System for delivery of a liquid below surface of skin

Abstract

Provided is a system (100) for multiple-repeated deliveries of a dose of a liquid below an exterior surface of a skin of a subject comprising: a cartridge (200) comprising a needle assembly (120) comprising a needle assembly body (122) and a set (124) of one or more hollow needle(s) (125) attached to the needle assembly body (122), each needle having a lumen for delivery of the dose of the liquid; a dosing element (800), configured for providing the liquid to the set (124) of hollow needle(s) (125) according to a flow cycle (400), wherein the flow cycle is a variation in flow rate during a flow cycle duration (406) to the set of needles and comprises a period of maximum flow rate and a period of a minimum flow rate; - a liquid supply system (900) having an outlet in fluid connection with an inlet of the dosing element (800); a movement inducer (140) configured to induce slidable movement in the needle assembly body (122) according to a stroke cycle (300), wherein the stroke cycle (300) contains a pattern of motion (320) of the needle assembly body (122) within a stroke cycle duration (306) and the flow cycle (400) is synchronized with the stroke cycle (300); and a primary control unit (700) configured to control at least the flow cycle (400), the stroke cycle (300), and their synchronisation.

Description

[0001] SYSTEM FOR DELIVERY OF A LIQUID BELOW SURFACE OF SKIN

[0002] Field of the invention

[0003] The field of the invention is systems for multiple-repeated deliveries of a dose of a liquid (e.g. for medical treatment or cosmetic applications) below an exterior surface of a skin of a subject.

[0004] Background to the invention

[0005] Injection of liquid below the exterior surface of the skin is a commonly performed procedure globally, useful for both therapeutic and cosmetic treatments. Despite a multitude of available devices to perform this procedure, most are inefficient owing to a large proportion of liquid not being injected below the exterior surface of the skin. The present invention aims to improve efficiency, in addition to increasing rate of dose delivery.

[0006] Summary of the invention

[0007] Described herein is a system (100) for multiple-repeated deliveries of a dose of a liquid below an exterior surface of a skin of a subject comprising:

[0008] - a cartridge (200) comprising:

[0009] - a needle assembly (120) comprising a needle assembly body (122) and a set (124) of one or more hollow needle(s) (125) attached to the needle assembly body (122), each needle having a lumen for delivery of the dose of the liquid;

[0010] - a dosing element (800), configured for providing the liquid to the set (124) of hollow needle(s) (125) according to a flow cycle (400), wherein the flow cycle is a variation in flow rate during a flow cycle duration (406) to the set of needles and comprises a period of maximum flow rate and a period of a minimum flow rate; - a liquid supply system (900) having an outlet in fluid connection with an inlet of the dosing element (800);

[0011] - a movement inducer (140) configured to induce slidable movement in the needle assembly body (122) according to a stroke cycle (300), wherein the stroke cycle (300) contains a pattern of motion (320) of the needle assembly body (122) within a stroke cycle duration (306) and the flow cycle (400) is synchronized with the stroke cycle (300); and

[0012] - a primary control unit (700) configured to control at least the flow cycle (400), the stroke cycle (300), and their synchronisation.

[0013] Also described herein is a system (100) for multiple-repeated deliveries of a dose of a liquid below an exterior surface of a skin of a subject comprising: - a cartridge (200) comprising:

[0014] - a needle assembly (120) comprising a needle assembly body (122) and a set (124) of one or more (preferably two or more) hollow needle(s) (125) attached to the needle assembly body (122), each needle having a lumen for delivery of the dose of the liquid;

[0015] - a dosing element (800), configured for providing the liquid to the set (124) of hollow needle(s) (125) according to a flow cycle (400), wherein the flow cycle is a variation in flow rate during a flow cycle duration (406) to the set of needles and comprises a period of maximum flow rate and a period of a minimum flow rate;

[0016] - a liquid supply system (900) having a outlet in fluid connection with an inlet of the dosing element (800), wherein the system (100) is configured such that the needle assembly body (122) is induced to slidably move during a stroke cycle (300), wherein the stroke cycle (300) contains a pattern of motion (320) of the needle assembly body (122) within a stroke cycle duration (306), and the flow cycle (400) is synchronized with the stroke cycle (300).

[0017] The flow cycle (400) is preferably synchronised with the stroke cycle (300) such that the minimum liquid flow rate is reached during a period in which the needle assembly body (122) is at a fully withdrawn position of the stroke cycle (300).

