Method for sampling nasal cavity and device

Abstract

To disclose a composition, a method, a system, and a device for collecting biologica materials from a target nasal cavity or from the olfactory region from a target nasal cavity.SOLUTION: In some embodiments, biological materials are collected from a sampled sub-region of a nasal cavity, such as a sampled sub-region of an olfactory region, and are specific to the sampled sub-region. In some embodiments, biological materials collected from a sampled sub-region are stored according to localization. In some embodiments, the biological materials include cerebrospinal fluid, at least one microorganism from microbiome of a patient, at least one component of metabolome of the patient, at least one pathogen, and / or at least one biomarker of interest. In some embodiments, a specific agent is sent into a nasal cavity to make collection of biological materials in the nasal cavity easier.SELECTED DRAWING: Figure 2D

Description

Technical Field

[0001] Cross-reference This application claims the benefit of U.S. Provisional Application No. 62 / 838,169, filed Apr. 24, 2019, which is hereby incorporated by reference in its entirety.

Background Art

[0002] The human nasal cavity is a host for various types of microorganisms that can be uniquely located in specific regions of the nasal cavity. The shape and non-uniformity of the nasal cavity provide various functions that result in such a distribution of microorganisms across different locations. Other types of biological materials are also found within the nasal cavity.

Summary of the Invention

[0003] In one aspect, provided herein is a method for collecting biological material from a patient's olfactory region, the method comprising: a) providing a formulation configured to capture biological material; b) inserting a delivery device having a delivery orifice into the patient's nasal cavity; c) delivering the formulation via the delivery device to the patient's olfactory region or a targeted sub-region of the olfactory region; d) enabling the formulation to capture the biological material; and e) withdrawing at least a portion of the formulation and the biological material captured therein, thereby collecting the biological material. In some embodiments, the delivery orifice is positioned such that delivery of the formulation is to a targeted sub-region of the olfactory region. In some embodiments, the method further comprises preserving the composition of the formulation and / or the captured biological material upon withdrawal. In some embodiments, the biological material comprises cerebrospinal fluid, one or more microorganisms of the patient's microbiota, one or more components of the patient's metabolome, one or more pathogens, and / or one or more biomarkers of interest. In some embodiments, the one or more pathogens comprise a virus or a part or derivative thereof. In some embodiments, the virus is SARS CoV-2. In some embodiments, the delivery device comprises a cannula and / or a microfluidic channel, and inserting the delivery device comprises inserting the cannula and / or the microfluidic channel into the patient's nasal cavity. In some embodiments, the method further comprises determining the length of the nasal cavity from the patient's nostril to the olfactory region and inserting the cannula and / or the microfluidic channel to a predetermined depth based on the determined length. In some embodiments, the method further comprises positioning a reference device on the patient's face to provide an anatomical reference point for accurately positioning the delivery orifice within the nasal cavity. In some embodiments, the biological material is captured from a targeted sub-region of the olfactory region.In some embodiments, the delivery device includes a sheath configured to minimize or prevent contamination of the cannula and / or the microfluidic channel, the delivery orifice, the formulation, and / or the captured biological material from the olfactory region of the nasal cavity and / or an olfactory region other than the targeted sub-region of the olfactory region. In some embodiments, the sheath comprises a protective coating disposed around the cannula and / or the microfluidic channel. In some embodiments, the sheath includes a cover or sleeve disposed around the cannula and / or the microfluidic channel. In some embodiments, the method further comprises inducing the patient to increase or decrease mucus production to facilitate capture and / or collection of the biological material. In some embodiments, the method further comprises inducing the patient to increase or decrease blood flow to facilitate capture and / or collection of the biological material. In some embodiments, the method further comprises inducing the patient to increase intracranial pressure to facilitate capture and / or collection of the biological material. In some embodiments, the method further comprises applying energy to facilitate capture and / or collection of the biological material. In some embodiments, the step of applying energy comprises applying heat to the formulation via UV / VIS / IR light, heating of the formulation in accordance with Ohm's law, or conduction from a heated element within the delivery device. In some embodiments, an electric field and / or a magnetic field is applied to facilitate capture of biological material by the formulation. In some embodiments, the delivery device is configured to deliver the flow of the formulation to the olfactory region or a targeted sub-region of the olfactory region such that the flow of the formulation is drawn as a continuous flow. In some embodiments, the method further comprises repeating the method of the present invention to increase collection of the biological material. In some embodiments, the formulation is any formulation disclosed herein, including those as disclosed in paragraph

[0008] .

[0004] In one aspect, provided herein is a method for collecting biological material from a patient's nasal cavity, the method comprising: a) providing a formulation configured to capture biological material; b) inserting a delivery device including a delivery orifice into the patient's nasal cavity or a targeted sub-region of the nasal cavity; c) delivering the formulation to the patient's nasal cavity via the delivery device; d) enabling the delivered formulation to capture the biological material; and e) withdrawing at least a portion of the formulation and the biological material captured therein. In some embodiments, the delivery orifice of the delivery device is positioned such that delivery of the formulation is to a targeted sub-region of the nasal cavity. In some embodiments, the method further comprises preserving the composition of the formulation and / or the captured biological material upon withdrawal. In some embodiments, the biological material includes cerebrospinal fluid (CSF), one or more microorganisms of the patient's microbiota, one or more components of the patient's metabolome, one or more pathogens, and / or one or more biomarkers of interest. In some embodiments, the one or more pathogens include a virus or a part or derivative thereof. In some embodiments, the virus is SARS CoV-2. In some embodiments, the delivery device includes a cannula and / or a microfluidic channel, and inserting the delivery device includes inserting the cannula and / or the microfluidic channel into the patient's nasal cavity. In some embodiments, the method further comprises determining the length of the nasal cavity from the patient's nostril to the olfactory region and inserting the cannula and / or the microfluidic channel to a predetermined depth based on the determined length. In some embodiments, the method further comprises positioning a reference device on the patient's face to provide an anatomical reference point for accurately positioning the delivery orifice within the nasal cavity. In some embodiments, the biological material is captured from a target region of the nasal cavity.In some embodiments, the delivery device includes a cannula and / or microfluidic channel, a delivery orifice, a formulation, and / or a sheath configured to minimize or prevent contamination of the captured biological material from non-target regions of the nasal cavity. In some embodiments, the sheath comprises a protective coating disposed around the cannula and / or microfluidic channel. In some embodiments, the sheath comprises a cover or sleeve disposed around the cannula and / or microfluidic channel. In some embodiments, the method further comprises inducing the patient to increase or decrease mucus production to facilitate capture and / or collection of the biological material. In some embodiments, the method further comprises inducing the patient to increase or decrease blood flow to facilitate capture and / or collection of the biological material. In some embodiments, the method further comprises inducing the patient to increase intracranial pressure to facilitate capture and / or collection of the biological material. In some embodiments, the method further comprises applying energy to facilitate capture and / or collection of the biological material. In some embodiments, the step of applying energy comprises applying heat to the formulation via UV / VIS / IR light, heating in accordance with Ohm's law of the formulation, or conduction from a heated element within the delivery device. In some embodiments, an electric field and / or magnetic field is applied to facilitate capture of the biological material by the formulation. In some embodiments, the delivery device is configured to deliver the flow of the formulation to the nasal cavity or a target sub-region of the nasal cavity such that the flow of the formulation is drawn as a continuous flow. In some embodiments, the method further comprises repeating the method to increase collection of the biological material. In some embodiments, the formulation is any formulation disclosed herein, including those as disclosed in paragraph

[0008] .

[0005] In one aspect, provided herein is an apparatus for collecting biological material from a patient's nasal cavity, the apparatus comprising: a) a first body containing a formulation configured to capture biological material; b) a first cannula and / or microfluidic channel configured to be positioned within the patient's nasal cavity and having a delivery orifice fluidly connected to the first body; c) a deployment mechanism for delivering the formulation to the patient's nasal cavity via the first cannula and / or microfluidic channel to capture biological material from the patient's nasal cavity; and d) a collection device for collecting the biological material captured from the patient's nasal cavity. In some embodiments, the delivery orifice is configured such that delivery of the formulation occurs in a targeted sub-region of the nasal cavity. In some embodiments, the delivery orifice is configured such that delivery of the formulation occurs in the olfactory region of the nasal cavity. In some embodiments, the delivery orifice is configured such that delivery of the formulation occurs in a targeted sub-region of the olfactory region. In some embodiments, the biological material is cerebrospinal fluid (CSF), one or more microorganisms of the patient's microbiota, one or more components of the patient's metabolome, one or more pathogens, and / or one or more biomarkers of interest. In some embodiments, the one or more pathogens include a virus or a part or derivative thereof. In some embodiments, the virus is SARS CoV-2. In some embodiments, the biological material is captured from a targeted sub-region of the nasal cavity. In some embodiments, the biological material is captured from the olfactory region of the nasal cavity. In some embodiments, the biological material is captured from a targeted sub-region of the olfactory region of the nasal cavity. In some embodiments, the apparatus further comprises a sheath configured to minimize or prevent contamination of the first body, the first cannula and / or microfluidic channel, the delivery orifice, the collection device, the formulation, and / or biological material captured from non-target regions of the nasal cavity.In some embodiments, the sheath is configured to minimize or prevent contamination of the first body, the first cannula and / or microfluidic channel, the delivery orifice, the collection device, the formulation, and / or captured biological material from non-target sub-regions of the olfactory region. In some embodiments, the sheath comprises a protective coating disposed around the first cannula and / or microfluidic channel. In some embodiments, the sheath comprises a cover or sleeve disposed around the first cannula and / or microfluidic channel. In some embodiments, the first body comprises a first container removably coupled to the first cannula and / or microfluidic channel. In some embodiments, the collection device comprises a second body removably coupled to the first cannula and / or microfluidic channel. In some embodiments, the collection device comprises the second body and a second cannula coupled to the second body. In some embodiments, the collection device is configured to preserve integrity and the biological material according to its localization when captured from the nasal cavity. In some embodiments, the deployment mechanism comprises a first actuator coupled to a first spring coupled to a first plunger. In some embodiments, the device further comprises a clip configured to couple to a patient's nose to facilitate positioning of the delivery orifice. In some embodiments, the first cannula and / or microfluidic channel is configured to move relative to the clip. In some embodiments, the collection device comprises a second actuator coupled to a second spring coupled to a second plunger. In some embodiments, the first body comprises a cable. In some embodiments, the first cannula and / or microfluidic channel is a flexible cannula. In some embodiments, the first cannula and / or microfluidic channel is a telescoping cannula.In some embodiments, the apparatus comprises mechanical features for preventing dangerous forces from being transmitted through the first cannula and / or the microfluidic channel. In some embodiments, the mechanical features include force-limiting springs, radial slip clutches, and / or axial slip clutches. In some embodiments, the targeted sub-region of the olfactory region is localized to individual millimeter regions within the olfactory region. In some embodiments, the formulation is any formulation disclosed herein, including those as disclosed in paragraph

[0008] .

[0006] In one aspect, there is provided herein a system for collecting biological material from a patient's nasal cavity, the system comprising: a) a first body configured to contain a formulation; b) a first cannula and / or microfluidic channel configured to be positioned within the patient's nasal cavity and having a delivery orifice fluidly connected to the first body; c) a deployment mechanism for delivering the formulation to the patient's nasal cavity through the first cannula and / or microfluidic channel; d) a collection device for collecting biological material from the patient's nasal cavity; e) a formulation configured to capture the biological material; Comprises. In some embodiments, the delivery orifice is configured such that delivery of the formulation is to a targeted sub-region of the nasal cavity. In some embodiments, the delivery orifice is configured such that delivery of the formulation is to the olfactory region of the nasal cavity. In some embodiments, the delivery orifice is configured such that delivery of the formulation is to a targeted sub-region of the olfactory region. In some embodiments, the biological material comprises cerebrospinal fluid (CSF), one or more microorganisms of the patient's microbiota, one or more components of the patient's metabolome, one or more pathogens, and / or one or more biomarkers of interest. In some embodiments, the one or more pathogens comprise a virus or a part or derivative thereof. In some embodiments, the virus is SARS CoV-2. In some embodiments, the biological material is captured from a target region of the nasal cavity. In some embodiments, the biological material is captured from the olfactory region of the nasal cavity. In some embodiments, the biological material is captured from a targeted sub-region of the olfactory region of the nasal cavity. In some embodiments, the system comprises a sheath configured to minimize or prevent contamination of the first body, the first cannula and / or microfluidic channel, the delivery orifice, the collection device, the formulation, and / or biological material captured from a non-target region of the nasal cavity. In some embodiments, the sheath is configured to minimize or prevent contamination of the first body, the first cannula and / or microfluidic channel, the delivery orifice, the collection device, the formulation and / or biological material captured from a non-olfactory region or non-targeted sub-region of the olfactory region of the nasal cavity. In some embodiments, the sheath comprises a protective coating disposed around the first cannula and / or microfluidic channel. In some embodiments, the sheath comprises a cover or sleeve disposed around the first cannula and / or microfluidic channel.In some embodiments, the first body comprises a first container removably coupled to the first cannula and / or microfluidic channel. In some embodiments, the collection device comprises a second body removably coupled to the first cannula and / or microfluidic channel. In some embodiments, the collection device comprises a second body and a second cannula coupled to the second body. In some embodiments, the collection device is configured to preserve integrity and biological material according to the localization of biological material when captured from the nasal cavity. In some embodiments, the deployment mechanism comprises a first actuator coupled to a first spring coupled to a first plunger. In some embodiments, the device further comprises a clip configured to couple to the patient's nose to facilitate positioning of the delivery orifice. In some embodiments, the first cannula and / or microfluidic channel is configured to move relative to the clip. In some embodiments, the collection device comprises a second actuator coupled to a second spring coupled to a second plunger. In some embodiments, the first body comprises a cable. In some embodiments, the first cannula and / or microfluidic channel is a flexible cannula. In some embodiments, the first cannula and / or microfluidic channel is a telescoping cannula. In some embodiments, the system comprises mechanical features to prevent dangerous forces from being transmitted through the cannula. In some embodiments, the mechanical features include a force limiting spring, a radial slip clutch, and / or an axial slip clutch. In some embodiments, the targeted sub-region of the olfactory region is localized to individual millimeter regions within the olfactory region. In some embodiments, the formulation is any formulation disclosed herein, including those as disclosed in paragraph

[0008] .

