Abstract:
A method for making a laminated carrier film for use in releasing interstitial fluid from skin for collection or measurement includes providing a printhead having an orifice and a reservoir containing a meltable absorber substance, the printhead being capable in response to electrical signals, to eject droplets of said meltable absorber substance from the orifice; supporting a carrier film having a series of spaced apart openings for a meltable absorber substance on a support base, in close proximity to the printhead, whereby the spaced apart openings on the carrier film can be positioned relative to the orifice to receive absorber substance droplets ejected from the printhead; filling the spaced apart openings of the carrier film with meltable absorber substance ejected from the printhead; and covering the carrier film on one side with a clear polymer film strip selected to allow laser energy to pass through the clear polymer film in order to reach the meltable absorber substance inside the openings.

Description:
This application is a divisional of U.S. Ser. No. 09/567,915, filed May 10, 2000, and now U.S. Pat. No. 6,334,851 which is a continuing application from U.S. Provisional application serial No. 60/133,360, filed May 10, 1999 for which benefit is claimed under 35 U.S.C. §119(e). 
    
    
     TECHNICAL FIELD OF THE INVENTION 
     The invention lies in the filed of medical diagnostic procedures and devices. 
     BACKGROUND OF THE INVENTION 
     There is a need for obtaining small samples of human interstitial fluid from the skin for the purpose of analyzing this fluid for biologically relevant molecules and electrolytes that may be found therein. More particularly, there is a need for carrying out the process of releasing and collecting the interstitial fluid for glucose measurements which is useful for diabetics. The most common current techniques for obtaining body fluid for glucose measurements is done by pricking the skin with a sharp object to create a small drop of blood. This sample can then be collected and analyzed in a test kit to determine the glucose contents. The process of pricking the skin to produce fluid samples is obviously undesirable because of the pain it creates. It would be desirable to have a more painless method of collecting and releasing interstitial fluid for this and other purposes. 
     A method of making a carrier film is disclosed. A carrier film base member with spaced openings is supported on a flat support and loaded with meltable absorber substance from a digitally operated heated printhead of the type used for “jetting” materials, similar to an ink jet for a computer printer. Indexing of the carrier film strip or the printhead sequentially fills the openings with the absorber substance. A cover is preferably adhesively laminated over the openings containing the meltable absorber substance creating a well-like opening that has an open side from which the material will be ejected when activated by a suitable laser beam. Both the cover strip and adhesive are selected to allow the laser beam to be focused on the meltable absorber substance inside the openings. A cover strip may be made in a batch process or, for example, in a reel-to-reel continuous process using flexible film technology. The carrier material is preferably a laminated carrier film although it is conceivable that a blind opening could be produced in a film having the requisite clarity to passage of laser energy in the nature of a blind opening. 
    
    
     BRIEF DESCRIPTION OF THE DRAWINGS 
     FIG. 1 is a side elevational view of the combination of a laser source focusing on a disposable laminated film strip in an area containing meltable absorber substance; 
     FIG. 2 shows the apparatus of FIG. 1 after the meltable absorber substance has been melted by the laser and ejected toward a patient&#39;s skin; 
     FIG. 3 shows how the melted absorber substance of FIG. 2 has impacted and spread on the surface of the patient&#39;s skin; 
     FIG. 4 shows the apparatus of FIGS. 1-3 wherein the strip of laminated polymer film material has been indexed in a horizontal direction to position the film over an aperture for the next step in the process; 
     FIG. 5 illustrates the application of the focused laser beam upon the spot of FIG. 5 whereby thermal heating of the skin surface forms a tiny blister containing interstitial fluid; 
     FIG. 6 illustrates a collection means for collecting the interstitial fluid from the ruptured blister of FIG. 5; 
     FIG. 7 is an elevational view of an automated means of placing the absorbing substance into holes in a sheet or strip of polymer film material containing previously formed openings; 
     FIG. 8 is an elevational view the process of automatically attaching and laminating transparent film to the base film material of FIG. 7 containing the meltable absorber substance. 
     FIG. 9 is a cross sectional view of a prototype opening, containing the meltable absorber substance, which has a nozzle from which the substance is ejected and a gas bubble which enhances ejection. 
    
    
     DETAILED DESCRIPTION OF THE INVENTION 
     FIG. 1 schematically illustrates a set-up for depositing a laser absorbing substance from a disposable film laminate onto the surface of a person&#39;s skin. A laser source  1  is capable of supplying enough energy in a pulse or on/off format to heat a meltable or thermoplastic material selected to absorb the laser energy, which forces the absorber substance out of an opening. The laser source  1  can make a hole into the skin if proper absorption of the laser energy takes place. Laser  1  is focused through a lens  2  capable of focusing a laser energy onto the meltable absorbing substance and the skin surface if positioned properly. A laser beam  3  is focused through lens  2  onto a target  6  comprising a meltable absorber substance formulated to absorb the laser energy. The absorber substance is formulated to contain an appropriate dye or particle filler material, such as carbon black. The laser energy absorbing substance may be a thermoplastic substance, such as a polymer, a thixotropic substance that becomes fluid when heated, a grease-like or wax composition or any other carrier for the absorbing pigment or dye which melts or changes viscosity when irradiated with a suitable laser wave length. The term “meltable” should be considered as including such substances. U.S. Pat. No. 5,092,864 which discussed methods of “jetting” dyes onto tissue for the purpose of increasing laser energy absorption efficiency for tissue welding, tissue cutting, tissue ablation, hole making, etc. is incorporated herein by reference. 