[0018] The flow cycle (400) is preferably synchronised with the stroke cycle such that the maximum flow rate is reached during a period of the stroke cycle in which the set of hollow needles protrudes from a skin contact surface (126), wherein the skin contact surface (126) is configured for making contact with the skin of the subject and provided with a least one needle aperture for passage therethrough of the set (124) of needles (125).

[0019] The flow cycle (400) is preferably synchronised with the stroke cycle such that the flow rate is increasing:

[0020] - during a period of the stroke cycle in which the set (124) of hollow needles (125) is greater than 0% protruding from a skin contact surface (126), the skin contact surface (126) configured for making contact with the skin of the subject and provided with a least one needle aperture for passage therethrough of the set (124) of needles (125), and - during a period of the stroke cycle in which the needle assembly body (122) is moving in a net direction towards 0% protruding from the skin contact surface (126); and

[0021] - after the needle assembly body (122) has reached a fully deployed position.

[0022] The primary control unit (700) is preferably configured to control the dosing element (800) such that the variation in the flow rate during the flow cycle (400) is met.

[0023] The dosing element (800) preferably comprises one of

[0024] - a volumetric pump, or

[0025] - a controlled valve.

[0026] The dosing element (800) preferably comprises a controlled valve, and further comprises a valve or primary control unit configured to regulate the controlled valve such that variation in the flow rate during the flow cycle duration (406) is met.

[0027] The dosing element (800) preferably comprises a volumetric pump and the volumetric pump is a peristaltic pump, a diaphragm pump, a membrane pump, a piston pump or plunger pump.

[0028] The cartridge (200) is preferably detachable and optionally disposable.

[0029] The dosing element (800) is preferably integrated into the cartridge (200).

[0030] The system (100) may further comprise a movement inducer configured to induce movement in the needle assembly body (122) according to the stroke cycle.

[0031] The primary control unit is preferably configured to control the movement inducer such that the slidable movement of the needle assembly body (122) induced in the needle assembly body (122) is according to the stroke cycle (400).

[0032] The dosing element (800) is preferably a controlled valve, and a liquid supply system (900) is provided to supply the controlled valve, wherein the liquid of liquid supply system (900) is outputted under positive pressure. Preferably, pressure in a conduit (910) between the liquid supply system (900) and the controlled valve (800) is controllable, responsive to the flow cycle dose that is a total volume of liquid outputted by the set (124) of one or more hollow needle(s) (125) in one flow cycle.

[0033] Preferably, pressure in the conduit (910) is determined from a pressure sensor in the conduit (910) and / or from a force sensor determining an applied force on an actuator of the liquid supply system (900).

[0034] Preferably, a flow rate setting of the liquid supply system (900) is adjustable responsive to a total volume of liquid outputted by the set (124) of one or more hollow needle(s) (125) in one flow cycle.

[0035] Preferably, a conduit (910)) between the liquid supply system (900) and the controlled valve (800) comprises a region of volumetric elasticity configured to act as a fluid buffer to reduce variation over time of a (hydrostatic) pressure at an inlet to the controlled valve (800).

[0036] Preferably, the needles are placed in one or two lines.

[0037] Figure Legends

[0038] FIG. 1 is a schematic illustration of an example of a system described herein for multiple- repeated deliveries of a dose of a liquid below an exterior surface of a skin of a subject.

[0039] FIG. 2 is a schematic illustration of an example of another system described herein for multiple-repeated deliveries of a dose of a liquid below an exterior surface of a skin of a subject.

[0040] FIG. 3 is a schematic illustration of a stroke cycle used in a system described herein.

[0041] FIG. 4 is a schematic illustration of a flow cycle used in a system described herein.

[0042] FIG. 5 is a schematic illustration of a flow cycle synchronised with a stroke cycle used in a system described herein.

[0043] FIG. 6 is a schematic illustration of a needle assembly body and a set of one or more hollow needle(s) attached to the needle assembly body, a needle length (c / n), and a guard distance (dg). FIG. 7 is a graph showing results of an intermittent flow implemented using syringe pump compared with a dosing element.

[0044] FIG. 8 is an exemplary schematic liquid flow path within a system presently described.

