Patent Publication Number: US-2016243548-A1

Title: Microfluidics sorter for cell detection and isolation

Description:
CROSS-REFERENCE TO RELATED APPLICATIONS 
     This U.S. non-provisional patent application is a U.S. national stage application, which was filed on Apr. 15, 2016 under 35 U.S.C. §371 and claims priority to PCT Patent Application No. PCT/SG2014/000487, which was filed on Oct. 16, 2014, and claims priority to Singapore Patent Application No. SG201307805-0, which was filed on Oct. 16, 2013. The contents of PCT Patent Application No. PCT/SG2014/000487 and Singapore Patent Application No. SG201307805-0 are incorporated herein by reference in their entirety. 
    
    
     FIELD 
     The invention relates to an interface for use with a microfluidic device. 
     BACKGROUND 
     Microfluidics based systems have evolved from being fabricated using glass/silicon to polymers. The polymer fabrication methods have replaced techniques borrowed from the microelectronics industry (MEMS), making their manufacturing simpler and cheaper. The biocompatibility of polymers makes them an attractive choice of material for lab-on-a-chip (LOC) or point-of-care (POC) devices for many diagnostics applications. Polydimethylsiloxane (PDMS), a soft rubber like polymer, has emerged as a popular material in research and academia to fabricate/manufacture microfluidics devices over traditional hard plastics such as, for example, polycarbonate (PC), poly methyl methacrylate (PMMA), polypropylene (PP), and polystyrene. A PDMS based microfluidic chip is appropriate for manual machining mainly due to low cost of manufacture. PDMS also has excellent optical, mechanical and chemical properties. Moreover, PDMS has high repeatability and accuracy over injection moulding, which also makes it a desirable material for the mass fabrication of the microfluidic chip with micro to sub-micro patterns that require high dimensional accuracy. 
     However, as microfluidics based devices have been rapidly developed over the last decade, interconnects to interface these devices with macro-world such as, for example, syringes, syringe pumps, pressure pumps, and the like still remains a technical challenge. Also, interconnects do not readily scale and often make the device bulky. This coupled with the pliant nature of PDMS makes this issue extremely challenging. The small size of the microfluidic devices typically warrants a custom solution and there is usually no ‘one size fits all’ packaging scheme for PDMS based devices. Unlike integrated circuits (IC) chips, there are no standards for microfluidics device packaging. 
     In this regard, PDMS is typically not the desired material when transitioning a microfluidic device from lab to commercial form. The pliant characteristics of PDMS make compression based clamping extremely difficult to achieve leak proof seals. Plastic chips made of hard material are typically preferred when evolving a lab set-up to an automated instrument with integrated fluid delivery modules. This is because it is easier to interface the hard plastic chips with fluid delivery instruments compared to a PDMS microfluidic chip. However, investment in time and money for production of hard plastic chips is substantial and this has usually been a barrier to successful microfluidic chip commercialization. Clearly, there is an issue when transitioning a microfluidic device transitions from lab to commercial form. 
     SUMMARY 
     In general terms the invention proposes a non deformable interface for a deformable microfluidic chip. This may have the advantage that the ports in the interface can be made tight tolerance and can be made to easily mate with the loose tolerance ports on the chip during manufacturing. The tight tolerance interface ports may therefore be able to easily mate with a fluid delivery platform and/or using a compression seal. 
     In a specific expression of the invention there is provided an interface comprising:
         a plurality of external ports configured to fluidically communicate with a plurality of ports of a fluidic delivery platform; and   a plurality of engaging conduits configured to fluidically communicate with a plurality of ports of a microfluidic biochip,   wherein a tolerance of both the plurality of external ports and/or the plurality of engaging conduits is significantly tighter than a tolerance of the plurality of ports of the microfluidic biochip.       

     Embodiments may be implemented according to any of claims  2  to  16 . 
    
