Abstract:
A skin retention device  10  for a medical jet-injection unit  20  having a contact face provided with adhesive  12  in the area surrounding and close to the injection opening(s)  11  of the nozzle  21  which ensures good contact between the nozzle  21  and the skin  30  of a subject in the area chosen for an injection. The injection force can be lowered dramatically. In case of two-stage jet-injections, the initial injection force can be lowered because the skin retention close to the injection point significantly reduces the energy consuming elastic expansion of the skin  30  in the injection area, and the second injection force can be lowered because of the high degree of fixed positioning of the injection opening of the nozzle  21  relative to the injection channel in the skin  30  made during the initial injection stage.

Description:
CROSS-REFERENCE TO RELATED APPLICATIONS 
     This application is a Divisional of U.S. application Ser. No. 12/158,025 filed Jun. 18, 2008 which is a 35 U.S.C. §371 national stage application of International Patent Application PCT/EP2006/067937 (published as WO 2007/071485), filed Oct. 30, 2006, which claimed priority of European Patent Application 05112490.7, filed Dec. 20, 2005; this application further claims priority under 35 U.S.C. §119 of U.S. Provisional Application 60/757,233, filed Jan. 9, 2006. 
    
    
     The invention relates to a nozzle device adapted for placement against a skin surface of a subject, the nozzle device providing a tool for retaining and stretching the skin. The nozzle device may advantageously be used in a drug delivery device to improve interaction between the delivery device and a skin surface. For example, the nozzle device may be used in combination with an impulse generating jet injection unit. 
     BACKGROUND OF THE INVENTION 
     Subcutaneous and intramuscular delivery of liquid drugs by injection is common in the medical arts. As some medications such as insulin must be given frequently by injection to an individual, easy performance of the injections is desirable. 
     Many patients dislike needle injections due to pain or fear for needles. Further, blood-borne pathogens, such as HIV and hepatitis, can be transmitted to health care workers by accidental needle-sticks. Also, the disposal of used needles is a growing concern. This disposal presents a problem to individuals other than healthcare workers. Children, for example, may find used needles in the garbage, putting them at risk of contracting infection. Discarded needles likewise pose a risk to waste disposal workers. 
     In efforts to minimize the fears and risks associated with needle injections, several types of needle-free jet injectors have been developed. These devices penetrate the skin using a high velocity fluid jet and deliver medication into the tissue of a patient. In order to accomplish this, a force is exerted on the liquid medication. Jet injectors in general contain a fluid drug which has been transferred into a chamber having a small orifice at one end. The high velocity fluid jet can be achieved for instance by having a drive means, e.g. a ram, accelerated using either a coil spring or a compressed gas energy source. The ram impacts a plunger which in turn creates a high pressure impulse within the chamber. This pressure impulse ejects the fluid medicament through the orifice at high velocity, piercing the skin. The energy source continues to apply a force to the plunger which quickly propels the drug through the opening in the skin, emptying the syringe in a fraction of a second. The drive means may be adapted to provide a two-stage injection, which is the case for ram mechanisms, i.e. a first penetrating burst of drug at a high pressure followed by a subsequent delivery of the remaining amount of drug at a lower pressure. 
     During injection the nozzle should be fixed at the same point relative to the skin. If this is not the case, the jet can cause incomplete injections, so called wet shots, where none or only a fraction of the dose is delivered through the skin and the desired blood glucose regulation is jeopardised in case of insulin injection. Another consequence of poor fixation can be lacerations of the skin in case the nozzle moves laterally across the skin during injection. 
     Addressing this problem, U.S. Pat. Nos. 5,911,703 and 6,406,456 each disclose an injector with an integral suction compartment for pulling the skin against the tip of the injection nozzle. As disclosed, the suction compartment functions to create a seal between the skin area and the injector tip without having to compress the skin area and underlying tissue. Further, the use of a suction compartment can prevent lacerations caused by the injector tip moving relatively to the skin during an injection. WO 03/000320 discloses a jet injection device in which sealing between the nozzle aperture and the skin is secured by a nozzle having a truncated cone configuration to embed in the skin to form a hydraulic seal. In WO 05/058393 a nozzle device with an adhesive to retain the skin against the nozzle device is described, the adhesive is confined to certain areas on the device and the device may have a plurality of skin stretching members or a concave skin stretching member. The device described in U.S. Pat. No. 6,537,242 comprising a cannula also has a concave skin stretching member which can be provided with an adhesive contacting the skin to form a friction enhancing member. In U.S. Pat. No. 6,149,625 an injection aid is disclosed having an adhesive provided around the injection area to maintain the injection aid at the desired location on the skin, the adhesive surrounding the injection area in a diameter of about 5 mm. WO 98/13087 discloses a needle less injector accessory comprising a patch covered on one side with adhesive material to be put on the skin of a subject prior to injection, the injection takes place through the patch material which is pierced by the stream of injectate. 