[0045] FIG. 9 panels A and B demonstrate a needle a system presently described during advancement (Panel A) and during retraction (Panel B) which creates a cavity.

[0046] FIG. 9 panels A and B demonstrate a needle a system presently described during advancement (Panel A) and during retraction (Panel B) which creates a cavity.

[0047] FIG. 10 depicts an exemplary system described herein.

[0048] FIG. 11 is a schematic illustration of an example of a system described herein for multiple- repeated deliveries of a dose of a liquid below an exterior surface of a skin of a subject, including a primary control unit.

[0049] FIG. 12 is a graph showing results of Example 4 herein, and deposition efficiency as a function offset between stroke pattern start time and flow pattern start time.

[0050] Detailed description of invention

[0051] Before the present system and method of the invention are described, it is to be understood that this invention is not limited to particular systems and methods or combinations described, since such systems and methods and combinations may, of course, vary. It is also to be understood that the terminology used herein is not intended to be limiting, since the scope of the present invention will be limited only by the appended claims.

[0052] As used herein, the singular forms "a", "an", and "the" include both singular and plural referents unless the context clearly dictates otherwise.

[0053] The terms "comprising", "comprises" and "comprised of' as used herein are synonymous with "including", "includes" or "containing", "contains", and are inclusive or open-ended and do not exclude additional, non-recited members, elements or method steps. It will be appreciated that the terms "comprising", "comprises" and "comprised of as used herein comprise the terms "consisting of", "consists" and "consists of.

[0054] The recitation of numerical ranges by endpoints includes all numbers and fractions subsumed within the respective ranges, as well as the recited endpoints. The term "about" or “approximately” as used herein when referring to a measurable value such as a parameter, an amount, a temporal duration, and the like, is meant to encompass variations of + / -10% or less, preferably + / -5% or less, more preferably + / -1 % or less, and still more preferably + / -0.1 % or less of and from the specified value, insofar such variations are appropriate to perform in the disclosed invention. It is to be understood that the value to which the modifier "about" or “approximately” refers is itself also specifically, and preferably, disclosed.

[0055] Whereas the terms “one or more” or “at least one”, such as one or more or at least one member(s) of a group of members, is clear per se, by means of further exemplification, the term encompasses inter alia a reference to any one of said members, or to any two or more of said members, such as, e.g., any >3, >4, >5, >6 or >7 etc. of said members, and up to all said members.

[0056] All references cited in the present specification are hereby incorporated by reference in their entirety. In particular, the teachings of all references herein specifically referred to are incorporated by reference.

[0057] Unless otherwise defined, all terms used in disclosing the invention, including technical and scientific terms, have the meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. By means of further guidance, term definitions are included to better appreciate the teaching of the present invention.

[0058] In the following passages, different aspects of the invention are defined in more detail. Each aspect so defined may be combined with any other aspect or aspects unless clearly indicated to the contrary. In particular, any feature indicated as being preferred or advantageous may be combined with any other feature or features indicated as being preferred or advantageous.

[0059] Reference throughout this specification to “one embodiment” or “an embodiment” means that a particular feature, structure or characteristic described in connection with the embodiment is included in at least one embodiment of the present invention. Thus, appearances of the phrases “in one embodiment” or “in an embodiment” in various places throughout this specification are not necessarily all referring to the same embodiment, but may. Furthermore, the particular features, structures or characteristics may be combined in any suitable manner, as would be apparent to a person skilled in the art from this disclosure, in one or more embodiments. Furthermore, while some embodiments described herein include some but not other features included in other embodiments, combinations of features of different embodiments are meant to be within the scope of the invention, and form different embodiments, as would be understood by those in the art. For example, in the appended claims, any of the claimed embodiments can be used in any combination.

[0060] In the present description of the invention, reference is made to the accompanying drawings that form a part hereof, and in which are shown by way of illustration only of specific embodiments in which the invention may be practiced. Parenthesized or emboldened reference numerals affixed to respective elements merely exemplify the elements by way of example, with which it is not intended to limit the respective elements. Unless otherwise indicated, all figures and drawings in this document are not to scale and are chosen for the purpose of illustrating different embodiments of the invention. In particular the dimensions of the various components are depicted in illustrative terms only, and no relationship between the dimensions of the various components should be inferred from the drawings, unless so indicated.