     The meltable absorber substance is contained in a disposable laminate comprising a polymer base material  5  of such a character that uniform holes  20  can be formed into it by means of known processes such as excimer laser ablation, hole punching, photolithography, etc. After the meltable absorber material  6  is placed in an opening  20  in polymer base material  5 , it is covered with a layer of polymer material  4  which is transparent to the laser energy. Polymer material film is selected to have good transmission to laser energy at the specific laser wave length used in laser source  1 . The disposable laminate is shown positioned just above a patient&#39;s skin  8  and contains an opening  7  which comprises an aperture through the laminated film structure for purposes to be described. The skin would be positioned a few millimeters from the film surface. It is to be understood that the figures are elevational views which do not show connecting portions of the film laminate on either side of aperture  7 . In a preferred embodiment, this substrate is a continuous strip which may have continuous side edge portions much like the sprocket tracks on movie film. The term film is meant to include primarily flexible material up to at least a thickness of 0.015 inches. Prototypes have been made where the base substrate layer was actually made from glass microscope slides which are only slightly flexible. 
     FIG. 2 illustrates the droplet ejection process of the apparatus found in FIG.  1 . The laser  1  is placed over the carrier film  4  and  5 . The beam  3  the laser produces is focused through a lens  2  onto meltable absorber substance  6  selected to absorb energy from laser beam  3 . Meltable absorber substance  6  is contained in opening  20  (or plurality of openings) in substrate strip  5 . The opening  20  containing substance  6  has an open side facing skin  8 . Laser beam  3  is positioned to pass through the clear layer  4  before it reaches the meltable absorbing substance  6 . The energy absorbed in substance  6  forces it to melt and ejects the melted substance out of the only opening available in the form of a droplet  9 . In the orientation of FIG. 2, the upper side of the opening  20  containing substance  6  is blocked by clear film  4  but open in the direction of skin  8 , facing skin  8 . Because of the laser energy absorbing characteristic of substance  6 , it is rapidly heated with laser energy in a manner similar to the thermal ink jet effect which occurs in commercial ink jet printers from companies like Hewlett Packard, Cannon and Lexmark. This rapid heating causes the meltable absorber substance  6  to melt and rapidly expand forming droplet  9 . Droplet  9  is thereby projected toward skin  8 . Pressure is believed to contribute to the ejection of the melted substance due to vaporization of a portion of the substance from the heat produced by absorption of laser energy. 
     FIG. 3 illustrates a continuation of the process showing how droplet  9  becomes a spot  10  of meltable absorber substance on skin surface  8 . The size of spot  10  on the skin and the thickness will be dependent upon the amount and wave length of the energy produced by the laser pulse, the amount of substance  6  and the liquid properties of the droplet  9  at impact. The laser can actually vaporize a small portion of the material  6  generating a pressure within the opening which contains substance  6  which drives the melted droplet  9  toward skin  8 . The desired size of the spot  10  would depend upon the volume of the interstitial fluid to be collected. A range of about 100 micrometers to perhaps 2000 micrometers would appear to be in the preferred range. Even so, it should be recognized that the diameter of the spot  10  is very small. The drawings are enlarged for clarity. 
     The stage is now set for the spot to be used to absorb laser energy in a subsequent step to release interstitial fluid from the skin. FIG. 4 illustrates a continuation of the process shown in FIGS. 1-3. In FIG. 4, the carrier film  4  and  5  has been moved horizontally or “indexed” in the direction of arrow  11  by an indexing means relative to skin  8  (or the skin moved relative to the film) so that aperture  7  is located between the spot of absorber substance  10  on the skin and the beam  3  produced by laser  1 . Now the process is continued by operating the laser, while directing beam  3  produced by laser  1  to the spot  10  of absorber substance on skin  8 , to thereby create a tiny blister containing interstitial fluid on the skin in the area where the spot  10  was formed. It is believed that indexing means for mechanically indexing carrier film  4  and  5  are circumstances which need not be described as being well known by persons of ordinary skill in the art. It might be noted that while film or sheet  4  is shown to be discontinuous at aperture  7 , it is capable of passing laser energy and could cover the top of aperture  7  at some reduction in efficiency. 
     FIG. 5 illustrates the result of the interaction of laser beam  3  with spot  10  on skin  8 . Thermal heating of the skin surface forms a blister  12  containing interstitial fluid. Blister  12  is formed in skin  8  due to rapid heating caused by laser energy being rapidly absorbed in the meltable absorber substance  10  laying on the skin surface. The pulse energy of beam  3  and the number of pulses can be adjusted until a blister forms and then opens up to release the fluid inside. Once the parameters of these conditions are established, the process should be repeatable. 