     In view of the above, one of the objectives of the present invention is to provide a nozzle device which can be used in combination with a jet expelling device and which aids in providing safe and reliable jet injection of a drug. Also, a main objective of the present invention is to provide a nozzle device which decreases the frequency of incomplete injections while at the same time making it possible to limit the amount of energy required for the jet beam to penetrate the skin. Furthermore, an objective of the present invention is to provide a nozzle device which minimizes the risk of intramuscular injections. The nozzle device should be small in size, easy to use and manufactured cost-effectively. 
     In the alternative, it is a further objective to provide a jet injection device similar to a conventional pen type injector as regards function and configuration, in order to make the patient comfortable with the jet injection device and so that the jet injection device can easily be utilized by a non-professional user, e.g. a insulin requiring diabetic. 
     SUMMARY OF THE INVENTION 
     In the disclosure of the present invention, embodiments and aspects will be described which will address one or more of the above objectives or which will address objectives apparent from the below disclosure as well as from the description of exemplary embodiments. 
     In a first aspect, a jet injection unit is provided comprising a nozzle portion with an outlet nozzle adapted to be applied to a skin surface of a subject, and a skin retention device comprising a contact face provided with adhesive to be applied in contact with the skin prior to an injection. The adhesive covers a part or all of the contact face, most importantly it surrounds the outlet nozzle opening in a very narrow distance. The adhesive used can have various material characteristics, where some adhesive types may be well suited to adhere on moist surfaces (as sweat covered skin), others can be well suited for hot or cold surfaces. Optionally the contact face can be covered with adhesive with different material characteristics in various segments. In this way, the contact face as a whole will be adapted for a range of situations because each adhesive segment has material characteristics suited for one of the situations. The adhesive segments can be located in different geometrical zones, such as concentric rings, dots and radial zones, the list not being exhaustive. These adhesive segments can have different skin retention force thereby compensating for differences in physical dimensions, climate, skin location etc. The device further comprises impulse generating means for expelling an amount of drug through the outlet nozzle, the impulse generating means being adapted to create a force for injecting liquid drug through the outlet nozzle and into the subject through the skin when the nozzle portion is arranged against the skin of a subject. The device typically comprises a variable-volume impulse chamber associated with the nozzle and on which the impulse generating means acts to empty the chamber. The impulse chamber may e.g. be prefilled, be filled through the nozzle prior to use, or the drug may be transferred to the impulse chamber from a reservoir within the device. Alternatively, a reservoir may serve as an impulse chamber, an impulse applied to the reservoir expelling only a portion of the drug contained in the reservoir. 
     In order for the jet beam of the jet injection unit to pierce the skin of a subject, a certain strain level is required. When at first the jet beam impacts the skin surface, an elastic expansion takes place before penetration. By narrowing down the inner diameter of the adhesive covered contact face surrounding the jet beam, the elastic expansion can be minimized. This is an expected effect, but studies have shown a remarkable and surprisingly radical increase of the strain index in the thus narrowed injection zone when the inner diameter of the adhesive covered contact face is under a certain limit area. The skin is pierced when a critical strain value is reached which is reflected in the strain index. More particularly, as will be further discussed, when the inner diameter is decreased below approximately 3 mm, the strain index rises significantly more than linearly compared to the decrease and when the inner diameter is decreased below approximately 0.8 mm the strain index rises dramatically, thus creating an earlier crack in the skin for a given penetration speed and pressure. The rise in strain index is so significant that a double advantage over the known art can be achieved: a so far unknown safe and reliable jet injection is ensured, however, by a lower injection force. Hitherto it has been necessary to apply an undesirable high injection force to minimize the risk of wet shots. This has increased the risk of damage caused by intramuscular injections and the risk of altering the pharmaco-kinetics resulting in unpredictable plasma levels of insulin. But when practicing the present invention the risk of wet shots is significantly minimized yet by a lower injection force. The retaining effect achieved by the adhesive not only serves the described purpose of increasing the strain index, but also ensures that the jet beam is positioned above the initially induced opening in the skin throughout the time of the injection, an advantage especially when using a two-stage injection having a lower delivery pressure in the second stage. Further, by providing an adhesive which ensures proper contact between the nozzle and the skin, the compression at the injection site by the user forcing the nozzle too hard against the skin may be omitted, which also reduces the likelihood of injection through the subcutaneous layer and into muscle tissue. Yet another advantage of the invention is that because of the stable and secure fixation of the nozzle orifice relative to the injection opening, the duration of the second, low-pressure injection stage can be prolonged without jeopardizing injection safety. Preferably the second injection stage shall last more than 100 milliseconds, more than 1 second or even up to more than 6 seconds. This allows for the medication to slowly enter the subcutaneous layer and minimize tissue damage. 