[0061] It is to be understood that other embodiments may be utilised and structural or logical changes may be made without departing from the scope of the present invention. The following detailed description, therefore, is not to be taken in a limiting sense, and the scope of the present invention is defined by the appended claims.

[0062] The terms "distal" and "proximal" are used through the specification to refer to a direction of the system, and are terms generally understood in the field. "Proximal" means towards the operator and thus away from the subject. Conversely, "distal" means towards the subject and, therefore, away from the operator.

[0063] The “subject” refers to a person receiving the multiple-repeated deliveries of a dose of a liquid below an exterior surface of a skin. The “operator” refers to a person or persons applying the system to the skin of the subject. The operator may be clinician, physician, a medical assistant, a health care professional, a wellness professional, a beauty professional.

[0064] Where the treatment is self-administered, the operator is the subject.

[0065] An “administration session” is a session with a subject during which multiple-repeated doses of a liquid are delivered below an exterior surface of a skin of a subject at different locations. During an administration session, the system is moved across the skin e.g. to treat a defined area of the skin. During an administration session, any settings of the system may remain unchanged or may be adjusted. During an administration session, one or more parameters may be dynamically adjusted (by the operator or automatically). The dynamic adjustment maybe responsive to local skin type. By dynamically adjusted, it is meant one or more changes to a parameter value may be made at one or more time points during an administration session. There may be multiple different administration sessions during an administration sitting by the subject.

[0066] Provided herein is a system (100) for multiple-repeated deliveries of a dose of a liquid below an exterior surface of a skin of a subject. Exemplary systems are shown in FIGs. 1 and 2.

[0067] The system (100) comprises a cartridge (200). The cartridge comprises a needle assembly (120) comprising a needle assembly body (122) and a set (124) of one or more hollow needle(s) (125) attached to the needle assembly body (122), each needle having a lumen for delivery of the dose of the liquid. A chamber (130) is provided in the needle assembly body (122) for receiving and distributing the liquid to the set (124) of one or more hollow needle(s) (125). An outlet of the dosing element (800) is in fluid connection with the chamber (130).

[0068] The conduit(s) (810) carrying liquid from an outlet from the dosing element (800) to the set of needles is resistant to expansion, or is non-expandable, or has low elasticity. A low elasticity is less than 10 mm3 / MPa, preferably less than 5 mm3 / MPa, even more preferably less than 1 mm3 / MPa as measured according to ISO 11623 measured at a maximum operating flow rate (giving a maximum operating pressure) of the device. The system (100) further comprises a dosing element (800), configured for providing the liquid to the set (124) of hollow needle(s) (125) according to a flow cycle, wherein the flow cycle is a variation in flow rate during a flow cycle duration (406) to the set of needles and comprises a period of maximum flow rate and a period of a minimum flow rate.

[0069] The system (100) further comprises a liquid supply system (900) having a outlet in fluid connection with an inlet of the dosing element (800). The liquid supply system (900) is connected to the dosing element (800) via a conduit (910).

[0070] The system (100) is configured such that the needle assembly body (122) is induced to slidably move during a stroke cycle, wherein the stroke cycle contains a pattern of motion of the needle assembly body (122) within a stroke cycle duration, and the flow cycle is synchronized with the stroke cycle.

[0071] A system (100) is configured for multiple-repeated deliveries of a dose of a liquid at targets locations that are below an exterior surface of the skin of the subject. Preferably the targets locations are in the epidermis layer and / or below the epidermis layer of the skin of the subject. Examples of target location include epidermis layer, dermis layer, or subcutaneous layer. Typically the target locations are 1 mm to 10 mm below the exterior surface of the skin of the subject.

[0072] The cartridge (200) comprises the needle assembly (120) comprising the needle assembly body (122) and the set (124) of one or more hollow needle(s) (125) attached to the needle assembly body (122). The cartridge preferably comprises a housing containing the needle assembly (120). The housing is preferably configured to remain fixed (stationary) relative to the needle assembly (120). The cartridge (200) may or may not include the skin contact surface (126) described below. The cartridge (200) may be detachable. The cartridge (200) may be disposable. The detachable cartridge (200) may attached to the system (100) using any attachment mechanism, such as, for example, snap fit, screw fit, bayonet fitting, one or more clips, one or more screws, and the like.

