Classifications

• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
  • B01D—SEPARATION
  • B01D63/00—Apparatus in general for separation processes using semi-permeable membranes
  • B01D63/02—Hollow fibre modules
  • B01D63/021—Manufacturing thereof
  • B01D63/0233—Manufacturing thereof forming the bundle
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
  • B01D—SEPARATION
  • B01D61/00—Processes of separation using semi-permeable membranes, e.g. dialysis, osmosis or ultrafiltration; Apparatus, accessories or auxiliary operations specially adapted therefor
  • B01D61/14—Ultrafiltration; Microfiltration
  • B01D61/18—Apparatus therefor
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
  • B01D—SEPARATION
  • B01D63/00—Apparatus in general for separation processes using semi-permeable membranes
  • B01D63/02—Hollow fibre modules
  • B01D63/024—Hollow fibre modules with a single potted end
  • B01D63/0241—Hollow fibre modules with a single potted end being U-shaped
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
  • B01D—SEPARATION
  • B01D63/00—Apparatus in general for separation processes using semi-permeable membranes
  • B01D63/02—Hollow fibre modules
  • B01D63/04—Hollow fibre modules comprising multiple hollow fibre assemblies
• • G—PHYSICS
  • G01—MEASURING; TESTING
  • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
  • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
  • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
  • G01N33/483—Physical analysis of biological material
  • G01N33/487—Physical analysis of biological material of liquid biological material
  • G01N33/49—Blood
  • G01N33/491—Blood by separating the blood components
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
  • B01D—SEPARATION
  • B01D2313/00—Details relating to membrane modules or apparatus
  • B01D2313/16—Specific vents