     In a further aspect of the invention, the skin retention device is also adapted to stretch the skin in the proximity of the injection point. The skin stretching means are arranged circumferentially relative to the outlet nozzle, the skin stretching means having an initial first configuration corresponding to an initial state in which the skin stretching means is adapted to be placed against the skin surface of the subject, the skin stretching means being moveable to a second configuration, wherein movement of the skin stretching means to the second configuration after the skin stretching means has been placed against the skin of the subject results in the skin being stretched relatively to the outlet nozzle. By engaging and stretching the skin the likelihood that the nozzle moves relative to the skin during injection is reduced. Further, stretching of the skin will aid in keeping open the injection channel during injection (e.g. through an initially established channel during the first stage of a two-stage injection), the channel subsequently being “closed” as the stretching action is removed. 
     Depending on the position of the skin-engaging nozzle portion before, during, and after actuation of the skin stretching and stretching means, the skin can be stretched in different ways. For example, when the nozzle portion engages the skin at an early stage, movement of the skin stretching means between the first and second configurations may result in the skin stretching means being displaced proximally relative to the outlet nozzle, thereby stretching the skin “upwardly around” the nozzle portion. If the nozzle portion engages the skin after movement of the skin stretching means between the first and second configurations, the nozzle will engage a radially stretched skin surface. Indeed, a number of combinations are possible, for example the skin may be stretched both radially and upwards relative to the outlet nozzle. 
     In an exemplary embodiment the skin stretching means is arranged such that the skin is stretched circumferentially away from the outlet nozzle, i.e. similar to a drum skin. The stretching may be accomplished by a flexible skin stretching means which continuously surrounds the outlet nozzle. 
     When it is defined that the skin stretching means has a second configuration, this does not mean that such a second configuration necessarily is well defined, i.e. the second configuration and the degree of stretching associated therewith may depend on how the nozzle device is used by a user. For example, when the skin stretching means is forced against the skin with a given force the skin stretching means may deflect to a certain degree thereby stretching the skin, whereas the skin stretching means may deflect to a higher degree if the a larger force is applied, this resulting in a greater degree of stretching. 
     However, the second configuration may also be well defined, for example in case the skin stretching means has a well-defined stop-position or in case the skin stretching means is bi-stable corresponding to the first and second configurations. 
     Correspondingly, in an exemplary embodiment the skin stretching means comprises a bi-stable member having a generally distally facing surface (i.e. against the skin) circumferentially surrounding the outlet nozzle, the bi-stable member having a distally concave configuration corresponding to the first configuration, and a distally convex configuration corresponding to the second configuration. To engage the skin, adhesive means is arranged corresponding to a peripheral portion of the distal surface, whereby movement of the skin contacting means between the first and second configurations results in the skin contacting means being displaced proximally relative to the outlet nozzle, thereby stretching the skin. 