[0073] The detachable cartridge (200) allows for an ease of exchange of needle assembly (120) for a different subject or for a new administration session on the same subject. It reduces possibility of infection and / or contagion between different subjects or different part of the skin of the same subject.

[0074] The stroke cycle is a cycle of slidable movement of the needle assembly body (122) (over time) within a stroke cycle duration in which the needle assembly body (122) undergoes one complete pattern of (slidable) motion, and optionally contains a stroke cycle pause before the pattern of motion and optionally contains a stroke cycle pause after the pattern of motion. The stroke cycle has a duration (stroke cycle duration), which is time between a start (stroke cycle start) and end (stroke cycle end) of the stroke cycle. The stroke cycle duration may be fixed or adjustable during an administration session.

[0075] An exemplary stroke cycle (300) is shown in FIG. 3. FIG. 3 sets out a plurality of parameters of the stroke cycle (300). The stroke cycle (300) contains a stroke cycle start (302) and a stroke cycle end (304). The stroke cycle (300) has a stroke cycle duration (306) which is a time between the stroke cycle start (302) and a stroke cycle end (304). Immediately after the stroke cycle start (302) is an optional (start) stroke cycle pause (310) having a stroke cycle pause duration (312). Immediately after the optional stroke cycle pause (310) is a pattern of motion (320). The pattern of motion (320) has a stroke pattern start position (322) at the beginning of the pattern of motion (320). The stroke pattern start position (322) is at a stroke pattern start time (324). The stroke pattern start position (322) is at a stroke cycle trigger position (326), that may be at a fully withdrawn position (328) of the needle assembly body (122). The pattern of motion (320) has a stroke pattern end position (332) at the end of the pattern of motion (320). The stroke pattern end position (332) is at a stroke pattern end time (334). The stroke pattern end position (332) is at the stroke cycle trigger position (326), that may be at a fully withdrawn position (328) of the needle assembly body (122). During the pattern of motion (320), the needle assembly body (122) reaches a fully deployed position (329). The pattern of motion (320) has a stroke pattern duration (330) which is a time between the stroke pattern start time (324) and a stroke pattern end time (334). Immediately after the pattern of motion (320) is an optional (end) stroke cycle pause (340) having a stroke cycle pause duration (342).

[0076] The fully deployed position (329) may or may not be adjustable by the operator. For instance, the fully deployed position (329) to be equal to or a fraction of a maximum deployed position. The maximum deployed position is at a limit of operation of the system where, owing to limitations of the system, the needle assembly body (122) can advance no further.

[0077] The fully withdrawn position (328) may or may not be adjustable by the operator. For instance, the fully withdrawn position (328) to be equal to or a fraction of a maximum withdrawn position. The maximum withdrawn position is at a limit of operation of the system where, owing to limitations of the system, the needle assembly body (122) can withdraw no further.

[0078] The stroke cycle is repeated (without delay) a plurality of times during an administration session. The stroke cycle may be identically repeated (e.g. stroke cycle duration, pattern of motion, stroke pattern duration, stroke cycle pause duration all remain constant) during an administration session. The stroke cycle may be varied (e.g. one or more of stroke cycle duration, pattern of motion, stroke pattern duration, stroke cycle pause duration between at least two stroke cycles is different) during an administration session.

[0079] A quantity of stroke cycles in one second is a stroke cycle frequency (Hz). The stroke cycle frequency is typically >5 Hz, preferably >10 Hz, most preferably >20 Hz. The stroke cycle frequency is preferably <50 Hz more preferably <25 Hz. The stroke cycle frequency may be constant during an administration session. The stroke cycle frequency may be adjustable (settable) between different administration sessions. Where an increase or decrease in the stroke cycle frequency is desired, a stroke cycle duration and / or a pause period duration where present, may be adjusted accordingly. Preferably, where an adjustment is made to the stroke cycle frequency, a proportionate adjustment is made to the stroke pattern duration. For instance, if the stroke cycle frequency is increased from 8 Hz to 12 Hz, stroke pattern duration is preferably proportionally shortened.

[0080] A pattern of motion is a linear sliding motion by the needle assembly body (122) starting from a stroke pattern start position (322) (typically the fully withdrawn position (328)) known as a cycle trigger position (326), progressing (optionally via one or more other motions) towards the fully deployed position (329), and returning (optionally via one or more other motions) back to the cycle trigger position (326) that is a stroke pattern end position (332) (typically the fully withdrawn position (328)). The fully withdrawn position (328) is at one extreme of the motion, and the fully deployed position (329) at the other extreme of the motion.