Definitions

• This invention generally relates to a disposable fil ⁇ ter comprising a bundle of hollow fibres arranged in a housing having an inlet for a particle-laden volume of liquid to be filtered, as well as an outlet or a collect ⁇ ing chamber for the permeate, said inlet communicating with the interior of the hollow fibres, and said outlet or collecting chamber communicating with the exterior there- of.
• the invention particularly concerns such a disposable filter for separating blood cells from whole blood.
• the invention generally relates to a separation method for removing small particles from a restricted volume of liquid. More precisely, the invention concerns a separation method for removing particles, such as cells, from a particle-laden volume of liquid by means of a fil ⁇ ter comprising a bundle of hollow fibres arranged in a housing having an inlet for said liquid, as well as an outlet or a collecting chamber for the permeate, the total area of said hollow fibres being dimensioned for maximum exploitation the once the disposable filter is used, said inlet communicating with the interior of the hollow fibres, and said outlet or collecting chamber communicat ⁇ ing with the exterior thereof, a pressure difference being generated between the interior and the exterior of said fibres when the volume of liquid is supplied to the fil ⁇ ter, thus increasing the yield of permeate and reducing the filtering time.
• a separation method for removing particles, such as cells from a particle-laden volume of liquid by means of a fil ⁇ ter comprising a bundle of hollow fibres arranged in a housing having an inlet for said liquid,
• the invention particularly concerns such a method for separating blood cells from whole blood.
• One prior art separation technique is filtering, by which relatively large, non- elastic particles are effectively removed.
• prior art filtering techniques for separating small, elastic particles are not up to the mark as to single use and restricted volumes of liquid.
• the present invention aims at providing a sepa ⁇ ration method and a device for implementing this method, both using a hollow-fibre filter and meeting the following requirements.
• the filter should be disposable and therefore inexpensive, which necessitates simplicity of construc ⁇ tion.
• the filter should be compact for easy manual handling.
• the filtering time should be very short, for example some ten seconds.
• the filter should give a high yield, i.e. as much permeate as possible, especially when the volumes of liquid are small.
• the yield should be at least 25%, as based on the volume of the liquid to be filtered.
• the filtering time mentioned above is the time needed for obtaining such a high yield.
• the particles to be removed must not be decomposed during filtering, since this would entail that parts of the particles might pass the filter.
• the permeate should allow a sufficiently accurate quantitative analysis.
• the concentrations of different substances in the permeate should essentially correspond to the concentrations in the original particle- laden liquid, the particle content thereof excluded.
• the prior art embraces a multitude of differently designed filters using one or more hollow fibres. These filters are either continuous, in which case they are, for obvious reasons, unsuitable for the purpose of this inven ⁇ tion, or disposable filters.
• EP-A-0,315,252 discloses a disposable filter comprising hollow fibres.
• the liquid to be filtered is passed over the exterior of a hollow fibre which, to enable a sufficient yield, must be surrounded by a tube or the like, to produce a feed chan ⁇ nel which is narrow enough.
• This construction unavoidably becomes very complicated if a large number of hollow fibres are used in order to obtain the large filter sur ⁇ face necessary for producing a considerable yield in a short time. Further, this filter is only suited for quali ⁇ tative analysis of the different components of the per ⁇ meate.
• DE-Al-3,608,062 also discloses a disposable filter with a single hollow fibre. This filter is comparable with that of EP-A-0,315,252.
• a disposable filter of the type mentioned in the introduction to this specification characterised in that the filter is hermetically sealed before use, and that the moisture content of said hollow fibres is lower than about 0.1%, preferably lower than about 0.05%.
• This filter can be made compact and, by suitable dimensioning of the hollow fibres, be given a total fil ⁇ tering area so as to obtain the desired yield and fil- tering time, while avoiding particle decomposition. Especially, this filter enables quantitative analysis owing to the very low moisture content, i.e. the low liquid content.
• conven ⁇ tional hollow fibres regarded as dry have a moisture con- tent which, when the fibres are used in a disposable fil ⁇ ter for filtering relatively small volumes of liquid, have a diluting effect on the permeate, causing a quantitative analysis thereof to give incorrect results as to the concentrations of analysed substances in the original volume of liquid.
• the hollow fibres used in filters normally have a quite significant moisture content in order to prevent damage to the hollow fibres and enable rapid start of the filtering operation, which usually requires wetting of the hollow fibre proper.
• the low mois ⁇ ture content according to the invention does not, however, cause any damage to the hollow fibres since the fibres are not dried until after having been mounted in the filter.
• Tests on hollow fibres consisting of cellulose ace- tate and having a moisture content of 2% (glycerol in aqueous solution) gave the following results when whole blood to which iodine had been added was used as testing liquid and permeate samples were taken at regular inter ⁇ vals of 30 sec. Samples Iodine (mg/ml)
• fibres of hydrophilic material are preferred since the filtering time otherwise tends to be too long.
• a hydrophilic material such as polysulfone, is wet through in 30 sec, and a very hydrophilic material, e.g. polyvinyl alcohol, is wet through in 15-20 sec.
• the cross-sectional area of the pores of the hollow fibres increases from the interior of the fibres to the exterior, because such pores give, at a certain pressure difference across the fibre wall, the desired yield in a shorter time than pores of a substantially constant cross- sectional area corresponding to the smallest cross-sec ⁇ tional area of the pores preferred according to the inven ⁇ tion.
• this .property may be used for lower ⁇ ing the pressure difference, thereby reducing the risk of decomposition of the particles in the liquid to be fil- tered.
• the dis ⁇ posable filter comprises a chamber for collecting the residue, said chamber communicating with the interior of the hollow fibres furthest away from the inlet in the lon- gitudinal direction of said fibres.
• this chamber is vented by means of at least one hollow fibre not used for the filtering.
• this residue-collecting chamber is formed of a part of the inner volume of the hollow fibres situated furthest away from the inlet in the longitudinal direction of said fibres.
• the interior surface of the hollow fibres is treated to reduce the friction against the particles of the liquid and/or to increase biocompatibility.
• the largest pore openings on the inside of the fibres should be smaller than about 1/5, preferably 1/10, of the size of the smallest particles to be removed from the liquid.
• the space between and around the hollow fibres in the housing may, to reduce the filtering time, be filled with a hydrophobic material, e.g. microspheres, permitting the passage of liquid.
• a hydrophobic material e.g. microspheres
• the disposable filter and the method according to the invention are particularly suited for separating blood corpuscles from whole blood, i.e producing blood plasma as permeate.
• Blood plasma which comprises all the components of whole blood, with the exception of the red and white blood corpuscles, is today an important source for determining the health of humans and animals.
• Large-scale plasma separation is used in biochemical technique, and is of great importance in the medical service.
• small sample volumes of plasma (0.001-5.0 ml) are generally desired, since this reduces the strain on the patient and involves a lower consumption of reagent for analysis.
• plasma is separated from whole blood mainly by centrifug- ing, which is a laborious and time-consuming procedure.
• the invention is particularly suitable for separating blood plasma from whole blood, the requisite pressure difference being in the range of 0.05-0.5 bar, preferably 0.1-0.3 bar, it is by no means restricted to this application, but may be used for many other purposes, especially in medicine, chemistry, microbiology, micrology and biochemistry.