[0007] In one aspect, provided herein is a method for diagnosing a patient, the method comprising: a) performing the method according to any one of claims 1 to 44, thereby collecting a biological material from the patient; b) analyzing the collected biological material; and c) diagnosing based on the analysis of step b. In some embodiments, the step of analyzing the biological material comprises identifying and / or quantifying biomarkers, pathogens, and / or microorganisms in the collected biological material. In some embodiments, the method further comprises correlating the identified and / or quantified biomarkers, pathogens, and / or microorganisms with corresponding physiological characteristics and / or medical conditions. In some embodiments, the step of analyzing the biological material comprises using a point-of-care assay system. In some embodiments, the point-of-care assay system is configured to receive a sample of the collected biological material from the delivery device from: a) any method disclosed herein, including those as disclosed in paragraphs

[0003] -

[0004] ; b) any device disclosed herein, including those as disclosed in paragraph

[0005] ; or c) any system disclosed herein, including those as disclosed in paragraph

[0006] .

[0008] In one aspect, provided herein is a formulation for collecting biological material from a patient's nasal cavity, the formulation being configured to capture biological material when delivered into the nasal cavity, and the delivered formulation being configured to be withdrawn from the nasal cavity together with the biological material. In some embodiments, the formulation is delivered to the olfactory region of the nasal cavity. In some embodiments, the formulation is configured to capture biological material from a targeted sub-region of the olfactory region. In some embodiments, the delivered formulation is configured to preserve the biological material captured when withdrawn. In some embodiments, the biological material includes cerebrospinal fluid (CSF), one or more microorganisms of the patient's microbiota, one or more components of the patient's metabolome, one or more pathogens, and / or one or more biomarkers of interest. In some embodiments, the formulation is configured to capture a specific biological material. In some embodiments, the formulation includes buffered saline. In some embodiments, the buffered saline is 100 mM phosphate buffered saline. In some embodiments, the formulation includes one or more gelling agents and / or thickening agents. In some embodiments, the formulation includes a viscosity modifier to provide a desired viscosity to the formulation. In some embodiments, the viscosity modifier includes at least one of glycerol, pectin, and polyethylene glycol. In some embodiments, the viscosity modifier constitutes 25 to 75% by volume of the formulation. In some embodiments, the formulation has a higher osmotic pressure than the fluid within the patient's nasal cavity, olfactory region, or targeted sub-region of the olfactory region. In some embodiments, the formulation has an osmotic pressure below that of the fluid within the patient's nasal cavity, olfactory region, or targeted sub-region of the olfactory region. In some embodiments, the desired osmotic pressure of the formulation is achieved by including salts, sugars, starches, albumin, dextran, or combinations thereof in the formulation.In some embodiments, the delivered formulation has an osmotic pressure that is adjusted such that the osmotic pressure equals the target osmotic pressure after the target volume of fluid other than the formulation is withdrawn from the nasal cavity, the region of the olfactory region, or the targeted sub-region of the olfactory region. In some embodiments, the osmotic pressure of the formulation is configured to change over time so as to capture biological material from the nasal cavity, the olfactory region, or the targeted sub-region of the olfactory region at a desired rate. In some embodiments, the osmotic pressure of the formulation is configured to change over time by including an osmotic pressure adjuster in the formulation. In some embodiments, the osmotic pressure adjuster includes microencapsulated particles of one or more osmotic pressure adjusters. In some embodiments, the one or more osmotic pressure adjusters include sodium chloride. In some embodiments, the microencapsulated particles include an enteric coating that includes one or more osmotic pressure adjusters. In some embodiments, the enteric coating is configured to release the one or more osmotic pressure adjusters when exposed to a predetermined condition within a predetermined time. In some embodiments, the predetermined condition includes one or more conditions selected from the group consisting of a temperature range, a pH range, and a predetermined shear force. In some embodiments, the formulation includes an agent that promotes mucus production within the nasal cavity, the olfactory region, or the targeted sub-region of the olfactory region, thereby facilitating the capture of the biological material. In some embodiments, the agent that promotes mucus production is capsaicin. In some embodiments, the formulation includes one or more agents that increase the viscosity of mucus within the nasal cavity, the olfactory region, or the targeted sub-region of the olfactory region, thereby preventing the delivered drug from moving and thereby increasing the residence time of the delivered formulation within the nasal cavity, the olfactory region, or the targeted sub-region of the olfactory region. In some embodiments, the formulation is configured to change from a liquid state to a semi-solid state when delivered to the nasal cavity, the olfactory region, or the targeted sub-region of the olfactory region. In some embodiments, the formulation is configured to initiate a cross-linking reaction upon delivery to the nasal cavity, the olfactory region, or the targeted sub-region of the olfactory region.In some embodiments, the formulation comprises two or more reagents. In some embodiments, the two or more reagents are configured to mix upon delivery to the nasal cavity, the olfactory region, or a targeted sub-region of the olfactory region to initiate a cross-linking reaction, thereby changing the formulation to a semi-solid state. In some embodiments, the formulation comprises a non-Newtonian fluid. In some embodiments, the formulation changes from a liquid state to a semi-solid state at a temperature approximately the same as human body temperature. In some embodiments, the formulation changes from a liquid state to a semi-solid state at a temperature from about 35°C to about 40°C. In some embodiments, the formulation changes from a liquid state to a semi-solid state at a temperature of about 37°C. In some embodiments, the formulation comprises a Bingham plastic. In some embodiments, the formulation behaves as a liquid when subjected to shear forces during delivery to the nasal cavity, the olfactory region, or a targeted sub-region of the olfactory region. In some embodiments, the formulation behaves as a semi-solid when not subjected to shear forces. In some embodiments, the formulation further comprises a tail formed by delivery and partial solidification of the formulation. In some embodiments, the tail is configured to be mechanically removed, thereby facilitating removal of the captured biological material. In some embodiments, the semi-solid state of the formulation is configured to preserve the captured biological material in accordance with the localization of the biological material. In some embodiments, the formulation acts as a carrier formulation. In some embodiments, the carrier formulation comprises encapsulated nanoparticles. In some embodiments, the encapsulated nanoparticles are encapsulated in a coating that degrades when exposed to predetermined conditions for a predetermined time. In some embodiments, the predetermined conditions are specific to the nasal cavity, the olfactory region, or a targeted sub-region of the olfactory region. In some embodiments, the predetermined conditions include temperature, pH, and / or contact with a specific biological material. In some embodiments, degradation of the coating releases a chemical configured to change the carrier formulation from a semi-solid state to a liquid state.In some embodiments, the formulation comprises one or more specific monoclonal or polyclonal antibodies to target a specific biological material. In some embodiments, the formulation comprises one or more specific aptamers to target a specific biological material. In some embodiments, the specific biological material is cystatin-C. In some embodiments, the specific biological material is a virus or a part or derivative thereof. In some embodiments, the virus is SARS-CoV-2. In some embodiments, the formulation comprises an antibacterial agent to preserve the captured biological material. In some embodiments, the antibacterial agent comprises 25% v / v ethanol and / or 5% w / v citric acid. In some embodiments, the formulation comprises a microbial enrichment and preservation material. In some embodiments, the microbial enrichment and preservation material comprises 25% v / v tryptic soy broth. In some embodiments, the formulation comprises a hydrogel. In some embodiments, the formulation comprises a sugar. In some embodiments, the formulation is thixotropic or shear thickening. In some embodiments, the formulation is immiscible with water. In some embodiments, the formulation is miscible with water. In some embodiments, the formulation is configured to preserve a biological material. In some embodiments, the formulation is configured to maintain the integrity of a biological material. In some embodiments, the formulation is configured to change into an aggregate after being delivered to the nasal cavity, the olfactory region, or a targeted sub-region of the olfactory region. In some embodiments, the formulation comprises a solvent that evaporates to change the formulation into an aggregate. In some embodiments, the formulation comprises a chemical that reacts a) after a time delay, b) with air, c) with a separately introduced gas or liquid, or d) with a patient's body fluid, resulting in the formation of an aggregate. In some embodiments, the formulation is configured to absorb a biological material from the olfactory region. In some embodiments, the formulation is provided, delivered, and / or withdrawn as a bolus of the formulation.

[0009] In some embodiments, the method, apparatus, and system include a robust and novel nasal microbiota sampling system that can collect and preserve biological materials captured from an olfactory region different from the shape of the lower nasal cavity. In some embodiments, the device is a Class II diagnostic device, which facilitates targeted sampling of the olfactory region. In some embodiments, the device comprises a telescopic sampling cannula that delivers a special formulation configured to coat and preserve biological materials containing microbiota of the microbiota according to its localization for further analysis. BRIEF DESCRIPTION OF THE DRAWINGS

[0010] A better understanding of the features and advantages of the present subject matter can be obtained by reference to the following detailed description that illustrates exemplary embodiments and the accompanying drawings. [Figure 1] A flowchart showing the steps in a method for collecting biological materials according to one embodiment is shown. [Figure 2A] An illustration of an embodiment for collecting biological materials from the nasal cavity is shown, which embodiment includes a device including a cannula inserted into the nasal cavity. [Figure 2B] An illustration of an embodiment for collecting biological materials according to FIG. 2A is shown, where a container holding a formulation is connected to the cannula. [Figure 2C] An illustration of an embodiment for collecting biological materials according to FIG. 2A is shown, where the formulation is delivered to the nasal cavity. [Figure 2D] An illustration of an embodiment for collecting biological materials according to FIG. 2A is shown, where the biological materials are captured by the formulation. [Figure 2E] An illustration of an embodiment for collecting biological materials according to FIG. 2A is shown, where a recovery vessel is connected to the cannula to draw out and collect the biological materials. [Figure 2F]FIG. 2A illustrates an embodiment for collecting biological material, where the formulation and the captured biological material are drawn into a collection container through a cannula. [Figure 3A] FIG. illustrates another embodiment for collecting biological material from the nasal cavity, which embodiment includes a device comprising a flexible bulb and a cannula inserted into the nasal cavity. [Figure 3B] FIG. 3A illustrates an embodiment for collecting biological material, where the formulation is delivered to the nasal cavity by pushing on the flexible bulb. [Figure 3C] FIG. 3A illustrates an embodiment for collecting biological material, where the biological material is captured by the formulation. [Figure 3D] FIG. 3A illustrates an embodiment for collecting biological material, where the flexible bulb can be relaxed to draw out and capture the biological material. [Figure 4A] FIG. illustrates another embodiment for collecting biological material from the nasal cavity, which embodiment includes a delivery device comprising a container holding the formulation, a deployment mechanism, and a cannula inserted into the nasal cavity. [Figure 4B] FIG. 4A illustrates an embodiment for collecting biological material, where the formulation is delivered to the nasal cavity by pushing on the deployment mechanism. [Figure 4C] FIG. illustrates an embodiment for collecting biological material according to FIG. 4A, where the delivery device is removed from the nasal cavity. [Figure 4D] FIG. 4A illustrates an embodiment for collecting biological material, where the biological material is captured by the formulation. [Figure 4E] FIG. 4A illustrates an embodiment for collecting biological material, where a recovery device filled with a wicking material and a recovery cannula are inserted into the nasal cavity. [Figure 4F]FIG. 4A illustrates an embodiment for collecting biological material, where the collection device draws the formulation and biological material through a cannula using a wicking material. DETAILED DESCRIPTION OF THE INVENTION

[0011] Biological materials found in the nasal cavity can include biomarkers, pathogens, microorganisms of the human microbiome, and other materials that provide information related to a person's health and / or condition. Disclosed herein are compositions, methods, systems, and devices for collecting biological materials from a person's nasal cavity. In some embodiments, the biological material is collected from the olfactory region of the nasal cavity. In some embodiments, the biological material is collected from a targeted sub-region of the olfactory region, and such biological material is unique and different from other sub-regions of the olfactory region and other non-olfactory regions of the nasal cavity. In some embodiments, the biological material collected from the targeted sub-region is preserved according to its localization. In some embodiments, the biological material includes cerebrospinal fluid, microorganisms of the human microbiome, metabolome, pathogens, and biomarkers of interest. In some embodiments, a specific formulation is delivered to a region within the nasal cavity to facilitate collection of the biological material located therein.

[0012] definition Unless otherwise defined, all technical terms, notations, and other technical and scientific terms or terminology used herein are intended to have the same meaning as commonly understood by one of ordinary skill in the art to which the claimed subject matter pertains. In some cases, terms with commonly understood meanings are defined herein for clarity and / or for ready reference, and including such definitions herein is not necessarily to be construed as representing a substantial difference from what is commonly understood in the art.

[0013] The term "biological material", as used herein, refers to materials produced by an organism and includes cerebrospinal fluid (CSF), one or more microorganisms of a patient's microbiota, biomarkers, sub - combinations of biomarkers, one or more pathogens, or one or more components of a patient's metabolome, other components, or any combination thereof.

[0014] The term "formulation", as used herein, refers to a composition configured to capture biological material from the nasal cavity and includes the olfactory region and targeted sub - regions within the olfactory region.

