and comprising said at least one dispenser; wherein said step of manufacturing said main body (1) provides that each doser (12) comprises a container element (12e) and a capping element (12f), selectively associable with each other to contain a releasing element (12a), said releasing element (12a) comprising said at least one dispenser.

143. Method of manufacturing according to any one of claims 137 to 142, wherein said step of manufacturing an inlet duct (2) provides equipping said inlet duct (2) with an inlet cannula needle (20) and wherein said step of manufacturing an outlet duct (3) provides equipping said outlet duct (3) with an outlet cannula needle (30).

Images