    
     
       DESCRIPTION OF FIGURES 
       In order that the present invention may be fully understood and readily put into practical effect, there shall now be described by way of non-limitative example only preferred embodiments of the present invention, the description being with reference to the accompanying illustrative figures. 
         FIG. 1  shows a first perspective view of an interface of an example embodiment. 
         FIG. 2  shows a first photograph of the interface. 
         FIG. 3  shows a second perspective view of the interface. 
         FIG. 4  shows a second photograph of the interface. 
         FIG. 5  shows a front view of a cover usable with the interface. 
         FIG. 6  shows a photograph of the cover. 
         FIG. 7  shows a photograph of the cover and the interface laid side-by-side. 
         FIG. 8  shows a photograph of the cover and the interface from an opposite side to the view shown in  FIG. 7 . 
         FIG. 9  shows a photograph of a manifold set-up for assessing the interface. 
         FIG. 10  shows a schematic view for a pressure test set-up. 
         FIG. 11  shows a photograph of the pressure test set-up of  FIG. 10 . 
         FIGS. 12( a ) to ( d )  show a sequence of images for coupling the interface with a biochip. 
         FIG. 13  shows a photograph of the interface undergoing compression. 
         FIG. 14  shows a section view of the interface coupled to a manifold of the fluid delivery platform, with the interface undergoing compression. 
     
    
    