[0015] The term "nasal cavity", as disclosed herein, includes at least the inferior nasal cavity, middle nasal cavity, and superior nasal cavity, and the superior nasal cavity includes at least the olfactory region.

[0016] The term "olfactory region" refers to the region above and superior to the superior turbinate and the adjacent nasal septum where the mucosa has olfactory epithelium and olfactory glands.

[0017] The term "target site", as used herein, refers to a desired location within the nasal cavity for capturing biological material. Desired locations within the nasal cavity include the olfactory region, inferior nasal cavity, middle nasal cavity, and / or targeted sub - regions of the olfactory region.

[0018] The term "target sub - region", as used herein, refers to a specific region of the nasal cavity, such as a specific region of the olfactory region and / or non - olfactory region, where a particular biological material is located.

[0019] The term "biomarker", as used herein, refers to a characteristic that is objectively measured as an indicator of a normal biological process, pathogenic process, or pharmacological response to a therapeutic intervention. A biomarker, as used herein, can refer to proteins, peptides, small molecules, and nucleic acids, microorganisms, the presence and / or concentration of which suggests or diagnoses a disease or other medical condition or indicates some biochemical imbalance in the brain.

[0020] The term CSF refers to cerebrospinal fluid.

[0021] The term microbiota, as used herein, refers to a collection of microorganisms (such as bacteria, fungi, and viruses) within a particular environment, particularly a collection of microorganisms living in or on the human body.

[0022] The term sample, as used herein, refers to a biological material captured from a particular location of a patient. A sample, as used herein, can refer to a biological material recovered from within the nasal cavity, including a particular region within the nasal cavity such as the olfactory region of the nasal cavity.

[0023] The term olfactory sample, as used herein, is a sample that includes a biological material recovered from the olfactory region of the nasal cavity and that includes microbiota, metabolome, CSF, other biomarkers of interest, and any sub - combination of biomarkers or other of its constituents.

[0024] The term sampling, as used herein, refers to collecting a sample of biological material from a particular location of a patient. For example, olfactory sampling refers to collecting a sample of biological material from the olfactory region.

[0025] The term capture is used interchangeably with obtain and recover. As used herein, the term capture (capturing) refers to a biological material obtained from a target site by a formulation.

[0026] The term collect (collecting) as used herein refers to extracting a biological material captured from a target site (regardless of the presence or absence of the corresponding formulation).

[0027] In some embodiments, the compositions, methods, systems, and devices described herein provide minimally invasive and user- and patient-friendly collection and analysis of biological materials for diagnosing a wide variety of infectious diseases that affect the brain and spinal cord, including but not limited to cancer, autoimmune diseases, and central nervous system trauma. In some embodiments, the devices and systems according to the present disclosure provide a platform that integrates, automates, and miniaturizes the collection, processing, and analysis of biological materials from the nasal cavity, including the olfactory region of the nasal cavity. Certain embodiments described herein enable researchers, clinicians, and first responders to collect biological materials (and / or biomarkers contained therein) in a minimally invasive and timely manner to advance treatment and resilience in neurological health and optimize human capabilities.

[0028] As described in International Patent Application No. PCT / CA2019 / 050455, filed Apr. 12, 2019, which is hereby incorporated by reference in its entirety, targeted drug delivery and precise bolus localization can be achieved with minimally invasive cannulas and delivery utilizing laminar flow and the Coandă effect. Using this approach, the administered volume adheres to the upper sidewalls of the nasal corridor, accounting for anthropometric variations and reducing the need for operator adjustment and size-specific catheters. Devices compliant with PCT / CA2019 / 050455 can be used for collection of biological materials in methods according to the present disclosure, providing the device with a small and lightweight form factor that has low training requirements, enables intuitive use, and does not require an assistive device for administration.

[0029] Recent in vivo dynamic PTE scans have shown that the human turbinates are a substantial part of the CSF clearance system (De Leon.M.J..Li.Y..Okamura.N..Tsui.W.H..Saint-Louis.L.A..Glodzik.L.....& Fossati.S.(2017).Cerebrospinal fluid clearance in Alzheimer disease measured with dynamic PET.Journal of Nuclear Medicine.58(9).1471). Assuming a CSF formation rate of 0.3 mL / min (Spector.R..Snodgrass.S.R..& Johanson.C.E.(2015).A balanced view of the cerebrospinal fluid composition and functions: focus on adult humans.Experimental neurology.273.57-68)), and assuming a potential range of 1-20% uptake through the lymphatic vessels near the cribriform plate (Sun.B.L..Wang.L.H..Yang.T..Sun.J.Y..Mao.L.L..Yang.M.F.....& Yang.X.Y.(2018).Lymphatic drainage system of the brain:A novel target for intervention of neurological diseases.Progress in neurobiology.163.118-143), a range of 3-60 μL / min of CSF in the nasal lymphatics is available for sampling by the methods and devices described herein.

[0030] The present disclosure provides a composition, herein referred to as a formulation, configured to collect biological material from the nasal cavity. In some embodiments, the formulation is configured to collect biological material specific to the olfactory region. In some embodiments, the formulation is configured to inhibit or enhance the recovery of specific biomarkers within the collected biological material, as discussed below. As a non-limiting example, as shown in Table 1 below, many protein biomarkers of diagnostic interest can be found in the collected biological material, particularly when the sample includes components of cerebrospinal fluid (CSF).

[0031]

Table 1

[0032] Hemopexin is a protein that binds to free heme, and its presence at >50,000 ng / mL is a predictor of cerebral ischemia after subarachnoid hemorrhage. In a 50 μL sample, this corresponds to the presence of >2,500 ng of analyte.

[0033] C-reactive protein is a marker for diagnosing purulent meningitis. The normal range is 3,420 - 5,420 ng in a 50 μL sample. An increase of 8,625 - 37,125 ng in a 50 μL sample is an indicator of meningitis in children, while a range of 6,610 - 20,310 ng in a 50 μL sample is an indicator for adults. This can also identify tuberculous meningitis, in which case it decreases and is classified in the range of 0 - 2,495 ng in children and 395 - 695 ng in adults.

[0034] Cystatin-C is a potential biomarker for amyotrophic lateral sclerosis (ALS). A decrease in levels of 65 - 290 ng in a 50 μL sample indicates the disease compared to healthy levels of 125 - 325 ng in 50 μL.

[0035] Certain embodiments provide CSF sampling formulations and devices that enhance the collection of CSF as compared to other components in normal nasal secretions. Table 2 provides several factors that distinguish CSF from normal nasal secretions.

[0036]

Table 2

[0037] Target Signs (Oh JW, Kim SH, Whang K. Traumatic Cerebrospinal Fluid Leak: Diagnosis and Management. Korean J Neurotrauma. 2017;13(2):63-67): When CSF is mixed with blood or nasal secretions, two rings are displayed because the CSF moves further on the filter paper and the blood moves closer. This is called the target sign, double ring sign, or halo sign. Embodiments of the device can utilize this to isolate the CSF (i.e., stacked membrane filters in a sample collection reservoir for isolating CSF from the blood present). Filter materials include natural cotton or synthetic fibers (such as polyester). Suitable materials include compatibility with materials commonly used in immunochromatography devices (such as pregnancy tests). Preferred materials include natural cotton fibers, treated polyester fibers, nitrocellulose membranes, or polycarbonate meshes.

[0038] Combined study (Oh JW, Kim SH, Whang K. Traumatic Cerebrospinal Fluid Leak: Diagnosis and Management. Korean J Neurotrauma. 2017;13(2):63-67): When the discharge from the nose passes through a dry adsorbent fabric (i.e., dry gauze), if it is non-sticky, the CSF is likely to become transparent. This step is a test for measuring the unclear and sticky nasal secretions due to mucin secretion from the nose. Suitable materials include compatibility with materials commonly used in immunochromatography devices (such as pregnancy tests). Preferred materials include natural cotton fibers, treated polyester fibers, nitrocellulose membranes, or polycarbonate meshes.

[0039] Glucose Oxidation Test: CSF glucose from nasal or ear secretions is a classical method when testing for CSF leakage. Generally, glucose oxidase strips show a positive result when the sample concentration exceeds 20 mg / dL. Since the normal concentration of nasal mucus is 10 mg / dL of glucose, it can be excluded if the glucose test is negative. However, due to high false positive and false negative rates depending on other medical conditions of the patient, this should only be used as a reference. Additionally, even if the concentration is less than 5 mg / dL, tear secretion can be tested. On the other hand, false positive results are seen in bloody nasal mucus, while false negative results are seen if the patient already has advanced meningitis. All these clinical conditions must be considered before interpreting and confirming CSF leakage. Preferred embodiments can incorporate glucose oxidase test strips into a sample reservoir or be performed as an additional step in the sampling process.

[0040] Glucose and chloride concentrations : When the serum glucose level is 0.5 - 0.67 mg / dL, a higher concentration suggests CSF. Since there is no doubt that the blood glucose level in CSF is affected by the blood glucose level in serum, it is important to consider the two parameters together when confirming the detection of CSF. Samples with a chloride concentration level of 100 mEq / L or higher indicate CSF. Preferred embodiments can incorporate glucose and chloride test strips into a sample reservoir or be performed as an additional step in the sampling process for confirming CSF sampling.

[0041] Beta-2 transferrin (tau protein): Beta-1 transferrin is ubiquitously found in serum, tears, nasal secretions, and saliva, while beta-2-transferrin is observed only in CSF, perilymph, and aqueous humor. Since beta-2 transferrin is specific to CSF, it is a well-known marker with very high sensitivity and specificity. It is generated from transferrin by the loss of sialic acid due to the presence of neuraminidase activity in the brain, and thus beta2 transferrin is localized only in CSF, perilymph, and aqueous humor. The absence of other body secretions makes its detection very valuable in confirming the diagnosis of CSF rhinorrhea or otorrhea (usually CSF leakage into the nose or ear canal as a result of head trauma, tumor, congenital malformation, or surgery) (beta2 transferrin / tau protein: http: / / www.viapath.co.uk / our-tests / beta-2-transferrintau-protein). Tau protein, discovered in 1975, is an intraneuronal protein mainly involved in axonal transport and microtubule stabilization. CSF tau protein is a neuronal protein and is commonly evaluated for the diagnosis of Alzheimer's disease (AD). Enzyme-linked immunosorbent assay (ELISA) measurement of tau protein in nasal leakage fluid may be a reliable biomarker for detecting the presence of CSF in nasal secretions and indicating the presence of CSF leakage (Oudart JB, Zucchini L, Maquart FX, et al. Tau protein as a possible marker of cerebrospinal fluid leakage in cerebrospinal fluid rhinorrhoea: A pilot study. Biochem Med (Zagreb). 2017;27(3):030703). Preferred embodiments may incorporate a lateral flow test strip having an antibody to TAU protein in a sample reservoir or be performed as an additional step in a sampling process to confirm CSF sampling. Embodiments of CSF sampling formulations may include an antibody or other selective element for selectively binding to a sample containing TAU protein to enhance the selective recovery of CSF fluid.

[0042] Beta Trace Protein (BTP) : Also known as prostaglandin D synthase, this protein is mainly synthesized in arachnoid cells, oligodendrocytes, and choroid plexus within the central nervous system (CNS). Beta-trace protein is also present in human testis, heart, and serum. It is altered by the presence of renal insufficiency, multiple sclerosis, cerebral infarction, and certain CNS tumors. This test has been used in multiple studies to diagnose CSF rhinorrhea, with a sensitivity of 92% and a specificity of 100% (What is the role of beta-trace protein testing in the workup of cerebrospinal fluid (CSF) rhinorrhea? https: / / www.medscape.com / answers / 861126-102445 / what-is-the-role-of-beta-trace-protein-testing-in-the-workup-of-cerebrospinal-fluid-csf-rhinorrhea). BTP is a 25 kDa protein identified as prostaglandin D synthase. It is the second most abundant CSF protein after albumin, at approximately 20 mg / L, and the CSF-to-serum ratio is 33, which is the highest among all CSF-specific proteins (Bernasconi, Luca & Huber, Andreas. (2017). Beta-trace Protein Quantification for Diagnosis of CSF Leakage Syndrome. White Paper). Preferred embodiments may incorporate a lateral flow test strip with an antibody for detecting BTP in a sample reservoir or be performed as an additional step in the sampling process to confirm CSF sampling. Embodiments of CSF sampling formulations may include an antibody or other selective element for selectively binding to a sample containing the BTP protein to enhance the selective recovery of CSF fluid.

[0043] For purposes of illustration and simplification, reference numbers may be repeated between figures to indicate corresponding or similar elements. For the sake of providing an understanding of the embodiments described herein, many details are shown. The embodiments can be practiced without these details. In other instances, well-known methods, procedures, and components have not been described in detail to avoid obscuring the described embodiments. The description should not be regarded as limited to the scope of the embodiments described herein.

[0044] FIG. 1 shows a flowchart of an exemplary method 100 for collecting biological material from a human nasal cavity, or specifically, the olfactory region of the nasal cavity. The exemplary method disclosed in FIG. 1 is applicable to other regions of the nasal cavity as well, and the reference to the olfactory region may be replaced by another target region of the nasal cavity, or the nasal cavity itself. Method 100 includes providing, at 102, a formulation configured to target biological material from the nasal cavity (such as the olfactory region), inserting, at 104, a formulation delivery device into the patient's nasal cavity, delivering, at 106, the formulation to the olfactory region, enabling, at 108, the formulation to capture biological material from the olfactory region (including biomarkers of interest therein), withdrawing, at 110, the formulation and the captured biological material, and analyzing, at 112, the captured biological material including biomarkers of interest therein. Each of these steps will be described in detail in the following sections. In some embodiments, the withdrawn and captured biological material (i.e., the collected biological material) is preserved. In some embodiments, the withdrawn and captured biological material is preserved according to its localization within the nasal cavity.