     The nozzle and the skin stretching means may be of unitary construction and adapted to be selectively mounted on a jet expelling device, thereby providing a fluid communication between the expelling device and the outlet nozzle. Typically the nozzle portion will comprise a jet outlet nozzle formed therein and terminating at a distal aperture, the outlet nozzle being adapted to create a skin-penetrating jet of a liquid when the aperture is positioned against the skin surface and a liquid is forced through the nozzle at a given pressure. Although reference is made to a single aperture (or nozzle) the nozzle of the invention may comprise any desired number of additional apertures. Further, the nozzle may comprise a pointed hollow needle adapted to penetrate a superficial layer of the skin of a user, thereby aiding the jet of drug to create an opening in the skin from the surface to the subcutaneous space. Such a needle may be relatively short, e.g. 1 mm or less. The nozzle and skin stretching means may be formed integrally with components of a jet expelling system, e.g. a cartridge containing an amount of drug to be injected or in combination with an impulse chamber. The impulse generating means for expelling an amount of drug through the aperture may be configured in any desirable way, for example corresponding to the jet injection devices shown in U.S. Pat. Nos. 5,911,703 and 5,836,911 or US patent applications 2003/0050592 and 2002/0055707. 
     Alternatively, the nozzle portion and the skin stretching means may be adapted to be releasably coupled to each other. Correspondingly, in a further aspect the invention provides an injection aid adapted to be mounted on an injection nozzle, such an aid corresponding to the above disclosure with the only difference that the nozzle portion has been replaced with means for engaging such a nozzle portion. 
     The invention further provides a jet expelling device as described above, further comprising a drive assembly for reducing the volume of the impulse chamber with a reduced force relative to the impulse generating assembly when a portion of the drug has been expelled by the impulse generating assembly. The device may comprise a dose titrating unit for selectable setting a dose of drug to be expelled. The selected amount may be transferred to the impulse chamber from a reservoir provided in the device. 
     In a further embodiment, the invention provides a jet expelling device of the above-described type, further comprising a dose setter for selectable setting a dose of drug to be expelled and transfer that amount of drug from a reservoir to the impulse chamber, an actuator for actuating the impulse generating assembly and the drive assembly, and an actuatable release, wherein actuation of the release causes the impulse generating assembly to expel a portion of the set dose from the impulse chamber at a high pressure through the outlet nozzle, followed by subsequent expelling of the remaining portion of the set dose from the impulse chamber through the outlet nozzle by means of the drive assembly. 
     The invention also provides a method of introducing an amount of a drug through the skin of a subject, comprising the steps of (a) providing a jet expelling device comprising a nozzle (e.g. of a type as described above), (b) stretching a skin portion of the subject circumferentially relative to a desired skin location for delivery of the amount of a drug, (c) arranging the nozzle against the desired skin location, (d) lifting the skin in the vicinity of the injection point either by force applied by the user or provided by the flex effect of the skin retention device and (e) activating the jet expelling device to generate an impulse for expelling an amount of drug through the nozzle and thereby through the stretched skin portion. Skin stretching means (e.g. of a type as described above) may be associated with the nozzle, whereby the skin portion is stretched when the nozzle is arranged against the desired skin location. 
     As used herein, the term “drug” is meant to encompass any drug-containing flowable medicine or medicament capable of being passed through a nozzle under high pressure in a controlled manner, such as a liquid, solution, gel or fine suspension. Representative drugs include pharmaceuticals such as peptides, proteins, and hormones, biologically derived or active agents, hormonal and gene based agents, nutritional formulas and other substances in both solid (dispensed) or liquid form. In the description of the exemplary embodiments reference will be made to the use of insulin. 
    
    
     
       DESCRIPTION OF THE DRAWINGS 
       In the following the invention will be further described with references to the drawings, wherein 
         FIG. 1  shows a side view of a jet injection unit and a skin retention device, the lower part of the unit and the skin retention device in sectional view. 
         FIG. 2  shows a sectional view of a skin retention device and the lower part of a jet injection unit. 
         FIG. 3  shows three sequences of the initial phase of an injection in the injection zone. 
         FIG. 4  shows a close up perspective view of the injection zone in an initial phase of an injection. 
         FIG. 5  shows a close up perspective view of the injection zone in an initial phase of an injection with smaller inner diameter of retention. 
         FIG. 6  a graph showing the coherence between train index and inner diameter of retention. 
         FIG. 7  shows a sectional view of the lower part of a jet injection unit and a skin retention device in a first configuration. 
         FIG. 8  shows a sectional view of the lower part of a jet injection unit and a skin retention device in a second configuration. 
         FIG. 9  shows a jet injection with a skin retention device in use during injection. 
         FIG. 10-13  shows a jet injection device integrated with the skin retention device comprising various protective covers and a plug. 