• the pressure difference is, at least part ⁇ ly, generated by producing a negative pressure in the housing before the liquid is supplied, by manually apply ⁇ ing a positive pressure to the inlet, and/or by applying a negative pressure to the outlet.
• the disposable filter may be equipped with a pressure relief valve ensur ⁇ ing the necessary restriction of the pressure difference.
• the inlet of the filter may have a throttle restricting the flow rate through the inlet, thereby indi ⁇ rectly restricting the pressure difference.
• the maximum pressure difference allowed depends on the ratio of the size of the smallest particles to be separated, to the size of the pore openings on the interior side of the hollow fibres.
• the particles may be elastic, which makes the smallest diameter variable, is also of importance, as is the fact that the pores may have a constant cross-sectional area or a cross-sectional area increasing towards the exterior of the hollow fibres.
• FIG. 1 is a side view showing a partly cut open first embodiment of a disposable filter according to the inven ⁇ tion
• Fig. 2A is a longitudinal section
• Fig. 2B a cross-section of a second embodiment of a disposable fil ⁇ ter according to the invention
• Fig. 3 is a schematic, much enlarged longitudinal section of a hollow fibre of the type used in the inven ⁇ tive disposable filter.
• Fig. 1 comprises a housing 1 made up of a cylindrical sleeve 2 whose upper end is closed by an inlet lid 3 with an inlet tube 4 and whose lower end is closed by a residue lid 5.
• a housing 1 made up of a cylindrical sleeve 2 whose upper end is closed by an inlet lid 3 with an inlet tube 4 and whose lower end is closed by a residue lid 5.
• an outlet tube 6 is fitted on the sleeve 2.
• a bundle of hol ⁇ low fibres 7 extend axially through the sleeve 2 and are, at the upper sleeve end, fitted into a sealing plug 8 in such a manner that the inlet tube communicates with the interior of the fibres, at the upper end thereof.
• the lower ends of the hollow fibres 7 are fitted into a second sealing plug 9 provided at the lower end of the sleeve 2, in such a manner that a residue chamber 10 formed between the sealing plug 9 and the bottom of the residue lid 5 communicates with the interior of the hollow fibres, at the lower end thereof.
• the outlet tube 6 communicates with the space around the hollow fibres 7 inside the sleeve 2.
• the total filter area of the hollow fibres is dimensioned such that a major part of the maximum permeate volume available can be obtained when the liquid flows once along the entire length of the hollow fibres, so that the filter can be discarded after a single use.
• At least one hollow fibre 7' is closed at its upper end, and the interior of this fibre 7' thus does not com- municate with the inlet tube 4, but with the residue cham ⁇ ber 10 for venting of the latter.
• a pressure difference is generated between the inlet 4 and the outlet 6.
• This may be achieved in diffe ⁇ rent ways, for example by manually applying a positive pressure to the inlet, by applying a negative pressure to the outlet, for instance by means of a so-called vacu- tainer, and/or by generating a negative pressure in the housing 1 before the liquid is supplied.
• the liquid will flow axially through the interior of the hollow fibres 7 from the inlet tube 4 towards the residue chamber 10.
• Figs 2A and 2B mainly differs from that of Fig. 1 in that the bundle of hollow fibres 7 is doubled, so that all the fibre ends are fitted into one and the same sealing plug 11.
• the housing 1' is formed of a cylindrical sleeve 2' whose one end is closed with the exception of an outlet tube 6' and whose other end is closed by an inlet lid 3' .
• a partition 12 is arranged in such a manner that one end of the hollow fibres 7 is situated on one side of the partition 12, and the other end of the hollow fibres 7 is situated on the other side of this partition.
• the inlet lid 3' is equipped with an inlet tube 4 1 .
• the embodiment of Fig. 2 comprises at least one hollow fibre 7' which is closed at the end facing the inlet tube 4' .
• a residue chamber 10' is formed between the inlet lid 3' and the sealing plug 11, on the side of the partition 12 where the inlet tube 4' is not arranged.
• a vent tube 13; 13' is suitably connected to the upper part of the sleeve 2; 2'.
• the tube 13; 13' is equipped with a nonreturn valve permitting nothing but air to leave the housing 1; 1' .
• the cross-section in Fig. 3 of a hollow fibre 7 illustrates the filtering procedure in a disposable fil ⁇ ter according to the invention.
• the total filter area of the hollow fibres 7 should be 10-100 cm 2/ml of whole blood, preferably 20-80 cm2/ml.
• the hollow fibres should have an internal diameter of 0.10-0.40 mm, preferably 0.15-0.30 mm, and a wall thick ⁇ ness of 0.001-0.150 mm, preferably 0.050-0.100 mm. More ⁇ over, the size of the fibre pores on the surface commu ⁇ nicating with the inlet should be 0.05-0.7 ⁇ m, prefer ⁇ ably 0.1-0.3 ⁇ m, and the porosity should be 60-95%. These values have been established in view of the fact that the red and white blood corpuscles constitute about 45% by volume of whole blood. Generally speaking, the invention is especially suitable for liquids in which the particles to be removed make up at least about 10% by volume of the total liquid. This requires a filter area of 5-100 cm 2/ml of liquid, preferably 15-50 cm2/ml of liquid.
• the smallest opening area of the pores 14 in the fibre walls should be situated closest to the surface communicating with the inlet, i.e. closest to the interior of the hollow fibres 7.
• the yield i.e. the relative proportion of the liquid that rid of particles passes through the fibre walls, is at its largest at the beginning of the procedure.
• the yield decreases as a result of the increasing con ⁇ centration of particles closest to the interior of the fibre walls, and the clogging of some of the pores 14. This also augments the risk of particles decomposing owing to contact with or friction against the interior of the fibre walls, which may aggravate the clogging of the pores 14, but also lead to the presence of parts of particles in the permeate, which is highly undesirable.
• the contact with or the friction against the inside of the hollow fibre 7 involves the risk of hemolysis.
• this risk is considerably reduced in that the inside of the fibre 7 is made biocompatible, e.g. by heparinisation or sulphating.
• the heparinisation or sulfating thus contributes to increase the flow through the fibre walls, thereby aug- menting the yield and/or reducing the filtering time required.
• Suitable fibre materials include polypropylene, poly ⁇ vinyl alcohol, cellulose acetate, polyamide, polysulfone, polyacrylonitrile, and fluorinated polymers.
• the dead volume in the housing i.e. the difference between the total inner volume of the housing and the volume of the hollow fibres in the housing, is as small as possible.
• the dead volume can be reduced by filling the space between and around the hollow fibres in the housing with a hydrophobic material permitting the passage of liquid.
• a material suitably consists of glass microspheres having a diameter in the order of e.g. 200-500 ⁇ m.
• the dead volume can be reduced to e.g. 10-30% of the total inner volume of the housing.
• the hollow fibres in an inventive disposable filter will take up at least 65% of the internal cross- sectional area of the housing; including the microspheres about 90% will be taken up.
• Figs 1 and 2A which only show a few fibres, are very schematic, and in actual practice the fibres are packed quite close together.
• the outlet may communicate with a per- meate-collecting chamber joined to the filter.
• the outlet 6' may even be left out, and the sleeve 2' may also form a permeate-collecting chamber.
• the sleeve 2' is extended downwards, beyond the lowermost parts of the hollow fibres 7, 7' to form a permeate-collecting chamber entirely or partly separated from the space taken up by the hollow fibres.
• the subsequent analysis of the permeate may, in some applications, be carried out without removing the chamber from the filter.
• the permeate chamber may be a known spectrophotometric cuvette. Chemical sub ⁇ stances, e.g. colour reagents and/or enzymes, reagent strips or the like, may be provided in advance in the cuvette, thus enabling direct analysis of the filtrate without further handling thereof.
• the inlet may be integrated or otherwise connected with a hypodermic needle.
• the different inlets and outlets of the filter may initially be closed by, for instance, a membrane which can be penetrated by e.g. a hypodermic needle.
• a membrane which can be penetrated by e.g. a hypodermic needle.
• other closing means are conceiv- able, albeit not shown in the embodiments described which, by the way, do not comprise any means for restricting the pressure difference across the fibre walls. However, such means are obvious to the expert.