[0045] Provision of formulations In some embodiments, exemplary method 100 includes providing a formulation at 102. In some embodiments, the formulation is configured to target biological material within the nasal cavity. In some embodiments, the formulation is configured for a target site within the nasal cavity. In some embodiments, the target site is the olfactory region, and the formulation is configured to target a specific biological material including a biomarker contained within the olfactory region. In some embodiments, such biological materials include CSF, microorganisms from the human microbiota, the metabolome, and other biomarkers of interest. In some embodiments, the target site is a targeted sub-region of the nasal cavity, e.g., a targeted sub-region within the olfactory region, and the formulation is configured to target a specific biological material within the targeted sub-region. In the following sections, examples of formulations for nasal sampling (nasal sampling formulations) including formulations for olfactory sampling (olfactory sampling formulations), as well as examples of formulations configured to target specific biological materials, will be described. As described herein, the term sampling refers to collecting a sample of biological material from a specific location, e.g., capturing and withdrawing biological material from the olfactory region (i.e., olfactory sampling). In some embodiments, a formulation such as an olfactory sampling formulation includes buffered saline. In some embodiments, the buffered saline includes a viscosity modifier to provide the desired viscosity to the formulation. In some embodiments, the formulation is composed of one or more inactive ingredients approved by the FDA or EMA for nasal administration.Both the FDA Inactive Ingredient Database and the Annex to the European Commission guideline on ’Excipients in the labelling and package leaflet of medicinal products for human use’ are incorporated herein by reference for the purpose of providing examples of excipients approved for spray or aerosol dosage forms and / or for nasal and inhalation routes of administration.

[0046] In some embodiments, the formulation is held in a container that a) provides a shelf life sufficient for the product to be viable, b) integrates with a suitable container filling line, and c) integrates with a dispensing system. For example, the formulation may be stored in a cartridge (single or multi-chamber), syringe (single or multi-chamber), disposable pipette, pipette, valve syringe, blow-fill-seal container (e.g., MicroDose™ single-use unit or SwabDose™ single-use unit), bellows, microfluidic cartridge, single-dose liquid cup, vial, ampoule, heat-seal bag (e.g., IV bag), formed bag, or custom component assembly. Exemplary formulations are described below.

[0047] Formulations containing buffered saline and viscosity modifiers In some embodiments, formulations for nasal sampling, including olfactory sampling, include 100 mM phosphate buffered saline containing an approved viscosity modifier such as glycerol in the range of 25 - 75% v / v. In some embodiments, the formulation includes 100 mM phosphate buffered saline containing an approved viscosity modifier such as pectin in the range of 25 - 75% v / v. In some embodiments, the formulation includes 100 mM phosphate buffered saline containing an approved viscosity modifier such as polyethylene glycol 3350 in the range of 25 - 75% v / v.

[0048] In some embodiments, the formulation is immiscible with water. In some such embodiments, the formulation is delivered to the olfactory region to form a bolus. In these embodiments, biological materials including microorganisms, metabolomes, CSF, and / or biomarkers of interest from the microbiota diffuse from the target site in the olfactory region into the formulation bolus.

[0049] In some embodiments, the formulation is miscible with water and has a lower osmotic pressure than the patient's body fluids (e.g., mucus, CSF, plasma, blood, serous effusion) at the target site in the olfactory region or other intranasal regions. For example, the osmotic pressure of plasma ranges from 275 to 299 milliosmoles / kg in healthy individuals and has a similar osmotic pressure range as CSF (average 270 milliosmoles / kg). However, such osmotic pressure ranges can vary depending on the disease state and may vary between individuals. In some embodiments, the formulation is designed to have an osmotic pressure lower than the extreme lower limits of various osmotic pressure ranges in order to adapt to this sampling function between individuals.

[0050] In some embodiments, the formulation is miscible with water and has an osmotic pressure equal to that of the patient's body fluids at the target site. In some such embodiments, the liquid from the formulation binds to specific biomarkers of interest in the patient's mucus layer, and the biomarkers of interest diffuse into the formulation.

[0051] In some embodiments, the formulation is miscible with water and has an osmotic pressure higher than that of the patient's body fluid at the target site. In some such embodiments, liquid is drawn from the patient's mucus layer into the formulation. In some embodiments, the osmotic pressure of the formulation is adjusted to be equal to the osmotic pressure of the target site after an appropriate amount of nasal fluid has been extracted from the target site. In some embodiments, the osmotic pressure in the formulation is adjusted by adding salts, sugars, starches, albumin, dextran, other agents, or combinations thereof. In some embodiments, suitable sugars include, but are not limited to, sucrose, glucose, dextrose, and sugar alcohols such as mannitol and xylitol.

[0052] In some embodiments, the formulation contains a compound that controls osmotic pressure over time to ensure that biological material is drawn from the target site at an appropriate rate. For example, in some embodiments, the formulation contains microencapsulated particles of saline or other osmotic pressure regulators encapsulated in an enteric coating that degrades when exposed to certain conditions such as temperature, pH, shear force, etc. In some embodiments, the coating of such microencapsulated particles degrades when exposed to such conditions for the required period of time.

[0053] In some embodiments, the formulation further comprises a hydrogel to facilitate transport of the biological material into the formulation bolus.

[0054] In some embodiments, the formulation contains a compound that enhances the recovery of biological material from the target site. For example, in some embodiments, the formulation contains capsaicin or another agent configured to increase mucus production at the target site, which increases the flow of biomarkers of interest into the formulation bolus. In some embodiments, the formulation contains an agent that thickens the mucus layer to prevent the formulation bolus from moving and thereby allows for a better residence time to draw in biological material.

[0055] In some embodiments, the formulation includes a gelling agent, thickening agent, or other agent to control its viscosity, perform shear thinning or shear thickening, or make it a Bingham plastic so that the formulation stays at the target site during capture of the biological material.

[0056] Formulations containing cross-linking reagents In some embodiments, the formulation includes two or more reagents that are mixed to initiate a cross-linking reaction. In some embodiments, the two or more reagents are included within the delivery device. In some embodiments, the two or more reagents are mixed upon nasal deployment. In some embodiments, upon mixing, the reagents cross-link to form a semi-solid state, allowing for longer retention and sampling times. In some embodiments, delivery of the formulation leaves a track extending from the delivery location of the formulation (i.e., the target site), which forms a semi-solid tail portion of the formulation. When the desired residence time is complete, the "tail" of the semi-solid formulation bolus is mechanically removed, containing the preserved captured biological material, including the biomarker of interest. In some embodiments, the cross-linked formulation enables preservation of the biological material according to its localization, i.e., the biological material collected from the target site is not mixed with biological material from other regions within the nasal cavity. In some embodiments, cross-linking of the formulation locks the captured biological material in place, thereby enabling preservation of the collected biological material according to its localization when the formulation is placed in the target region for accurate localization of the biological material. In some embodiments, the multi-component configuration (e.g., use of two or more reagents) allows for a longer shelf life of the formulation and formation of a profile upon deployment of the formulation, enabling sampling across a large population of diverse anatomical structures.

[0057] Formulations using non-Newtonian fluids In some embodiments, the formulation includes a non-Newtonian fluid, such that the formulation is liquid when stored at room temperature and when deployed, and the formulation becomes semi-solid at a temperature approximately human body temperature, forming a semi-solid state that allows for longer retention and sampling times. In some embodiments, the formulation becomes semi-solid at a temperature of about 37°C. In some embodiments, the formulation becomes semi-solid at a temperature from about 35°C to about 40°C. In some embodiments, delivery of the formulation leaves a trail extending from the delivery location of the formulation (i.e., the target site), which forms a semi-solid tail portion of the formulation. In some embodiments, when the desired residence time is complete, the "tail" of the semi-solid formulation bolus is mechanically removed, which contains the captured biological material. In some embodiments, a single-component formulation is required, and the profile of the formulation is formed upon deployment to allow sampling across a large population of diverse anatomical structures. In some embodiments, the semi-solid state of the formulation enables preservation of the captured biological material according to its localization. In some embodiments, the semi-solid formulation locks the captured biological material in place, such that when the formulation is placed in the target region for accurate localization of the biological material, preservation of the captured biological material is enabled according to its localization.

[0058] Formulations containing Bingham plastic fluids In some embodiments, the formulation comprises a Bingham plastic fluid, whereby the deployment of the formulation under shear causes the formulation to behave as a liquid state, enabling easy deployment to the target area. In some embodiments, once the formulation is placed at the target site, the shear force is removed, and the Bingham plastic fluid causes the formulation to return to a semi-solid state and solidify, allowing for a longer retention and sampling time. In some embodiments, upon completion of the desired residence time, application of a shear force to the formulation (e.g., by aspiration) causes the Bingham plastic to be converted to a liquid state, enabling easy removal and extraction. At least one advantage of this embodiment is that only one single formulation is required, and the profile of the formulation is formed upon deployment, allowing for sampling across a large population of diverse anatomical structures and facilitating removal and sample handling for post-sampling analysis through the liquid side of the sampling formulation. In some embodiments, the semi-solid state of the formulation enables the preservation of the captured biological material according to its localization. In some embodiments, the semi-solid formulation locks the captured biological material in place, thereby enabling the preservation of the captured biological material according to its localization when the formulation is placed at the target area for accurate localization of the biological material.

[0059] Formulations containing any combination of the preceding examples In some embodiments, the formulation comprises any combination of the above examples of formulations, including Bingham plastics, crosslinking reactions, and / or any combination using non-Newtonian fluids. In some embodiments, a formulation comprising any combination of the foregoing examples is deployed in a liquid state and solidifies at the target site. In some embodiments, a formulation comprising any of the foregoing examples acts as a carrier formulation. In some embodiments, the carrier formulation further comprises encapsulated nanoparticles encapsulated in a coating that degrades under specific conditions unique to the target region. In some embodiments, such conditions include temperature, pH, and contact with a specific biomarker of interest. In some embodiments, the coating of such encapsulated particles degrades when exposed to such conditions for the required time. In some embodiments, the encapsulated nanoparticles are tuned to degrade under various specific biological conditions to reflect different desired biological states. In some embodiments, the degradation of the coating releases a chemical designed to react with the carrier formulation in a semi-solid state and return it to its liquid state. At least one advantage of these embodiments includes contouring upon deployment that enables sampling across a large population of diverse anatomical structures, and removal and sample processing for post-sampling analysis facilitated through the liquid aspect of the sampling formulation.

[0060] Formulations configured to target specific biological materials In some embodiments, the formulation is configured to target specific biological materials located at the target site. In some embodiments, it is desirable to enhance or limit the detection, preservation, isolation, and / or recovery of specific biological materials located at the target site. Examples of specific approaches are described below.

[0061] Some embodiments provide a specific biological material targeted by a sampling formulation, including a formulation according to any of the examples discussed above, further comprising a specific monoclonal or polyclonal antibody against a specific biological material of interest. In some embodiments, the specific biological material of interest is a virus or a part or derivative of a virus. For example, in some embodiments, the virus is SARS CoV-2. In some embodiments, the specific biological material of interest is cystatin C.

[0062] Some embodiments provide a specific biological material targeted by a sampling formulation, including a formulation according to any of the examples discussed above, further comprising a specific aptamer against a specific biological material of interest. In some embodiments, the specific biological material of interest is a virus or a part or derivative of a virus. For example, in some embodiments, the virus is SARS CoV-2. In some embodiments, the specific biological material of interest is cystatin C.

[0063] Some embodiments provide a formulation having antibacterial properties to assist in the preservation of biological materials, such as a specific biological material targeted by a sampling formulation according to any of the formulation examples discussed above, further comprising an antibacterial agent. In some embodiments, the antibacterial agent comprises 25% v / v ethanol and / or 5% w / v citric acid.

[0064] Some embodiments provide a formulation having antibacterial properties to assist in the preservation of biological materials, such as a specific biological material targeted by a sampling formulation according to any of the formulation examples discussed above, further comprising an antibacterial agent. In some embodiments, the antibacterial agent comprises a beta-lactam antibiotic for removing only microorganisms containing peptidoglycan.

[0065] Some embodiments provide a formulation for enriching specific microorganisms, such as specific biological materials targeted at sampling formulations according to any of the formulation examples discussed above, further comprising a specific microorganism enrichment and preservation material such as 25% v / v tryptic soy broth (e.g., for detection and culture of microbial meningitis).

[0066] As will be appreciated by those skilled in the art, other specific configurations of the formulation, including any or all combinations of the features discussed in the above examples, may be provided in other embodiments.

[0067] Inserting the Device Method 100 further comprises inserting the device into the nasal cavity at 104. In some embodiments, the device is inserted at 104 in proximity to the olfactory region of the patient. In some embodiments, the device comprises a flexible cannula, a container holding the formulation, the container being fluidly connected to the cannula, and a deployment mechanism for extruding the formulation from the container into the cannula. Suitable nasal cannulas are well known in the art. In some embodiments, the cannula is a telescopic cannula. In some embodiments, the cannula comprises a delivery orifice through which the formulation is discharged from the cannula.

[0068] In some embodiments, the device includes features for positioning the device on the patient's anatomical structure to enhance insertion safety and support self-administration. In some embodiments, the device includes features positioned relative to the external base of the nose and / or nostrils as discussed below with reference to FIG. 2a. In some embodiments, the insertion of the device is performed by feel / patient comfort.