[0081] Preferably, a pattern of motion (320) is a linear sliding motion by the needle assembly body (122) that includes one or more movements between the fully withdrawn position and the fully deployed position. Preferably, a pattern of motion is a linear sliding motion by the needle assembly body (122) starting from the fully withdrawn position, progressing towards the fully deployed position, and returning back to the fully withdrawn position.

[0082] A pattern of motion has a duration (stroke pattern duration (330)) which is a time interval between the stroke pattern start time (324) and the stroke pattern end time (334). The stroke pattern start time is the time, starting from the stroke cycle start time (t=0), at which the needle assembly body (122) is at the stroke pattern start position. The stroke pattern end time is the time, starting from the stroke cycle start time, at which the needle assembly body (122) is at the stroke pattern end position.

[0083] The stroke pattern duration (330) may be 10 % to 100 % of the stroke cycle duration (306). Each stroke pattern duration may be of the same duration during an administration session, or at least two stroke pattern duration may be different during an administration session.

[0084] A pattern of motion preferably contains one apex (a period of a fully advanced position (329)), preceded by a period of gradual movement from a fully withdrawn position (328) to the apex, and proceeded by a period of gradual movement from the apex to the fully withdrawn position (328) as exemplified in FIG. 3.

[0085] A stroke cycle pause (310, 340) may or may not be present within a stroke cycle. A stroke cycle pause is a period before (310) or after (340) a pattern of motion where there is no motion by the needle assembly body (122) while the needle assembly is in the starting or fully withdrawn position. A stroke cycle pause (310, 340) has a duration (stroke cycle pause duration (312, 342)). The stroke cycle optionally contains a stroke cycle pause (310) before the pattern of motion (having a stroke cycle pause duration) and optionally contains a stroke cycle pause (340) after the pattern of motion (having a stroke cycle pause duration). Where the stroke cycle pause is present both before and after a pattern of motion, there are two stroke cycle pauses.

[0086] Each stroke cycle pause (310, 340) may be of the same duration (pause period duration) during an administration session, or at least two stroke cycle pauses may be different during an administration session.

[0087] A stroke cycle pause (310, 340) maybe provide a time window for displacement of the system between different locations on the skin surface.

[0088] There may be several different stroke cycles (300), each having a same pattern of motion (e.g. selected from a library of 5 to 10 patterns of motion) within an administration session.

[0089] There may be several different stroke cycles (300), each having a different pattern of motion (e.g. selected from a library of 5 to 10 patterns of motion) within an administration session. Each different pattern of motion may have: a different stroke pattern duration, and / or a different fully withdrawn position and / or different fully deployed position, and / or a different movement path from the stroke pattern start position / time to the stroke pattern end position / time.

[0090] Where there are several different stroke cycles within an administration session, each having a different pattern of motion, they may be implemented in a defined order or randomly. Where they are implemented in a defined order, the defined order is repeated during the administration session.

[0091] Each stroke cycle pause (310, 340) may be of the same duration (312, 342) (pause period duration) during an administration session, or at least two stroke cycle pauses may be different during an administration session.

[0092] A stroke cycle pause (310, 340) may be used to displace the system between different locations on the skin surface.

[0093] Where there are several different pattern of motion within an administration session, each having a different stroke cycle duration, stroke cycle pause may be adjusted so that the stroke cycle duration is constant (and corresponds to the stroke cycle frequency set during an administration session).

[0094] The flow cycle is variation in flow rate (over time) to the set of needles within a flow cycle period in which the flow rate undergoes one complete pattern of flow, and optionally contains a flow cycle pause period before the pattern of flow and optionally contains a flow cycle pause period after the pattern of flow. The flow cycle has a duration (flow cycle duration), which is time between a start (flow cycle start) and end (flow cycle end) of the flow cycle. The flow cycle duration may be fixed or adjustable during an administration session.