     
    
    
     In the figures like structures are generally identified by like reference numerals. 
     DESCRIPTION OF EXEMPLARY EMBODIMENTS 
     When in the following terms as “distal”, “proximal” and “radial” or similar relative expressions are used, these only refer to the appended figures and not necessarily to an actual situation of use. The shown figures are schematic representations for which reason the configuration of the different structures as well as there relative dimensions are intended to serve illustrative purposes only. 
       FIG. 1  shows a side view of a jet injection unit  20  and a skin retention device  10  connected thereto. The lower part of the unit is shown in sectional view to show the piston  23  slidingly arranged in a housing thereby defining a variable-volume impulse chamber  22  in flow communication with the aperture through a nozzle conduit  21 . In the shown embodiment the impulse chamber is adapted for being filled with a liquid drug by suction through the nozzle conduit by moving the piston  23  proximally, however the impulse chamber unit  22  may also be provided with an opening in either the housing or the piston  23  allowing a drug to be introduced therethrough by either suction or external pressure in which case the nozzle aperture  21  should be closable. The skin retention device  10  connects the injection unit  20  to the skin  30  of a subject by means of the adhesive  12  provided on the contact face. The adhesive surrounds the injection opening  11  of the retention device  10 , said opening  11  is in close communication with the nozzle  21  for injecting the liquid drug when the injection button  24  is activated. 
       FIG. 2  shows in greater detail the skin retention device  10  when contacting and retaining the skin  30  just prior to an injection. When supplied, the skin retention device  10  will preferably have a protective peel-able film (not shown) covering the adhesive  12 . When preparing for an injection, the user will peel off the protective film and by holding the injection unit  20  press the retention device  10  against the skin  30  on the location where the injection is desired. Further the retention device can comprise a plug sealing off the injection opening (not shown) to ensure integrity of the contained liquid and minimize evaporation. The plug can be fixed in various ways: It can be fixed to the inside of a hard cover protecting the contact face, it can be pressed against the injection opening by a flexible cover, and it can be in various shapes either covering the injection opening or sealing it by partly entering and press on the inside walls of the injection opening—this list not being exhaustive. The contact face of the retention device can have various shapes, flat or curved. The flat surface has production advantages, whereas the curved shapes can have positive performing effects. In the embodiment on  FIG. 2 , the retention device  10  has a distal convex shape. The user shall apply sufficient force on the retention device  10  to ensure good contact between the retention device  10 , via the adhesive  12 , to the skin  30  on all off the contact face covered by adhesive  12 . When doing this, a stretch of the skin  30  is applied radial away from the injection point, this process can be seen on  FIGS. 7 and 8 . Once this is done, the user can ease off the pressing force or even apply a drawing force through the injection unit  20  to the retention device  10  as shown on  FIG. 9 , which will have the effect that the skin  30  in the injection area is drawn away from the underlying tissue, thereby minimising the risk of injection into muscle tissue. This is achieved by means of the adhesive layer  12 , which also ensures that the stretch of the skin  30  and the correct position of the nozzle  11  over the injection point is maintained throughout the injection period.  FIGS. 7 and 8  further illustrates a specific embodiment, comprising a bi-stable retention device  10 . Thus the retention device  10  has an initial configuration ( FIG. 7 ) in which it is adapted to be placed against the skin  30  surface of the subject, and being movable to a second configuration ( FIG. 8 ) where the retention device  10  in a “flip-flop” manner presses the injection opening of the nozzle  21  against the skin  30  while stretching the skin  30  in the area in contact with the contact face, by lifting the skin  30  surrounding the injection point. 