[0069] In some embodiments, the device is positioned relative to the internal nasal anatomy (e.g., the roof of the olfactory chamber below the cribriform plate or in front of the sphenoid sinus). For example, in some embodiments, the device includes mechanical features (e.g., force-limiting springs, radial slip clutches, and / or axial slip clutches) that prevent dangerous forces from being transmitted through the cannula. In one embodiment, the cannula and delivery system float within the device and are spring-mounted to the device. In some embodiments, forces from the body of the device are transmitted to the cannula via the spring. In some embodiments, when the cannula contacts the patient, the spring limits the maximum force that the device can transmit to the patient.

[0070] In other embodiments, the device is positioned relative to other external facial anatomy, e.g., with reference to the bridge of the nose, cheekbones, below the eyebrows, or in front of the teeth. In another embodiment, the device is positioned on the face as a pair of glasses resting on the bridge of the nose.

[0071] In some embodiments, the device includes a sheath configured to prevent or minimize contamination of the cannula from non-target areas within the nasal cavity. In some embodiments, the sheath is configured to prevent or minimize cross-contamination of biological materials and / or formulations with non-target areas of the nasal cavity. In some embodiments where the target site is the olfactory region, the non-target areas include the lower nasal cavity, middle nasal cavity, and regions of the upper nasal cavity other than the olfactory region. In some embodiments where the target site is a targeted sub-region of the olfactory region, the non-targeted regions include the lower and middle nasal cavities of the olfactory region and non-targeted sub-regions.

[0072] Delivery of the formulation Method 100 further includes delivering the formulation through the device to the olfactory region of the patient in the nasal cavity, e.g., 106. In some embodiments, when deposited in the nasal cavity, the formulation is a formulation bolus. In some embodiments, the formulation is delivered using a cannula or other microfluidic channel. In some embodiments, the formulation is delivered to a targeted sub-region of the nasal cavity or olfactory region. In some embodiments, the formulation is discharged from the device through the orifice of the cannula, and the orifice is arranged to deliver the formulation to the targeted sub-region. In some embodiments, the targeted sub-region is localized to an individual millimeter region within the olfactory region.

[0073] In some embodiments, the formulation is driven through the device to move to the olfactory region by various mechanical methods, e.g., by a spring force, a motor force, a pneumatic pressure, a vacuum, or a force provided by hand, from a cartridge (single, multi-chamber), a syringe (single, multi-chamber), a disposable pipette, a pipette, a valve syringe, a blow-fill-seal container (e.g., MicroDose™ single use unit), a bellows, a microfluidic cartridge, or a molded bag. In some embodiments, the formulation is moved by a pump (e.g., a peristaltic pump, a piston pump, a gear pump, etc.). In some embodiments, the formulation is moved by a compressed gas provided by a pump (e.g., a peristaltic pump, a piston pump, a gear pump, etc.) or by a reservoir of compressed gas (e.g., a CO2 cylinder). In some embodiments, the force or pressure required to move the formulation can be provided by an electric motor, a voice coil, a solenoid, or a magnet. For example, in some embodiments, the formulation can be delivered using a device having features as disclosed in International Patent Application No. PCT / CA2019 / 050455.

[0074] In another embodiment, the patient exhales or inhales into the device through the mouth to provide air pressure or vacuum to drive the formulation from the device to the target site. In some embodiments, the device includes a mouthpiece that is placed in the patient's mouth when the device is inserted into the nose. In some embodiments, the patient exhales into the mouthpiece. In some embodiments, the applied pressure moves a piston, which pushes the formulation from the device through a cannula to the target site. In some embodiments, the applied pressure further compresses a bag or bellows filled with the formulation. In some embodiments, the patient inhales through the mouthpiece, thereby creating a vacuum that moves the piston. In some embodiments, the moving piston is connected to a second piston that moves the formulation through a cannula to the target site.

[0075] In another embodiment, the patient exhales or inhales through the nose with the device inserted to provide air pressure or vacuum to move the formulation. In some embodiments, when inserted, the device seals the nostrils with an elastomeric plug (either a facial seal outside the nose or a radial seal on the inner surface of the nostril). In some embodiments, when the patient aspirates through the nose, this draws a vacuum into the nostrils, which draws the formulation from the device, through a cannula, and to the target site. In some embodiments, the device seals against the nostrils as described above, but the patient is instructed to blow, thereby building pressure within the nostrils. In some embodiments, the device includes a port that allows air to flow from the nose into the device, and the air flow pushes a plunger to extrude the formulation from the device through a cannula to the target site. In some embodiments, the patient may block an alternate nostril, or the device may include a second elastomeric plug to block the second nostril.

[0076] In another embodiment, the formulation can also be wicked to the target site by capillary forces within the nasal cavity, such as within the narrow shape of the olfactory region. This occurs when the formulation has an appropriate surface tension and wetting angle with respect to the olfactory mucus. In some embodiments, wicking the formulation to the target site is only feasible in some patients due to natural variations in the patient's anatomical structure. In this embodiment, the formulation is contained within a bag connected to a cannula. In some embodiments, the cannula is positioned in contact with the narrow upper portion of the olfactory region. In some embodiments, the bag is depressed partially to fill the cannula with the formulation, the formulation is brought into contact with the narrow upper portion of the olfactory region, and then capillary pressure draws the formulation from the bag into the olfactory region.

[0077] In another embodiment, the formulation is supplied to the nasal cavity by gravity. In some embodiments, the cannula is inserted into the patient such that the tip contacts the target site within the nasal olfactory region. In some embodiments, a container (e.g., an IV bag) holding the formulation is connected to the cannula and held above the olfactory region. Then, by gravity, the formulation is pushed from the container through the cannula into the olfactory region. In another embodiment, the patient is positioned upside down (e.g., the patient lies on their side on a table and the head is tilted backwards) such that the olfactory region holds the formulation without the need for capillary forces. In another embodiment, the patient is positioned upside down such that the formulation and cannula are partially inserted into the nose (rather than the olfactory region). Then, by gravity, the formulation flows from the cannula down the upper part of the nasal cavity into the olfactory region.

[0078] In some embodiments, the formulation can be placed directly on the target site using a rigid body (e.g., a spoon, a cotton swab). In some embodiments, the rigid body can be articulated to improve placement. In some embodiments, the rigid body is an endoscope or a cannula sheath. In some embodiments, a cotton swab saturated with the formulation is placed on the target site, left for a period of time, and then removed to recover the formulation.

[0079] Capture of biological material Method 100 further includes enabling the delivered formulation to capture biological material at 108. As disclosed herein, the term "biological material" and related terms refer to substances produced by living organisms and include cerebrospinal fluid (CSF), one or more microorganisms of a patient's microbiota, biomarkers, sub-combinations of biomarkers, one or more pathogens, one or more components of a patient's metabolome, other components, or any combination thereof. In some embodiments, the one or more pathogens are a virus, or a part or derivative of a virus. For example, in some embodiments, the virus is SARS CoV-2.

[0080] In some embodiments, when the formulation is delivered to a target site (e.g., the olfactory region), biological material such as a biomarker of interest located at the target site is absorbed by the formulation bolus and / or the formulation diffuses the biomarker of interest directly from the surrounding tissue and body fluid into the formulation. In some embodiments, the biological material adheres to the delivered formulation.

[0081] In some embodiments, during capture of the biological material by the formulation, an air flow (from the patient's breath or generated by the device) is used to evaporate fluid from the formulation bolus. In some embodiments, the patient provides a controlled respiratory rate to ensure an appropriate level of evaporation. In some embodiments, the device includes a second cannula inserted into the nose and a spring-driven bellows, a fan, a canister of compressed gas, or other source for delivering air or gas onto the bolus. This increases the osmotic pressure of the bolus, causing additional liquid to be absorbed from the target site by the formulation and concentrating a sample of the relevant biological material in the formulation bolus.

[0082] In some embodiments, to prepare for the capture of biological material by the formulation, the patient either a) increases mucus production, b) decreases mucus production, c) increases blood flow, d) decreases blood flow, or e) increases intracranial pressure to improve the transport of biomarkers of interest to the formulation bolus at the time of application. In some embodiments, the patient is induced using drug therapy.

[0083] In some embodiments, energy is applied to enhance the transport of nasal fluid containing biological material and / or to enhance the transport of biological material, including the transport of biomarkers from adjacent tissue / fluid to the formulation. For example, in some embodiments, heat is applied to the formulation via UV / VIS / IR light, heating of the formulation according to Ohm's law, or conduction from a heated element within the device. In some embodiments, an electric / magnetic field is applied to move biological material containing the biomarker of interest into the formulation. In some embodiments, vibration, sound, or ultrasonic energy is applied to agitate the formulation or the patient to increase transport.

[0084] In some embodiments, the device can repeatedly eject and retrieve the formulation to enhance the recovery of biological material from the target site within the nasal cavity or olfactory region. In some embodiments, the device can pulse in and pulse out a small portion of the bolus to enhance recovery.

[0085] In some embodiments, the device produces a flow of formulation that exits the device, washes the target site, and is retrieved in a series of boluses or as a continuous stream.

[0086] Preparation and recovery of captured biological material Method 100 further includes the step of withdrawing the formulation and the captured biological material from a target site within the nasal cavity, such as the olfactory region 110 (i.e., the step of collecting the captured biological material). In some embodiments, the formulation and the biological material are withdrawn using a cannula or other microfluidic channel. In some embodiments, the formulation and the biological material are withdrawn through the same orifices and cannulas used for delivery of the formulation. In some embodiments, the formulation and the biological material are withdrawn through different orifices and cannulas used for delivery of the formulation. In some embodiments, the formulation and the biological material are captured within the same container used to contain the formulation prior to delivery to the target site. In some embodiments, the formulation and the biological material are captured within a container different from the container used to contain the formulation prior to delivery to the target site.

[0087] In some embodiments, the pressure differential moves the formulation and the biological material from the target site through a fluid path (e.g., a cannula or microfluidic channel) into the device. In some embodiments, the pressure differential is provided by a spring force, a motor force, a pneumatic pressure, a vacuum, or a force provided by hand, and moves the plunger of a capule (single, multi-chamber), a syringe (single, multi-chamber), or a pipette. In some embodiments, the pressure differential is provided by the relaxation of a previously compressed disposable pipette, a blow-fill-seal container (e.g., a MicroDose™ single-use unit), a bellows, a microfluidic cartridge, or a formed bag. In some embodiments, the pressure differential is provided by a pump (e.g., a peristaltic pump, a piston pump, a gear pump, etc.). In some embodiments, the vacuum is provided by a evacuated container (e.g., a vacutainer, a bottle, a machined chamber), by the relaxation of a previously compressed disposable pipette, a valve syringe, or a bellows, or by a pump.

[0088] In some embodiments, the patient exhales or inhales through the mouth into the device to provide air pressure or vacuum to move a formulation containing biological material from the target site into the device. In some embodiments, the patient exhales or inhales through the nose into which the device is inserted to provide air pressure or vacuum to move a formulation containing biological material from the target site into the device. In some embodiments, the device includes a mouthpiece that is placed in the patient's mouth when the device is inserted into the nose. In some embodiments, the patient inhales through the mouthpiece. In some embodiments, the applied vacuum moves a piston, which draws the formulation into the device through a cannula from the target site. In some embodiments, the applied vacuum also draws the formulation into a bag or bellows. In some embodiments, the formulation can also be drawn into a fluid knockout chamber such as a suction cannister. In some embodiments, the patient exhales into the mouthpiece. In some embodiments, the applied pressure moves a piston. In some embodiments, the moving piston is connected to a second piston that draws the formulation through the cannula into the target site.

[0089] In another embodiment, the patient exhales or inhales through the nose while the device is inserted to provide air pressure or vacuum to move a formulation containing biological material into the device. In some embodiments, upon insertion, the device seals the nostril with an elastomeric plug (either by an outer surface seal of the nose or a radial seal of the inner surface of the nostril). In some embodiments, when the patient exhales through the nose, this creates pressure within the nasal cavity and pushes fluid from the target site through the cannula into the device. In some embodiments, the device seals the nostril as described above, but the patient is instructed to inhale, thereby drawing a vacuum into the nose. In some embodiments, the device comprises a port that allows air to flow from the device into the nose. In some embodiments, within the device, the air flow moves a plunger, which draws fluid into the device through the cannula. In some embodiments, the patient occludes the alternate nostril or the device comprises a second elastomeric plug for blocking the second nostril.

[0090] In some embodiments, the formulation containing biological material is drawn from the target site into the device via capillary pressure and the fluid is drawn into an absorbent swab, absorbent pad, sponge, wick, or lateral flow assay strip. In some embodiments, a rigid body such as a thin aluminum rod with an absorbent pad attached to the tip is used to facilitate contact of the biological material with the formulation at the target site. In some embodiments, the rigid body is inserted into the nose such that the absorbent pad contacts and absorbs the formulation, after which the pad is withdrawn from the nose. In some embodiments, the pad is compressed to extrude the formulation into a standard sample holding container. In some embodiments, the entire absorbent pad is placed into the body of a standard preservative within the sample holding container. In some embodiments, the rod and pad are coated to prevent contamination of the pad during insertion.

[0091] In some embodiments, the wicking element provides a flow path from the sampling site out of the nose and to the device. In some embodiments, the formulation containing the captured biological material is wicked through a flow path (e.g., a cannula or microfluidic channel). In some embodiments, a cannula filled with an absorbent open cell foam is placed in the olfactory region, and the tip of the cannula has an exposed portion of the foam. In some embodiments, when the foam contacts the formulation, the formulation is wicked into the foam and down the cannula. In some embodiments, at the base of the cannula, the fluid is wicked into a chamber filled with absorbent foam. In some embodiments, the foam contains a lyophilized preservative to protect the captured biological material. In some embodiments, the foam chamber is replaced by a lateral flow assay strip to provide point-of-care diagnostics.

