Microfluidic method and system for isolating particles from biological fluid

Abstract

The invention relates to a system and method for isolating particles from a biological fluid, including: obtaining a sample of biological fluid from a source (e.g. a patient) in which the sample contains particles of multiple sample particle types; tagging particles in the sample with tagging agents, including mixing the sample with a solution of magnetic tagging agents that selectively bind to particles of at least one of the sample particle types, thereby forming a group of tagged particles in the sample; passing the sample through a magnetic conduit having a magnetic field that interacts with at least some of the tagged particles; sorting the particles of the sample into multiple groups based on the interaction between the tagged particles and the magnetic field; and optionally returning selected portions of the processed fluid back to its source with or without the addition of appropriate therapeutic agents.

We claim: 
     
         1 . A method for sorting particles from biological fluid of a patient, comprising:
 receiving a sample of biological fluid from the patient, wherein the sample contains particles of a set of sample particle types, each sample particle type being classified as a targeted particle or a non-targeted particle;   at a tagging conduit including a textured surface, mixing the sample with a first solution of magnetic tagging agents that selectively bind to particles of at least one of the set of sample particle types, thereby forming a tagged particle subset and an untagged particle subset within the sample;   passing the sample through a magnetic conduit, coupled to the tagging conduit, having a magnet that provides a magnetic field isolated to a region of the magnetic conduit, that interacts with the tagged particle subset; and   delivering the tagged particle subset and the untagged particle subset from at least one outlet of the magnetic conduit, based on an interaction between the tagged particle subset and the magnetic field, thereby producing at least one sorted particle group.   
     
     
         2 . The method of  claim 1 , wherein obtaining the sample of biological fluid includes obtaining at least one of blood, cerebrospinal fluid, and urine at a cannula fluidly coupled to the patient, at a point of care of the patient, and to the tagging conduit. 
     
     
         3 . The method of  claim 2 , further comprising automatically determining an enumeration of at least one sorted particle group, recirculating a portion of the sample into the patient, and automatically administering a therapeutic agent to the patient based upon the enumeration, wherein administering the therapeutic agent includes adding the therapeutic agent to the portion of sample recirculating in the patient. 
     
     
         4 . The method of  claim 3 , wherein mixing includes selectively binding a magnetic bead functionalized with an antibody that is specific in binding to at least one targeted particle. 
     
     
         5 . The method of  claim 1 , wherein delivering includes:
 diverting a first portion of the tagged particle subset to flow through a first outlet of the magnetic conduit, by way of the magnetic field, thereby forming a first sorted group, and   allowing the untagged particle subset to flow through a second outlet of the magnetic conduit, thereby forming a second sorted group.   
     
     
         6 . The method of  claim 5 , wherein delivering further includes diverting a second portion of the tagged particle subset to flow through a third outlet of the magnetic conduit, by way of the magnetic field, thereby forming a third sorted group. 
     
     
         7 . The method of  claim 6 , wherein diverting the first portion of the tagged particle subset includes diverting the first portion of the tagged particle subset into a buffer stream separate from the sample. 
     
     
         8 . The method of  claim 6 , wherein diverting the first and the second portions of the tagged particle subset comprise diverting the second portion of the tagged particle subset through the third outlet, in parallel with diverting the first portion of the tagged particle subset through the first outlet, and wherein the first and the third outlets flank the second outlet. 
     
     
         9 . The method of  claim 8 , wherein diverting the first portion of the tagged particle subset includes allowing the magnetic field to repel the first portion of the tagged particle subset towards the first outlet, and wherein diverting the second portion of the tagged particle subset includes allowing the magnetic field to attract the second portion of the tagged particle subset towards the third outlet. 
     
     
         10 . The method of  claim 1 , wherein passing the sample through the magnetic conduit includes:
 capturing a first portion of the tagged particle subset at a first surface of the magnetic conduit with the magnetic field, thereby forming a first sorted group; and   allowing the untagged particle subset to flow through an outlet of the magnetic conduit, thereby forming a second sorted group.   
     
     
         11 . The method of  claim 10 , wherein capturing the first portion of the tagged particle subset includes allowing the magnetic field to repel the first portion of the tagged particle subset toward the first surface. 
     
     
         12 . The method of  claim 10 , further including capturing a second portion of the tagged particle subset at a second surface of the magnetic conduit with the magnetic field, thereby forming a third sorted group. 
     
     
         13 . The method of  claim 12 , wherein capturing the first and the second portion of the tagged particle subset includes capturing at a serpentine-shaped sorting region of the magnetic conduit including the first surface configured to immobilize the first portion of the tagged particle subset by the magnetic field and allow passage of the untagged particle subset, and the second surface configured to immobilize the second portion of the tagged particle subset by the magnetic field and allow passage of the untagged particle subset, wherein the first surface and the second surface are coupled by a channel not within the magnetic field, that angularly displaces flow passing the first surface toward the second surface. 
     
     
         14 . The method of  claim 13 , further comprising mixing the sample with a second solution of magnetic tagging agents that selectively bind to particles of at least one of the set of sample particle types, wherein mixing the second solution of tagging agents is performed downstream of mixing the first solution of tagging agents and upstream of capturing the second portion of the tagged particle subset. 
     
     
         15 . The method of  claim 12 , wherein capturing the first portion of the tagged particle subset includes allowing the magnetic field to repel the first portion of the tagged particle subset towards the first surface and wherein capturing the second portion of the tagged particle subset includes allowing the magnetic field to attract the second portion of the tagged particle subset towards the second surface. 
     
     
         16 . The method of  claim 12 , further comprising removing a first part of the magnetic field to release the first portion of the tagged particle subset out of the magnetic conduit and removing a second part of the magnetic field to release the second portion of the tagged particle subset out of the magnetic conduit, wherein removing includes adjusting the magnetic field by way of at least one of a group of magnets and an electromagnet. 
     
     
         17 . The method of  claim 16 , wherein removing the second part of the magnetic field is performed before removing the first part of the magnetic field. 
     
     
         18 . The method of  claim 1 , further comprising lysing at least one untargeted sample particle with a lytic solution, at the tagging conduit, that selectively lyses particles of at least one of the set of sample particle types to release an intracellular particle subset, and wherein the intracellular particle subset is sorted at the magnetic conduit by way of the magnetic field. 
     
     
         19 . The method of  claim 1 , further comprising capturing particles of at least one of the set of sample particle types, including passing the sample through a chamber fluidly coupled to the tagging conduit and having a surface with capture particles that selectively bind to and capture at least one of the set of sample particle types according to immunoaffinity-based capture. 
     
     
         20 . The method of  claim 1 , wherein at least some of the particles in the sample are cells having cell membranes, and wherein the method further comprises: producing fixed cell membranes of at least a subset of cells in the sample with a fixation solution; and permeabilizing at least some of the fixed cell membranes with a permeabilization solution to facilitate access of intracellular particles; wherein mixing includes binding a first tagging agent to an intracellular particle through a fixed cell membrane. 
     
     
         21 . The method of  claim 20 , wherein mixing further includes binding a second tagging agent to an extracellular particle.