     DETAILED DESCRIPTION 
     Embodiments may provide an interface with ports that allows a PDMS based microfluidic device to interface readily and reliably with a fluidic delivery platform. The interface is able to overcome issues which arise whenever a fluidic delivery platform is required to interface with a PDMS based microfluidic device. Consequently, the interface may serve as a basis for a variety of economical solutions involving microfluidic devices. 
     Referring to  FIGS. 1 to 8 , there is provided various views of an interface  20  with ports, showing either illustrations or photographs of respective components/portions of the interface  20 . The interface  20  comprises a plurality of external ports  22  configured to fluidically communicate with a plurality of ports of a fluidic delivery platform (not shown). Specifically, the plurality of external ports  22  typically interfaces with a manifold on an instrument integrated with the fluidic delivery platform, such as, for example, pressure pumps, syringe pumps, and so forth. Each of the plurality of external ports  22  includes a recess  24  configured for affixing an o-ring  26 . Alternatively, gaskets, washers or similar objects are used to provide a leak proof seal while under compression. The o-rings  26  are used for providing a seal with the manifold. The diameter/depth of the recess is approximately 0.2-0.6 mm smaller than an outer diameter of the o-rings  26  to ensure that the o-rings are able to sit within the each recess  24  tightly. The interface  20  also includes at least one receptor  34  at an outer surface  36  for aligning the interface  20  with the manifold of the fluidic delivery platform. 
     The interface  20  also comprises a plurality of engaging conduits  28  which are configured to fluidically communicate with a plurality of ports of a microfluidic biochip  50 . Each of the plurality of engaging conduits  28  is of a frusto-conical shape and each engaging conduit  28  is co-axial with an external port  22 . Each external port  22  is configured to fluidically communicate with each co-axial engaging conduit  28 . The external ports  22  provide through-hole access to the engaging conduits  28  within the interface  20 . These external ports  22  align with ports on the manifold of the fluid delivery platform (specifically an instrument integrated with the fluid delivery platform), fluidically connecting the microfluidic biochip  50  with the fluid delivery platform. The fluid can be any liquid or gas being pumped into the microfluidic biochip  50 . It is possible that the fluid is a biological sample such as, for example, blood, saliva, pleural effusion, urine, and so forth being pumped into the microfluidic chip  50  for diagnostic applications. 
     Each of the plurality of engaging conduits  28  mates with each of the plurality of ports of the microfluidic biochip  50  to provide a leak-proof seal.  FIG. 12  shows the external port  22  and the engaging conduit  28  sharing a channel  25  of uniform diameter. However, the diameters of the external port  22  and the engaging conduit  28  can be different so long as flow rates are kept moderate (eg:, 0.01 to 5 ml/min) to avoid turbulent flow. Also keeping the diameters of the external port  22  and the engaging conduit  28  relatively uniform avoids a high shear environment which can damage cells. An open end  29  of the engaging conduit  28  has a smaller diameter compared to an interface end  27 . The plurality of ports  49  of the microfluidic biochip  50  are distorted due to shrinkage of material during the curing process. During engagement, the open end  29  forces the deformable ports  49  to mate and provide a leak-proof seal against the interface end  27  as shown in  FIGS. 12( a )-( d ) . 
     Since the microfluidic biochip  50  is typically made from PDMS, each of the plurality of ports  49  of the microfluidic biochip  50  can be fitted to (mates with) each of the plurality of engaging conduits  28  to provide the leak-proof seal when the microfluidic biochip is aligned in an appropriate manner with the interface  20  as shown in  FIG. 8 . 
     The microfluidic biochip  50  can have varying dimensions (thickness, width, breadth). It should be appreciated that the external surfaces of the four engaging conduits  28  may also act as alignment features for the microfluidic biochip  50 . A depth of insertion (depth of each engaging conduit  28  being inserted into each port  49  of the chip  50 ) when fitting (mating) the plurality of ports  49  of the microfluidic biochip  50  to the engaging conduits  28  is determined by a thickness of the PDMS mould and a height of the interface  20 . 
     The desired range of the inclination angles of each engaging conduit  28  is between 0° to 15°. Each engaging conduit  28  has a frusto-conical shape with the open end  29  having an external diameter of between 0.1 mm to 1 mm smaller that a diameter of the ports  49 . Each engaging conduit  28  is mated to the ports  49  such that they are inserted to between 50 to 90% of the thickness of the microfluidic biochip  50 . The interface end  27  external diameter of each engaging conduit  28  is between 0.2 mm to 1.5 mm larger than the diameter of the ports  49  to ensure good compression seal between the engaging conduits  28  and the ports  49 . 