[0092] In some embodiments, the viscosity of the formulation decreases after sampling is complete, and the formulation containing the biological material is simply discharged from the nose. For example, in some embodiments, the formulation contains a chemical that reacts or disintegrates a) after a time delay, b) with air, c) with a separately introduced gas or liquid, or d) with the patient's body fluid so that the viscosity of the formulation decreases. In some embodiments, the formulation is thickened by a long-chain natural sugar polymer (polysaccharide). In some embodiments, the formulation containing the biological material is mixed with an enzyme in a double-chambered carple prior to delivery. In some embodiments, the enzyme degrades the sugar polymer over time, thereby reducing the viscosity of the formulation. In some embodiments, the formulation is then discharged from the nose by gravity and captured in a suitable container (e.g., a bottle, jar, or lateral flow assay strip).

[0093] In some embodiments, a formulation containing a biological material changes into an aggregate and is withdrawn from the nose by a tensile force, enabling the preservation of the biological material according to the localization of its target site. For example, in some embodiments, the formulation contains a solvent (e.g., ethanol) that evaporates to convert the formulation into an aggregate. In some embodiments, the formulation contains a chemical agent that reacts a) after a time delay, b) with air, c) with a separately introduced gas or liquid, or with the patient's body fluid to form an aggregate. In some embodiments, the aggregate is then pulled from the nose, blown out of the nose, or dropped from the nose to recover the formulation.

[0094] In some embodiments, the formulation stays only at the target site for the position of the patient. In some embodiments, a change in the position of the patient enables the formulation to be discharged from the nose.

[0095] In some embodiments, the biological material captured from the targeted sub-region is preserved with respect to its localization (geography).

[0096] Analysis of collected biological material Method 100 further includes analyzing the biological material at 112. For example, in some embodiments, biological materials such as biomarkers (e.g., proteins) captured by the formulation are detected or quantified to inform a diagnosis. In some embodiments, the analysis is performed 1) immediately using a point-of-care assay system (e.g., a lateral flow assay), and / or 2) later and / or at another site, where the formulation can be mixed with a preservative.

[0097] In some embodiments, for point-of-care diagnosis, the formulation is removed from the device (e.g., withdrawn with a disposable pipette) and placed in a separate point-of-care system (e.g., a lateral flow assay strip). In some embodiments, the point-of-care system is integrated within the device. For example, in some embodiments, the formulation is recovered by capillary pressure provided by a lateral flow assay strip, and the formulation is withdrawn directly from a target site within the lateral flow assay strip. In some embodiments, the collection container for receiving the formulation and / or biological material contains a chemical that produces a color change to indicate the presence of a specific biological material, such as a target biomarker (e.g., SARS-CoV-2 pathogen), captured within the formulation.

[0098] In some embodiments, for diagnosis at another site, the formulation is mixed with a preservative solution and placed in a suitable container for transport. In some embodiments, the formulation is removed from the device (e.g., withdrawn with a disposable pipette) and placed in a separate container containing a preservative (e.g., a vial containing lyophilized preservative). In some embodiments, the formulation is drawn into a transportable container containing a preservative (e.g., a collection container) that is integrated with a device (e.g., a cap, or a syringe) that can be removed from the device for transport (e.g., the collection container may contain a preservative to stabilize the biological material). In some embodiments, the formulation is drawn into a section of the device containing a preservative that can be detached or otherwise removed from the device for transport. In some embodiments, the formulation itself may also contain the necessary preservative elements.

[0099] In some embodiments, the formulation is configured to preserve the collected biological material and enable its downstream processing. In some embodiments, such downstream processing includes 16S sequencing, metagenomic sequencing, transcriptomics, mass spectrometry, and live bacterial culture. In some embodiments, the factors affecting the compositions, systems, methods, and devices disclosed herein are 1) collection of an appropriate amount of biological material, and 2) appropriate local preservation of the material from the collection site through the sample preparation process. In some embodiments, considering the geography of the nasal anatomical structure, accurate local sampling is in the range of individual millimeters.

[0100] Exemplary Apparatus and Method As described in more detail below, FIGS. 2A-2F, FIGS. 3A-3D, and FIGS. 4A-4F illustrate exemplary embodiments for collecting biological material from a patient's nasal cavity, such as the olfactory region of the nasal cavity. The exemplary embodiments and methods described herein are also applicable to collecting biological material from other regions of the nasal cavity, as disclosed herein. FIGS. 2A-2F show the steps of an exemplary method using a device 200 comprising a common cannula 202 and separate containers 220 and 250 for delivering and recovering the formulation, respectively. FIGS. 3A-3D show the steps of an exemplary method using a device 300 comprising a cannula 302 and a valve 304 attached for both delivery and recovery of the formulation. FIGS. 4A-4F show the steps of an exemplary method using a device 400 comprising a container 420 having a cannula 402 for formulation delivery and another container 450 having a cannula 452 for formulation recovery. The details of these sample devices and their operation are described below.

[0101] As shown in FIG. 2A, device 200 comprises a cannula 202 that is flexible, rigid, or conformable. In some embodiments, the cannula of 202 incorporates a coating mechanism to protect the olfactory region from contamination from the lower nasal cavity and to protect biological material from contamination during the acquisition phase. In some embodiments, device 200 comprises a container 220 (FIG. 2B) having a body for holding a formulation 226. In some embodiments, container 220 comprises a deployment mechanism 224 for discharging formulation 226 from container 220, as shown in FIG. 2B. In some embodiments, container 220 is removably attached to cannula 202. In some embodiments, container 220 comprises a cap 222.

[0102] In some embodiments, device 200 is positioned relative to an external base of the nose. For example, in some embodiments, as shown in FIG. 2A, the device comprises a clip 212 attached to a clip base 206. Clip 212 provides an anatomical reference point for the precise placement of cannula 202 and maintains a consistent placement of cannula 202.

[0103] In some embodiments, cannula 202 is of a fixed length suitable for the general population. In some embodiments, cannula 202 is of a variable length that is set to a particular measurement of the patient. For example, in some embodiments, cannula 202 is slidably attached to base 206 so as to be movable relative to clip 212. In some embodiments, cannula 202 comprises graduations (e.g., markings on the cannula) to assist with placement. For example, the graduations can be used to insert the cannula to a predetermined depth such that the tip of cannula 202 reaches the olfactory region 210 without damaging tissue. In some embodiments, the predetermined depth is determined, for example, by performing pre-insertion measurements on an individual patient using a CT scan or an otoscope, or by utilizing a maximum safe length determined by analyzing a database of nasal pool anthropometric measurements.

[0104] In some embodiments, the deployment mechanism comprises any delivery mechanism as disclosed herein. For example, as shown in FIG. 2B, the deployment mechanism 224 is coupled to the container 220 and is configured such that when the deployment mechanism 224 is actuated, the formulation 226 is discharged from the container 220 through the cannula 202 and deposited onto the olfactory region 210 of the patient as shown in FIG. 2C. In some embodiments, the deployment mechanism is activated by the user. In some embodiments, the cannula 202 comprises an orifice arranged to deliver the formulation 226 to a targeted sub-region (not shown).

[0105] In some embodiments, the deployment mechanism 224 comprises a button, a spring, and a plunger (not shown). When the button is pressed, the spring is thereby released and the plunger moves to push the formulation 226 from the container 220 into the olfactory region 210. The deployment mechanism 224 can take other forms in other embodiments.

[0106] As described above, in some embodiments, the formulation has a higher osmotic pressure than the mucus of the olfactory region 210. In some embodiments, the formulation contains sugars for both increasing the osmotic pressure and creating an agglomerating fluid that can be completely extracted. In some embodiments, the increase in osmotic pressure creates an osmotic pressure gradient that is advantageous for the uptake of biological materials such as specific biomarker targets 240 into the formulation 226 deposited on the olfactory region 210 as shown in FIG. 2D. In some embodiments, the formulation 226 is shear thinning to facilitate the distribution of the formulation 226 into the narrow spaces within the olfactory region 210.

[0107] In some embodiments, the retrieval of the formulation and / or biological material includes any retrieval mechanism as disclosed herein. For example, as shown in FIG. 2E, in some embodiments, the container 220 is detached from the cannula 202 and exchanged with a retrieval container 250. In some embodiments, the retrieval container 250 comprises a body configured to hold the withdrawn formulation and / or biological material. In some embodiments, the retrieval container 250 comprises a cap 252, a deployment button 254, a spring (not shown) and / or a plunger (not shown). As shown in FIG. 2F, when the deployment button 254 is pressed, the spring moves the plunger, drawing the formulation 226 and biological material 240 through the cannula 202 into the retrieval container 250. In some embodiments, the system shape and movement speed of the plunger are controlled (e.g., by wetting) to ensure that the formulation 226 is not drawn in too quickly (e.g., minimizing or preventing the shear forces received by the captured biological material 240 that would affect the analysis results through damage to the contents of the captured biological material, and minimizing or preventing air from being retrieved instead of the full amount of formulation and biological material).

[0108] The formulation 226 is any formulation as disclosed herein. For example, in some embodiments, the formulation shown in FIG. 2F cross-links upon exposure to air or other means (described herein), thereby changing the formulation to a semi-solid state. In some embodiments, the semi-solid formulation facilitates the preservation of the captured biological material according to its localization at the target site, while the semi-solid formulation is withdrawn and stored in the container at 252.

[0109] In some embodiments, the cannula 202 is coated to prevent or minimize cross-contamination of biological materials and / or contamination of the olfactory region by cannula inoculation from the underlying nasal anatomical structure.

[0110] Figure 3A shows another embodiment of device 300 including cannula 302 and flexible valve 304. As shown in Figure 3B, when flexible valve 304 is pushed, formulation 226 is pushed through cannula 302 into olfactory region 210. In some embodiments, cannula 302 comprises an orifice arranged to deliver formulation 226 to a targeted sub-region (not shown). The formulation can be any formulation disclosed herein.

[0111] Figure 3C shows formulation 226 having a higher osmotic pressure than biological material 240, creating an osmotic pressure gradient favorable for the uptake of biological material containing biomarker 240 of interest into formulation 226.

[0112] As shown in Figure 3D, flexible valve 302 can relax, drawing formulation 226 and biological material 240 through cannula 302 into valve 304.

[0113] In some embodiments, cannula 302 is coated to prevent or minimize cross-contamination of biological materials and / or contamination of the olfactory region by cannula inoculation from underlying nasal anatomical structures.

[0114] Figures 4A-D show a device 400 comprising a container 420 holding a formulation 226 having a deployment mechanism 424 configured to expel the formulation through cannula 402, similar to the operation of device 200 described above. In some embodiments, container 420 comprises a cap 422. In some embodiments, cannula 402 comprises an orifice arranged to deliver formulation 226 to a targeted sub-region (not shown). In some embodiments, the deployment mechanism includes any delivery mechanism as disclosed herein. The formulation can be any formulation disclosed herein.

[0115] As shown in FIG. 4E, the collection device 450 can be inserted into the patient's nose. In some embodiments, the collection device includes a body for holding the formulation and / or biological material after being withdrawn. In some embodiments, the collection device comprises a collection cannula different from the cannula used to deliver the formulation to the olfactory region. In some embodiments, the collection cannula is removably coupled to a collection container. In some embodiments, the collection device comprises any collection mechanism as disclosed herein. For example, in some embodiments, the collection device has a chamber 454 filled with a wicking material and a collection cannula 452 filled with a wicking material configured to draw up fluid. In some embodiments, the wicking material includes natural or synthetic fibers, spun, woven, or randomly oriented materials, and / or capillaries that draw up fluid. In some embodiments, the collection device 450 and the wicking material are used to withdraw the formulation 226 and biological material 240 from the patient's olfactory region 210 as shown in FIG. 4F.

[0116] In some embodiments, the cannula 402 is coated to prevent or minimize contamination of the olfactory region by cross - contamination of biological materials and / or cannula inoculation from the underlying nasal anatomical structures.

[0117] The foregoing discussion provides many exemplary embodiments of the subject matter of the present invention. Each embodiment represents a single combination of elements of the present invention, but the subject matter of the present invention is considered to include all possible combinations of the disclosed elements. Thus, if one embodiment includes elements A, B, and C and a second embodiment includes elements B and D, the subject matter of the present invention is also considered to include other remaining combinations of A, B, C, or D, even if not explicitly disclosed.

[0118] Examples of Housekeeping Protein Detection in Human Sample Fluid Cerebrospinal fluid (CSF)-predominant proteins tau and human prostaglandin-H2 D-isomerase (PTGDS) were successfully detected in human body fluids. Human CSF, nasal fluid (NF), and nasal lavage (NL) were analyzed using commercially available sandwich ELISA kits and qualitative mass spectrometry (LC-MS / MS) analysis. Mass spectrometry detected PTGDS in both CSF and NF, but PTGDS may have been too dilute to detect in NL. The ELISA kit used was unable to detect PTGDS in CSF, rendering further use invalid. Tau protein was detected by ELISA at levels expected in CSF. Mass spectrometry was unable to detect tau - presumably due to its low natural abundance. Tau is present in CSF at a concentration approximately 1000-fold lower than PTGDS and may be below the detection limit of this mass spectrometry protocol. ELISA detected that levels of both tau and PTGDS from NF were excessively high and that PTGDS levels were low in NL. This data was not supported by spectroscopic analysis and may be due to non-specific reactions between the sticky nasal material and the detection system of the ELISA kit. Tables 3 and 4 provide the results of the detection analysis of tau and PTGDS, where the first 4 samples listed were diluted with ELISA sample diluent and the last sample listed (pooled human cerebrospinal fluid) was diluted with synthetic CSF analog solution.