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• Engineering & Computer Science (AREA)
• Chemical & Material Sciences (AREA)
• Chemical Kinetics & Catalysis (AREA)
• Health & Medical Sciences (AREA)
• Life Sciences & Earth Sciences (AREA)
• Biomedical Technology (AREA)
• Physics & Mathematics (AREA)
• Manufacturing & Machinery (AREA)
• Hematology (AREA)
• Water Supply & Treatment (AREA)
• Medicinal Chemistry (AREA)
• Biophysics (AREA)
• Molecular Biology (AREA)
• Urology & Nephrology (AREA)
• Food Science & Technology (AREA)
• Ecology (AREA)
• Analytical Chemistry (AREA)
• Biochemistry (AREA)
• General Health & Medical Sciences (AREA)
• General Physics & Mathematics (AREA)
• Immunology (AREA)
• Pathology (AREA)
• Separation Using Semi-Permeable Membranes (AREA)

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Cited By (13)

Citations (7)

• 1989
  • 1989-12-07 SE SE8904133A patent/SE465355B/sv not_active IP Right Cessation
• 1990
  • 1990-12-07 WO PCT/SE1990/000811 patent/WO1991008782A1/en unknown
  • 1990-12-07 AU AU69553/91A patent/AU6955391A/en not_active Abandoned

Patent Citations (7)

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