     It should be appreciated that connection of the plurality of external ports  22  to the manifold is more easily carried out compared to mating of the plurality of engaging conduits  28  to the microfluidic biochip  50 . This is due primarily to the micro dimensions and flexibility of the ports  49  of the microfluidic biochip  50  which leads to greater difficulty when mating to the plurality of engaging conduits  28  of the interface  20 . The positions of the plurality of external ports  22  and the plurality of engaging conduits  28  are fixed on the interface  20 . Given that the ports  49  of the microfluidic biochip  50  are flexible, the ports  49  of the microfluidic biochip  50  are able to mate with and be secured to the affixed plurality of engaging conduits  28  to ensure that the interface  20  can be used to enable fluidic communication between the fluid delivery platform and the microfluidic biochip  50 . In this regard, a tolerance (in relation to the physical configuration) of both the plurality of external ports  22  and the plurality of engaging conduits  28  is significantly tighter (more accurate or dependable) than a tolerance (in relation to the physical configuration) of the plurality of ports  49  of the microfluidic biochip  50  (more prone to deformation due to curing). Thus the high variance of the plurality of ports  49  may be accommodated due to the tight tolerance of the external ports  22  and engaging conduits  28 . The tolerance of the PDMS thickness is ±0.5 mm. Due to the 2 to 5% shrinkage of the PDMS during the curing process, the tolerance of the plurality of the ports can also reach ±0.5 mm. The interface  20 , dimensional tolerance can be controlled to within ±0.1 mm in all the directions depending on the moulding technique and material used. 
     The interface  20  is fabricated from a hard plastic such as, for example, PC, PMMA, PVC, HDPE, LDPE, PS, PP and the like. The interface  20  can be readily manufactured using economical and scalable processes such as, for example, injection moulding or other plastic moulding techniques. The interface  20  is non-deformable and also includes a plurality of rib structures  30  at an inner surface  32  of the interface  20 . The plurality of rib structures  30  at the inner surface  32  provide structural rigidity and prevent the interface  20  from collapsing and consequently damaging the attached microfluidic biochip  50  when undergoing high compression loads. This is essential as a high compression load is necessary to achieve a good seal between the interface  20  and the microfluidic chip  50 . Without the interface  20 , it would be very challenging to apply a constant load to the microfluidic chip  50  without occurrence of significant deformation and damage to the microfluidic chip  50 . 
     Once the microfluidic chip  50  is mated to the interface  20 , the interface  20  subsequently sealed with a cover  60  (which is shown in  FIGS. 5 and 6 ). During assembly, the microfluidic chip  50  is manually aligned approximately to the plurality of engaging conduits  28  as shown in  FIG. 12( a ) . Then the chip  50  is pressed onto the engaging conduits  28  so that the deformable ports  49  are forced to mate as shown in  FIG. 12( b ) . Finally the cover  60  is then closed to secure the microfluidic chip  50  as shown in  FIG. 12( c ) . The cover  60  is able to be permanently secured (locked) to the interface  20  using at least one tamper-proof lock  62  integrated with the cover  60 . This will ensure reliability and prevent reuse. Depending on the thickness of the chip  50 , it is possible it may be suspended within the cover  60  from the compression fit to the engaging conduits  28 . As such the interface  20  can be a standard size to accommodate a range of different models of chip  50 . For higher pressure applications, it may be designed to press against the bottom of the inside of cover  60  to ensure the seal is not forced apart during use. 
       FIGS. 12( d ) ,  13  and  14  shows the interface  20  undergoing compression coupled to a manifold  10  of the fluid delivery platform. The o-rings  26  are compressed and thus provide a high reliability seal form the manifold  10  to the microfluidic chip  50 . 
     Testing is carried out to determine a maximum pressure that the interface  20  can withstand. A manifold  99  was fabricated using aluminum (as shown in  FIG. 9 ) to simulate typical interfacing of a microfluidic based automated system. The manifold  99  is connected to a primary syringe  100  and a pressure meter  120  during testing, as shown schematically in  FIG. 10 . The actual set-up is shown in  FIG. 11 . The primary syringe  100  filled with air drives a plunger of a secondary syringe (with adaptor assembly)  110  filled with water. The pressure in the secondary syringe  110  is allowed to build up. The pressure meter  120  which is able to measure up to 200 kPa is connected using a 3-way T-junction to measure the built-up pressure in the secondary syringe  110 . During testing, with a load of 30 N being applied to the manifold  99 , the primary syringe  100  is allowed to pump at 10 ml/min and the pressure of the system is monitored. The primary syringe  100  also has a maximum pressure rating of 200 kPa after which it stalls in operation returning an error state. The interface  20  is shown to be successfully able to withstand up to 200 kPa of pressure for at least  15  min using the aforementioned set-up. The test set-up may be for both testing proof of concept and quality control of the interface  20  during manufacturing/assembly. 
     It is appreciated that the interface  20  may provide one or more advantages: 
     - Able to provide a blockage-free seal which is typically prevalent in adhesive/glue based alternatives; 
     - Low cost since the interface  20  can be made from economical processes and materials; 
     - Repeatability since the interface  20  is able to sufficiently protect the microfluidic biochip  50  which is mated to the interface  20 ; 
     - Low dead volume—important when working with low sample volumes and expensive reagents since wastage of the aforementioned liquids is minimized when using the interface  20 ; 
     - Able to withstand high pressure of approximately  200  kPa which ensures a good seal between the interface  20  and the microfluidic chip  50 ; and 
     - Scalable manufacturing due to the low cost of production. 
     Whilst there have been described in the foregoing description preferred embodiments of the present invention, it will be understood by those skilled in the technology concerned that many variations or modifications in details of design or construction may be made without departing from the present invention.