[0119]

Table 3

[0120]

Table 4

[0121] LC / MS / MS analysis of the samples was able to detect an additional 147 proteins in the CSF that were not seen in either the NF or NL. These proteins provide potential marker options for tracking CSF fluid infiltration in patients experiencing rhinorrhea. Additionally, a number of CSF-derived proteins were detected in either the NF or NL. Using a quantitative approach, normal baseline values for the selected proteins can be established and central nervous system diseases resulting from increased protein levels can be diagnosed. Finally, mass spectrometry detected a number of proteins within the NL that did not occur in the NF (and vice versa). This indicates that a targeted sampling approach may be very effective in capturing proteins from geometrically distinct regions of the olfactory system. By adjusting the sampling method, rapid detection and early diagnosis of site-specific diseases can be provided.

[0122] Preferred embodiments of the present disclosure have been shown and described herein, but it will be apparent to those skilled in the art that such embodiments are provided by way of example only. Numerous variations, changes, and substitutions will occur to those skilled in the art without departing from the present disclosure. It should be understood that various alternatives to the embodiments described herein, or combinations of one or more of these embodiments or aspects described herein, can be used in practicing the present disclosure. The following claims define the scope of the present disclosure, and methods and structures within the scope of these claims, as well as their equivalents, are intended to be covered thereby.

Claims

1. A method for collecting a biological material from the olfactory region of a patient, the method comprising: a. providing a formulation configured to capture the biological material; b. inserting a delivery device having a delivery orifice into the patient's nasal cavity; c. delivering the formulation, via the delivery device, to the olfactory region of the patient or a targeted sub-region of the olfactory region of the patient; d. enabling the formulation to capture the biological material; e. withdrawing at least a portion of the formulation and the biological material captured therein, thereby collecting the biological material. A method as described above.

2. The method according to claim 1, wherein the delivery orifice is arranged such that the delivery of the formulation is performed on a targeted sub-region of the olfactory region.

3. The method according to claim 1 or 2, further comprising preserving the composition of the formulation and / or the captured biological material during withdrawal.

4. The method according to any one of claims 1 to 3, wherein the biological material comprises cerebrospinal fluid, one or more microorganisms of the patient's microbiota, one or more components of the patient's metabolome, one or more pathogens, and / or one or more biomarkers of interest.

5. The method according to claim 4, wherein the one or more pathogens comprise a virus or a part or derivative thereof.

6. The method according to claim 5, wherein the virus is SARS-CoV-2.

7. The method according to any one of claims 1 to 6, wherein the delivery device comprises a cannula and / or a microfluidic channel, and the step of inserting the delivery device comprises inserting the cannula and / or the microfluidic channel into the patient's nasal cavity.

8. The method according to claim 7, further comprising determining the length of the nasal cavity from the patient's nostril to the olfactory region and inserting the cannula and / or the microfluidic channel to a predetermined depth based on the determined length.

9. The method according to any one of claims 1 to 8, further comprising arranging a reference device on the patient's face to provide an anatomical reference point for accurately positioning the delivery orifice within the nasal cavity.

10. The method according to any one of claims 1 to 9, wherein the biological material is captured from a targeted sub-region of the olfactory region.

11. The method according to any one of claims 1 to 10, wherein the delivery device comprises a sheath configured to minimize or prevent contamination of the cannula and / or the microfluidic channel, the delivery orifice, the formulation, and / or the captured biological material from the olfactory region of the nasal cavity and / or an olfactory region other than the targeted sub-region of the olfactory region.

12. The method according to claim 11, wherein the sheath comprises a protective coating disposed around the cannula and / or the microfluidic channel.

13. The method according to claim 11, wherein the sheath comprises a cover or sleeve disposed around the cannula and / or the microfluidic channel.

14. The method according to any one of claims 1 to 13, further comprising the step of inducing the patient to increase or decrease mucus production to facilitate capture and / or collection of the biological material.

15. The method according to any one of claims 1 to 14, further comprising the step of inducing the patient to increase or decrease blood flow to facilitate capture and / or collection of the biological material.

16. The method according to any one of claims 1 to 15, further comprising the step of inducing the patient to increase intracranial pressure to facilitate capture and / or collection of the biological material.

17. The method according to any one of claims 1 to 16, further comprising the step of applying energy to facilitate capture and / or collection of the biological material.

18. The method according to claim 17, wherein the step of applying energy comprises applying heat to the formulation via UV / VIS / IR light, heating of the formulation according to Ohm's law, or conduction from a heated element within the delivery device.

19. The method according to any one of claims 1 to 18, wherein an electric field and / or a magnetic field is applied to facilitate capture of the biological material by the formulation.

20. The method according to any one of claims 1 to 19, wherein the delivery device is configured to deliver a flow of the formulation to the olfactory region or a targeted sub-region of the olfactory region such that the flow of the formulation is drawn as a continuous flow.

21. The method according to any one of claims 1 to 20, further comprising the step of repeating the method according to any one of claims 1 to 20 in order to increase the collection of the biological material.

22. The method according to any one of claims 1 to 21, wherein the formulation is the formulation according to any one of claims 108 to 174.

23. A method for collecting biological material from a patient's nasal cavity, the method comprising: a. providing a formulation configured to capture biological material; b. inserting a delivery device including a delivery orifice into the patient's nasal cavity or a targeted sub-region of the nasal cavity; c. delivering the formulation to the patient's nasal cavity via the delivery device; d. enabling the delivered formulation to capture the biological material; e. withdrawing at least a portion of the formulation and the biological material captured therein. A method comprising the steps of:

24. The method according to claim 23, wherein the delivery orifice is arranged such that the delivery of the formulation is performed in a targeted sub-region of the nasal cavity.

25. The method according to claim 23 or 24, further comprising the step of preserving the composition of the formulation and / or the captured biological material when withdrawing.

26. The method according to any one of claims 23 to 25, wherein the biological material comprises cerebrospinal fluid (CSF), one or more microorganisms of the patient's microbiota, one or more components of the patient's metabolome, one or more pathogens, and / or one or more biomarkers of interest.

27. The method according to claim 26, wherein the one or more pathogens comprise a virus or a part or derivative thereof.

28. The method according to claim 27, wherein the virus is SARS-CoV-2.

29. The method according to any one of claims 23 to 28, wherein the delivery device includes a cannula and / or a microfluidic channel, and the step of inserting the delivery device includes inserting the cannula and / or the microfluidic channel into the patient's nasal cavity.

30. The method according to claim 29, further comprising the step of determining the length of the nasal cavity from the patient's nostril to the olfactory region and inserting the cannula and / or the microfluidic channel to a predetermined depth based on the determined length.

31. The method according to any one of claims 23 to 30, further comprising the step of placing a reference device on the face of the patient so as to provide an anatomical reference point for accurately placing the delivery orifice within the nasal cavity.

32. The method according to any one of claims 23 to 31, wherein the biological material is captured from the target region of the nasal cavity.

33. The method according to claim 32, wherein the delivery device includes a cannula and / or a microfluidic channel, a delivery orifice, a formulation, and / or a sheath configured to minimize or prevent contamination of the captured biological material from non-target regions of the nasal cavity.

34. The method according to claim 33, wherein the sheath comprises a protective coating disposed around the cannula and / or the microfluidic channel.

35. The method according to claim 33, wherein the sheath comprises a cover or sleeve disposed around the cannula and / or the microfluidic channel.

36. The method according to any one of claims 23 to 35, further comprising the step of inducing the patient to increase or decrease mucus production to facilitate capture and / or collection of the biological material.

37. The method according to any one of claims 23 to 36, further comprising the step of inducing the patient to increase or decrease blood flow to facilitate capture and / or collection of the biological material.

38. The method according to any one of claims 23 to 37, further comprising the step of inducing the patient to increase intracranial pressure to facilitate capture and / or collection of the biological material.

39. The method according to any one of claims 23 to 38, further comprising the step of applying energy to facilitate capture and / or collection of the biological material.

40. The method according to claim 39, wherein the step of applying the energy includes applying heat to the formulation via UV / VIS / IR light, heating according to Ohm's law of the formulation, or conduction from a heated element within the delivery device.

41. The method according to any one of claims 23 to 40, wherein an electric field and / or a magnetic field is applied to facilitate capture of the biological material by the formulation.

42. The method according to any one of claims 23 to 41, wherein the delivery device is configured to deliver the flow of the formulation to the nasal cavity or a target sub-region of the nasal cavity such that the flow of the formulation is drawn out as a continuous flow.

43. The method according to any one of claims 23 to 42, further comprising the step of repeating the method according to any one of claims 23 to 42 in order to increase the collection of the biological material.

44. The method according to any one of claims 23 to 43, wherein the formulation is the formulation according to any one of claims 108 to 174.

45. An apparatus for collecting biological material from a patient's nasal cavity, the apparatus comprising: a. a first body containing a formulation configured to capture biological material; b. a first cannula and / or microfluidic channel configured to be positioned within the patient's nasal cavity and having a delivery orifice fluidly connected to the first body; c. a deployment mechanism for delivering the formulation to the patient's nasal cavity via the first cannula and / or microfluidic channel to capture biological material from the patient's nasal cavity; d. a collection device for collecting the biological material captured from the patient's nasal cavity and comprising the apparatus.

46. The apparatus according to claim 45, wherein the delivery orifice is configured such that the delivery of the formulation is performed in a targeted sub-region of the nasal cavity.

47. The apparatus according to claim 45, wherein the delivery orifice is configured such that the delivery of the formulation is performed in the olfactory region of the nasal cavity.

48. The apparatus according to claim 47, wherein the delivery orifice is configured such that the delivery of the formulation is performed in a targeted sub-region of the olfactory region.

49. The apparatus according to any one of claims 45 to 48, wherein the biological material is cerebrospinal fluid (CSF), one or more microorganisms of the patient's microbiota, one or more components of the patient's metabolome, one or more pathogens, and / or one or more biomarkers of interest.

50. The apparatus according to claim 49, wherein the one or more pathogens comprise a virus or a part or derivative thereof.

51. The apparatus according to claim 50, wherein the virus is SARS-CoV-2.

52. The apparatus according to any one of claims 45 to 51, wherein the biological material is captured from a targeted sub-region of the nasal cavity.

53. The device according to any one of claims 45 to 51, wherein the biological material is captured from the olfactory region of the nasal cavity.

54. The device according to claim 53, wherein the biological material is captured from a targeted sub-region of the olfactory region of the nasal cavity.

55. The device according to any one of claims 45 to 55, comprising the first body, the first cannula and / or microfluidic channel, the delivery orifice, the collection device, the formulation, and / or a sheath configured to minimize or prevent contamination of biological material captured from non-target regions of the nasal cavity.

56. The device according to any one of claims 45 to 55, wherein the sheath is configured to minimize or prevent contamination of the first body, the first cannula and / or microfluidic channel, the delivery orifice, the collection device, the formulation and / or biological material captured from non-target sub-regions of the olfactory region.

57. The device according to claim 55 or 56, wherein the sheath comprises a protective coating disposed around the first cannula and / or microfluidic channel.

58. The device according to claim 55 or 56, wherein the sheath comprises a cover or sleeve disposed around the first cannula and / or microfluidic channel.

59. The device according to any one of claims 45 to 58, wherein the first body comprises a first container removably coupled to the first cannula and / or microfluidic channel.

60. The device according to any one of claims 45 to 59, wherein the collection device comprises a second body removably coupled to the first cannula and / or microfluidic channel.

61. The device according to any one of claims 45 to 60, wherein the collection device comprises the second body and a second cannula coupled to the second body.

62. The device according to any one of claims 45 to 61, wherein the collection device is configured to preserve the integrity and the biological material according to its localization when captured from the nasal cavity.

63. The device according to any one of claims 45 to 62, wherein the deployment mechanism comprises a first actuator coupled to a first spring coupled to a first plunger.

64. The device according to any one of claims 45 to 63, further comprising a clip configured to be connected to a patient's nose so as to facilitate positioning of the delivery orifice.

65. The device according to claim 64, wherein the first cannula and / or the microfluidic channel is configured to move relative to the clip.

66. The device according to any one of claims 45 to 65, wherein the collection device comprises a second actuator connected to a second spring connected to a second plunger.

67. The device according to any one of claims 45 to 66, wherein the first body comprises a cable.

68. The device according to any one of claims 45 to 67, wherein the first cannula and / or the microfluidic channel is a flexible cannula.

69. The device according to any one of claims 45 to 67, wherein the first cannula and / or the microfluidic channel is a telescopic cannula.

70. The device according to any one of claims 45 to 69, wherein the device comprises mechanical features for preventing dangerous forces from being transmitted through the first cannula and / or the microfluidic channel.

71. The device according to claim 70, wherein the mechanical features include a force-limiting spring, a radial slip clutch, and / or an axial slip clutch.

72. The device according to any one of claims 45 to 71, wherein the targeted sub-region of the olfactory region is localized in an individual millimeter region within the olfactory region.

73. The device according to any one of claims 45 to 72, wherein the formulation is the formulation according to any one of claims 108 to 174.

74. A system for collecting biological material from a patient's nasal cavity, the system comprising: a. a first body configured to contain a formulation; b. a first cannula and / or a microfluidic channel configured to be positioned within a patient's nasal cavity and having a delivery orifice fluidly connected to the first body; c. a deployment mechanism for delivering the formulation to the patient's nasal cavity via the first cannula and / or the microfluidic channel; d. a collection device for collecting biological material from the patient's nasal cavity; e. a formulation configured to capture the biological material and comprising a system.

75. The system according to claim 74, wherein the delivery orifice is configured such that delivery of the formulation occurs in a targeted sub-region of the nasal cavity.

76. The system according to claim 74, wherein the delivery orifice is configured such that delivery of the formulation occurs in the olfactory region of the nasal cavity.