     A close interaction between the nozzle  21  and the retention device  10  in the injection zone is achieved by the chamfered outline of the nozzle  21  in the contact zone, which can be seen close up on  FIG. 2 . This has the important advantage that the adhesive  12  can ensure retention of the skin  30  very close to the injection point, enabling the inner diameter  13  of retention to be very small. In another embodiment of the invention (not shown), the same result can be reached by making the face of the nozzle  21  which contacts the skin  30 , flush with the contact face of the retention device  10 ; adhesive  12  can then be applied on both surfaces, thereby making the nozzle  21  face an integrated part of the retention device  10  contact face, whereby the inner diameter  13  of the adhesive covered contact face is no bigger than the actual diameter of the nozzle  21  orifice. Even if the face of the nozzle  21  is not flush with the retention device  10  contact face, this effect can still be achieved, as long as the nozzle  21  face is covered with adhesive  12  to a narrow diameter. In yet another embodiment shown on  FIG. 10-13  making the nozzle  21  face an integrated part of the retention device  10  contact face is achieved by manufacturing the nozzle  21  and the retention device  10  in one piece for example in a moulded polymer or a blend of a polymer and an elastomer material. This gives advantageous low production costs, and a simple device. The drawback is, that the skin retention device  10  can not be flexible and/or bi-stable as seen on  FIG. 7  and  FIG. 8 . but when sufficient initial applying force is preformed by the user, skin  30  stretching, adhering and skin  30  lifting once the applying force is eased off, can still be achieved even with a not-flexible, convex contact surface. On  FIGS. 10 and 11  a concept is shown where a stiff protecting cover  26  is attached to the integrated retention device and nozzle, done by any known technique such as a thread, bayonet coupling or a clamping as shown. A plug  28  either entering the orifice or just pressing on the edge of the orifice ensures closure and integrity of the nozzle thereby minimizing evaporation of the liquid, In  FIG. 10 , a ridge on the rim of the contact face ensures distance between the adhesive layer and the inner surface of the cover, in  FIG. 11  this is ensured only by the stiffness of the cover material and the distance to the adhesive layer provided by the plug  28 . Further, it can also be possible to let the cover have contact to the adhesive layer depending on the material characteristics. The cover can be made of moulded material analogue to the material of the nozzle itself, by a metal such as aluminium or any known adequate material. In a slightly different concept shown on  FIGS. 12 and 13 , the cover material  27  is flexible whereby the connection to the nozzle can be ensured by stretching the rim of the flexible cover over the rim of the nozzle/contact face, analogue to  FIGS. 12 and 13 , a plug  28  is provided to ensure integrity of the content of the nozzle. In  FIG. 13  the flexibility of the cover material is utilized not only to fix the cover to the device, but also to apply a down force on the plug towards the orifice. Further in  FIGS. 12 and 13  an “ear”  29  is provided to ensure a save grip when the cover is taken off. The concepts shown on  FIG. 10-13  are not exhaustive, further variations can be used such as peel off covers adhered to the device, with or without a plug, or devices with a cover but without adhesive material, where the adhesive can be a double sided gluing film applied to the skin and the contact surface of the device immediate prior to injection, where the injection jet beam penetrates both the gluing film and the skin. 
       FIGS. 3 ,  4  and  5  shows the course of a jet injection in the injection zone.  FIG. 3  shows the beginning of an injection where the jet beam  25  reaches the skin  30  surface, fills out the present void between the skin  30 , the nozzle  21  face and the retention device  10  and builds up pressure which leads to an elastic expansion of the skin  30  before penetration. In  FIG. 3C  the maximum strain index is illustrated at position  40 . The effect that the inner retention diameter  13  (the inner diameter of the adhesive covered area of the retention device  10 ) has on the skin stretch (strain) level due to jet beam  25  impact can be seen on  FIG. 4  and  FIG. 5 . These figures shows two different retention cases where the jet beam  25  penetration speed and pressure are the same in both cases, but where the inner retention diameter  13  is 1 mm in  FIG. 4  and 0.6 mm in  FIG. 5 . As can be seen, in the case of the smaller retention diameter  13 , the strain level  40  is significantly bigger, which means that penetration of the skin  30  is reached at an earlier stage. As the inner retention diameter  13  is decreased, so is the energy absorbing elastic expansion of the skin  30  before penetration. And as the energy absorption before penetration is decreased, the energy (pressure) applied to the jet beam  25  can be decreased accordingly, while keeping the same or better security of penetration. Pressure applied and risk of tissue damage is decreased while injection safety is increased. 
     While this relative connection between inner retention diameter  13  and strain index  40  might be expected, studies have shown a surprising development when reaching a certain diameter  13  level.  FIG. 6  shows how the strain index is slowly rising with falling retention diameter  13  until a certain small diameter  13  level is reached, where the strain index rises dramatically with falling retention diameter  13 . For the given penetration speed and pressure shown on  FIG. 6  the strain index rises dramatically when the retention diameter  13  falls under approx. 0.8 mm, however the area where this development is achieved can vary with different jet beam  25  penetration speeds and pressures.