     FIG. 6 illustrates one means of collection of the interstitial fluid from the ruptured blister. A collection means  13  is used to remove to interstitial fluid  14  from the surface of skin  8 . Collections means  13  is illustrated in this Figure as a glass tube. The fluid is made available by rupturing the tiny blister in the skin. Surface tension draws the fluid into the tube where it is collected and may be transferred to a diagnostic device for measurements. The interstitial fluid volume collected would be expected to be fall within the range of about 25 nanoliters to about 25 microliters. It should be recognized to one skilled in the art that various means could be used to collect the interstitial fluid from the blister  12  on skin  8 . This drawing, like the other drawings, is exaggerated to illustrate the invention. The blister that is formed in this process is very small. 
     FIG. 7 illustrates a means of making the laminated carrier film or substrate which contains the meltable absorber substance. More specifically, FIG. 7 illustrates a digitally controlled means of placing the meltable absorbing substance into holes  20  of a preferably polymer film or sheet substrate  5 . Holes  20  in polymer film  5  have been previously made by excimer laser ablation or some other suitable process in a strip of material which, for example, might be wound on a reel. The film may have edge portions (not shown) which, in the manner of sprocket tracks on movie film; might hold the individual center portions together so they can be manipulated as a strip. It is also possible that the “film”  5  could be a strip of non-flexible material or a series of lengths of such material more in the nature of a batch process. Prototypes of the carrier strip have actually been made out of glass slides. 
     In FIG. 7 carrier film or strip  5  is supported on a support base  15 . A digitally operated printhead  17  has an orifice  23  at its lower end in fluid communication with an internal reservoir, or is connected to a reservoir, containing the meltable absorber substance  6 . Printhead  17  may be supplied with one or more heaters  16  for raising the temperature of the printhead so that the meltable materials would melt or have their viscosity reduced so as to have the appropriate fluid properties in the printhead for digitally jetting droplets from orifice  23  by means of modified ink jet technology. Strip  5  is shown positioned with an orifice  20  positioned directly under orifice  23 . Printhead  17  is dispensing one or a plurality of droplets  19  of meltable absorbing substance  6  to fill holes  20  in film strip  5 . This type of printhead could be similar to the ones described in U.S. Pat. Nos. 5,053,100, 5,498,444 and 5,772,106 which are hereby incorporated by reference. 
     The arrow  18  indicates relative movement between printhead  17  and base strip  5  in order to position orifice  23  over each successive opening  20 . Although arrow  18  indicates movement of printhead  17 , the strip  5  could be moved and positioned under a stationary printhead  17  as an alternative process. A mechanism (not shown) for moving either the strip  5  or the printhead  17  a specified distance or to a specified location by means of an X-Y stage is believed to be well known in the art and not actually a part of the present invention. 
     FIG. 8 illustrates a continuation of the process of FIG. 7 whereby the film strip layer  4  is laminated onto the top of base strip  5  to cover what will be the backside of the openings  20  now containing the meltable absorbing substance  6 . This may be accomplished by a schematically illustrated laminated wheel  21  which presses the unbonded polymer film strip  22  onto the base strip  5  where it would be held in place by an adhesive. The adhesive could be preapplied to the film strip or applied in an inline process to either or both of the surfaces to be joined as shown in FIG.  8 . 
     In the best mode, FIG. 9 illustrates a current prototype of the invention. What is referred to as the film sheet  24  in FIG. 9 corresponds to the base sheet  5  in the previous Figures (the structure has been rotated 180°). The opening  25  corresponds to the opening containing meltable absorber substance  6  in the previous Figures and is shown as being filled with the substance  6 . Opening  25  is a cylindrical shaped opening in film sheet  24 . It has a conical portion  26  as a coincidence of producing opening  25  by means of a tiny drill. Opening  25  in film sheet  24  culminates in a nozzle  27  from which absorber substance will be projected. Film sheet  24  is made from Ultem® sheet which is adhesively joined by means of a UV curable optical adhesive  28  to a backing film sheet  29  corresponding to the film cover  4  in the previous Figures. In this particular embodiment, the cover material is actually a glass microscope slide. Absorber  6  is a high viscosity, paste-like dispersion of one or more colorants and/or pigments in a nonaqueous oleophilic base. Also shown is an optional gas bubble  30 , in this case air. The presence of an air bubble seems to enhance the ejection of the droplet  9  from nozzle  27 . It allows the absorber to expand on the side heated by the laser without pushing material out through the orifice. This means the gas in the gas bubble may become pressurized and ready to expand rapidly when the absorber becomes soft enough to flow through the orifice. The gas is capable of expanding rapidly, thus giving the ejected absorber substance a higher velocity than if a thermal expansion of the absorber substance were the only driving force. In this particular prototype the sheet  24  is about 0.015 inches thick with a nozzle which is approximately 0.002 inches in diameter. The main volume of the well which constitutes opening  25  and conical portion  26  is drilled with a 0.005 inches diameter drill to a depth that leaves about a 0.002 thickness for the nozzle to be drilled through. The diameter of the nozzle is approximately 50 micrometers and the diameter of the main portion of opening  25  is approximately 250 micrometers. The current absorber substance uses carbon black as a pigment.