77. The system according to claim 76, wherein the delivery orifice is configured such that delivery of the formulation occurs in a targeted sub-region of the olfactory region.

78. The system according to any one of claims 74 to 77, wherein the biological material comprises cerebrospinal fluid (CSF), one or more microorganisms of the patient's microbiota, one or more components of the patient's metabolome, one or more pathogens, and / or one or more biomarkers of interest.

79. The system according to claim 78, wherein the one or more pathogens comprise a virus or a part or derivative thereof.

80. The system according to claim 79, wherein the virus is SARS-CoV-2.

81. The system according to any one of claims 74 to 80, wherein the biological material is captured from a target region of the nasal cavity.

82. The system according to any one of claims 74 to 80, wherein the biological material is captured from the olfactory region of the nasal cavity.

83. The system according to claim 82, wherein the biological material is captured from a targeted sub-region of the olfactory region of the nasal cavity.

84. The system according to any one of claims 74 to 83, comprising a sheath configured to minimize or prevent contamination of the first body, the first cannula and / or microfluidic channel, the delivery orifice, the collection device, the formulation, and / or biological material captured from a non-target region of the nasal cavity.

85. The system according to any one of claims 74 to 83, wherein the sheath is configured to minimize or prevent contamination of the first body, the first cannula and / or microfluidic channel, the delivery orifice, the collection device, the formulation, and / or biological material captured from a non-olfactory region or a non-targeted sub-region of the olfactory region of the nasal cavity.

86. The system according to claim 84 or 85, wherein the sheath comprises a protective coating disposed around the first cannula and / or microfluidic channel.

87. The system according to claim 84 or 85, wherein the sheath comprises a cover or sleeve disposed around the first cannula and / or the microfluidic channel.

88. The system according to any one of claims 74 to 87, wherein the first body comprises a first container removably coupled to the first cannula and / or the microfluidic channel.

89. The system according to any one of claims 74 to 88, wherein the collection device comprises a second body removably coupled to the first cannula and / or the microfluidic channel.

90. The system according to any one of claims 74 to 89, wherein the collection device comprises a second body and a second cannula coupled to the second body.

91. The system according to any one of claims 74 to 90, wherein the collection device is configured to preserve integrity and biological material according to the localization of biological material when captured from the nasal cavity.

92. The system according to any one of claims 74 to 91, wherein the deployment mechanism comprises a first actuator coupled to a first spring coupled to a first plunger.

93. The system according to any one of claims 74 to 92, further comprising a clip configured to couple to the patient's nose to facilitate positioning of the delivery orifice.

94. The system according to claim 93, wherein the first cannula and / or the microfluidic channel is configured to move relative to the clip.

95. The system according to any one of claims 74 to 94, wherein the collection device comprises a second actuator coupled to a second spring coupled to a second plunger.

96. The system according to any one of claims 74 to 95, wherein the first body comprises a cable.

97. The system according to any one of claims 74 to 96, wherein the first cannula and / or the microfluidic channel is a flexible cannula.

98. The system according to any one of claims 74 to 96, wherein the first cannula and / or the microfluidic channel is a telescopic cannula.

99. The system according to any one of claims 74 to 98, comprising mechanical features for preventing dangerous forces from being transmitted through the cannula.

100. The system according to claim 99, wherein the mechanical features include a force-limiting spring, a radial slip clutch, and / or an axial slip clutch.

101. The system according to any one of claims 74 to 100, wherein the targeted sub-region of the olfactory region is localized to an individual millimeter region within the olfactory region.

102. The system according to any one of claims 74 to 101, wherein the formulation is the formulation according to any one of claims 108 to 174.

103. A method for diagnosing a patient, the method comprising: a. performing the method according to any one of claims 1 to 44, thereby collecting a biological material from the patient; b. analyzing the collected biological material; c. diagnosing based on the analysis of step b and including.

104. The method according to claim 103, wherein the step of analyzing the biological material includes identifying and / or quantifying biomarkers, pathogens, and / or microorganisms in the collected biological material.

105. The method according to claim 104, further comprising correlating the identified and / or quantified biomarkers, pathogens, and / or microorganisms with corresponding physiological characteristics and / or medical conditions.

106. The method according to any one of claims 103 to 105, wherein the step of analyzing the biological material includes using a point-of-care assay system.

107. The point-of-care assay system is configured to receive a sample of the collected biological material from the delivery device according to any one of claims 1 to 44, the device according to any one of claims 45 to 73, or the system according to any one of claims 74 to 102, according to claim 100.

108. A formulation for collecting a biological material from a patient's nasal cavity, the formulation being configured to capture the biological material when delivered into the nasal cavity, and the delivered formulation being configured to be withdrawn from the nasal cavity together with the biological material.

109. The formulation according to claim 108, wherein the formulation is delivered to the olfactory region of the nasal cavity.

110. The formulation according to claim 108, wherein the formulation is configured to capture biological material from a targeted sub-region of the olfactory region.

111. The formulation according to any one of claims 108 to 110, wherein the delivered formulation is configured to preserve the biological material captured when withdrawn.

112. The formulation according to any one of claims 108 to 111, wherein the biological material comprises cerebrospinal fluid (CSF), one or more microorganisms of the patient's microbiota, one or more components of the patient's metabolome, one or more pathogens, and / or one or more biomarkers of interest.

113. The formulation according to claim 112, wherein the formulation is configured to capture a specific biological material.

114. The formulation according to any one of claims 108 to 113, wherein the formulation comprises buffered saline.

115. The formulation according to claim 114, wherein the buffered saline is 100 mM phosphate buffered saline.

116. The formulation according to any one of claims 108 to 115, wherein the formulation comprises one or more gelling agents and / or thickening agents.

117. The formulation according to any one of claims 108 to 116, wherein the formulation comprises a viscosity modifier to provide a desired viscosity to the formulation.

118. The formulation according to claim 117, wherein the viscosity modifier comprises at least one of glycerol, pectin, and polyethylene glycol.

119. The formulation according to claim 117 or 118, wherein the viscosity modifier constitutes 25 to 75% by volume of the formulation.

120. The formulation according to any one of claims 108 to 119, wherein the formulation has an osmotic pressure higher than that of the fluid in the patient's nasal cavity, olfactory region, or targeted sub-region of the olfactory region.

121. The formulation according to any one of claims 108 to 119, wherein the formulation has an osmotic pressure below that of the fluid in the patient's nasal cavity, olfactory region, or targeted sub-region of the olfactory region.

122. The formulation according to any one of claims 108 to 121, wherein the desired osmotic pressure of the formulation is achieved by including salts, sugars, starches, albumin, dextran, or combinations thereof in the formulation.

123. The formulation according to any one of claims 108 to 122, wherein after the target volume of fluid other than the formulation is withdrawn from the nasal cavity, the olfactory region, or a targeted sub-region of the olfactory region, the osmotic pressure is adjusted to be equal to the target osmotic pressure.

124. The formulation according to any one of claims 108 to 123, wherein the osmotic pressure of the formulation is configured to change over time so as to capture biological material from the nasal cavity, the olfactory region, or a targeted sub-region of the olfactory region at a desired rate.

125. The formulation according to claim 124, wherein the osmotic pressure of the formulation is configured to change over time by including an osmotic pressure adjuster in the formulation.

126. The formulation according to claim 125, wherein the osmotic pressure adjuster includes microencapsulated particles of one or more osmotic pressure adjusters.

127. The formulation according to claim 125 or 126, wherein the one or more osmotic pressure adjusters include sodium chloride.

128. The formulation according to any one of claims 125 to 127, wherein the microencapsulated particles include an enteric coating containing one or more osmotic pressure adjusters.

129. The formulation according to claim 128, wherein the enteric coating is configured to release the one or more osmotic pressure adjusters when exposed to predetermined conditions within a predetermined time.

130. The formulation according to claim 129, wherein the predetermined conditions include one or more conditions selected from the group consisting of a temperature range, a pH range, and a predetermined shear force.

131. The formulation according to any one of claims 108 to 132, wherein the formulation includes an agent that promotes mucus production within the nasal cavity, the olfactory region, or a targeted sub-region of the olfactory region, thereby facilitating the capture of the biological material.

132. The formulation according to claim 131, wherein the agent that promotes mucus production is capsaicin.

133. The formulation according to any one of claims 108 to 132, wherein the formulation includes one or more agents that increase the viscosity of mucus within the nasal cavity, the olfactory region, or a targeted sub-region of the olfactory region, thereby preventing the delivered drug from moving and increasing the residence time of the delivered formulation within the nasal cavity, the olfactory region, or the targeted sub-region of the olfactory region.

134. The preparation according to any one of claims 108 to 133, which is configured to change from a liquid state to a semi-solid state when delivered to the nasal cavity, the olfactory region, or a targeted sub-region of the olfactory region.

135. The preparation according to claim 134, which is configured to initiate a cross-linking reaction upon delivery to the nasal cavity, the olfactory region, or a targeted sub-region of the olfactory region.

136. The preparation according to claim 135, wherein the preparation contains two or more reagents.

137. The preparation according to claim 136, wherein the two or more reagents are configured to be mixed upon delivery to the nasal cavity, the olfactory region, or a targeted sub-region of the olfactory region to initiate a cross-linking reaction, thereby changing the preparation to a semi-solid state.

138. The preparation according to any one of claims 134 to 137, wherein the preparation contains a non-Newtonian fluid.

139. The preparation according to claim 138, wherein the preparation changes from a liquid state to a semi-solid state at a temperature substantially the same as human body temperature.

140. The preparation according to claim 138, wherein the preparation changes from a liquid state to a semi-solid state at a temperature from about 35 °C to about 40 °C.

141. The preparation according to claim 138, wherein the preparation changes from a liquid state to a semi-solid state at a temperature of about 37 °C.

142. The preparation according to any one of claims 134 to 141, wherein the preparation contains a Bingham plastic.

143. The preparation according to claim 142, which behaves as a liquid when subjected to shear force during delivery to the nasal cavity, the olfactory region, or a targeted sub-region of the olfactory region.

144. The preparation according to claim 143, which behaves as a semi-solid when not subjected to shear force.

145. The preparation according to any one of claims 134 to 144, further comprising a tail formed by the delivery and partial solidification of the preparation.

146. The preparation according to claim 145, wherein the tail is configured to be mechanically removed, thereby facilitating the removal of the captured biological material.

147. The preparation according to any one of claims 134 to 146, wherein the semi-solid state of the preparation is configured to preserve the captured biological material according to the localization of the biological material.

148. The preparation according to any one of claims 108 to 147, wherein the preparation acts as a carrier preparation.

149. The formulation according to claim 148, wherein the carrier formulation comprises encapsulated nanoparticles.

150. The formulation according to claim 149, wherein the encapsulated nanoparticles are encapsulated in a coating that degrades when exposed to predetermined conditions for a predetermined time.

151. The formulation according to claim 150, wherein the predetermined conditions are specific to the nasal cavity, the olfactory region, or a targeted sub-region of the olfactory region.

152. The formulation according to claim 150 or 151, wherein the predetermined conditions include temperature, pH, and / or contact with a specific biological material.

153. The formulation according to any one of claims 150 to 152, wherein the degradation of the coating releases a chemical substance configured to change the carrier formulation from a semi-solid state to a liquid state.

154. The formulation according to any one of claims 108 to 153, wherein the formulation comprises one or more specific monoclonal or polyclonal antibodies so as to target a specific biological material.

155. The formulation according to any one of claims 108 to 154, wherein the formulation comprises one or more specific aptamers so as to target a specific biological material.

156. The formulation according to claim 154 or 155, wherein the specific biological material is cystatin-C.

157. The formulation according to claim 154 or 155, wherein the specific biological material is a virus or a part or derivative thereof.

158. The formulation according to claim 157, wherein the virus is SARS-CoV-2.

159. The formulation according to any one of claims 108 to 158, comprising an antibacterial agent for preserving the captured biological material.

160. The formulation according to claim 159, wherein the antibacterial agent comprises 25% v / v ethanol and / or 5% w / v citric acid.

161. The formulation according to any one of claims 108 to 160, wherein the formulation comprises a microbial enrichment and preservation material.

162. The formulation according to claim 161, wherein the microbial enrichment and preservation material comprises 25% v / v tryptic soy broth.

163. The formulation according to any one of claims 108 to 162, wherein the formulation comprises a hydrogel.

164. The formulation according to any one of claims 108 to 163, wherein the formulation comprises a sugar.

165. The formulation according to any one of claims 108 to 164, wherein the formulation is thixotropic or shear-thickening.

166. The formulation according to any one of claims 108 to 165, wherein the formulation is immiscible with water.

167. The formulation according to any one of claims 108 to 166, wherein the formulation is miscible with water.

168. The formulation according to any one of claims 108 to 167, wherein the formulation is configured to preserve biological material.

169. The formulation according to any one of claims 108 to 168, wherein the formulation is configured to maintain the integrity of biological material.

170. The formulation according to any one of claims 108 to 169, wherein the formulation is configured to change into an aggregate after being delivered to the nasal cavity, the olfactory region, or a targeted sub-region of the olfactory region.

171. The formulation according to claim 170, wherein the formulation contains a solvent that evaporates to change the formulation into an aggregate.

172. The formulation according to claim 171, comprising a chemical that: a) reacts after a time delay, b) reacts with air, c) reacts with a separately introduced gas or liquid, or d) reacts with a patient's body fluid, resulting in the formation of an aggregate.

173. The formulation according to any one of claims 108 to 172, wherein the formulation is configured to absorb biological material from the olfactory region.

174. The formulation according to any one of claims 108 to 173, wherein the formulation is provided, delivered, and / or withdrawn as a bolus of the formulation.

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