[0095] An exemplary flow cycle (400) is shown in FIG. 4. FIG. 4 sets out a plurality of parameters of the flow cycle (400). The flow cycle (400) contains a flow cycle start (402) and a flow cycle end (404). The flow cycle (400) has a flow cycle duration (406) which is a time between the flow cycle start (402) and a flow cycle end (404). Immediately after the flow cycle start (402) is an optional (start) flow cycle pause (410) having a flow cycle pause duration (412). Immediately after the optional flow cycle pause (410) is a pattern of flow (420). The pattern of flow (420) has a flow pattern start rate (422) at the beginning of the pattern of flow (420). The flow pattern start rate (422) is at a flow pattern start time (424). The flow pattern start rate (422) is at a flow cycle trigger rate (426), that may a minimum flow rate (428). The pattern of flow (420) has a flow pattern end rate (432) at the end of the pattern of flow (420). The flow pattern end rate (432) is at a flow pattern end time (434). The flow pattern end rate (432) is at the flow cycle trigger rate (426), that may the minimum flow rate (428). During the pattern of flow (420), the flow rate reaches a maximum flow rate (429). The pattern of flow (420) has a flow pattern duration (430) which is a time between the flow pattern start time (424) and a flow pattern end time (434). Immediately after the pattern of flow (420) is an optional (end) flow cycle pause (440) having a flow cycle pause duration (442).

[0096] The maximum flow rate (429) may or may not be adjustable by the operator. For instance, the maximum flow rate (429) to be equal to or a fraction of a system absolute flow rate. The system absolute flow rate is at a limit of operation of the system where, owing to limitations of the system, the flow rate can be increased no further.

[0097] The minimum flow rate (429) is preferably zero. The dose per flow cycle (flow cycle dose) is a total volume of liquid outputted by the set (124) of one or more hollow needle(s) (125) in one flow cycle. The flow cycle dose may be adjusted by the operator. The flow cycle dose desired by the operator may be reached or be maintained at a certain rate using a sensor (such as a pressure, force or flow sensor) as part of a closed feedback loop for controlling the dosing element (800) and optionally the liquid supply system (900).

[0098] The flow cycle (400) is repeated (without delay) a plurality of times during an administration session. The flow cycle may be identically repeated (e.g. flow cycle duration, pattern of flow, flow pattern duration, flow pause duration all remain constant) during an administration session. The flow cycle may be varied (e.g. one or more of flow cycle duration, pattern of flow, flow pattern duration, flow pause duration between at least two flow cycles is different) during an administration session.

[0099] A quantity of flow cycles (400) in one second is a flow cycle frequency (Hz). The flow cycle frequency is typically >5 Hz, preferably >10 Hz, most preferably >20 Hz. The flow cycle frequency may be constant during an administration session. The flow cycle frequency may be adjustable (settable) between different administration sessions. The flow cycle frequency may be adjustable (settable) during an administration session. Where an increase or decrease in the flow cycle frequency is desired, a flow cycle duration and / or a flow cycle pause period duration where present, may be adjusted accordingly. Preferably, where an adjustment is made to the flow cycle frequency , a proportionate adjustment is made to the flow pattern duration. For instance, if the flow cycle frequency is increased from 8 Hz to 12 Hz, flow pattern duration is preferably proportionally shortened.

[0100] A pattern of flow (400) is variation in flow rate to the needle assembly body (122) starting from a flow pattern start rate (minimum flow rate, usually zero), progressing (optionally via one or more other flow rate variations) towards a maximum flow rate, and returning (optionally via one or more other flow rate variations) back to a flow pattern end rate (minimum flow rate, usually zero). The minimum flow rate is at one extreme of the flow rate scale, and the maximum flow rate at the other extreme of the flow rate scale. A pattern of flow has a duration (flow pattern duration (430)) which is a time interval between the flow pattern start rate and the flow pattern end rate. The flow pattern start time (424) is the time, starting from the flow cycle start (402) time (t=0), at which the flow is at the flow pattern start rate (422). The flow pattern end time (434) is the time, starting from the flow cycle start (402), at which the flow is at the flow pattern end rate (432).

[0101] The flow pattern duration (430) may be 10 % to 100 % of the flow cycle duration. Each flow pattern duration may be of the same duration during an administration session, or at least two flow pattern durations may be different during an administration session.

[0102] A pattern of flow preferably contains one apex (a period of a maximum flow (429)), preceded by a period of gradual flow increase from a minimum flow rate to the apex (429)), and proceeded by a period of gradual flow decrease from the apex to the minimum flow rate.

[0103] A flow cycle pause (410, 440) may or may not be present within a flow cycle (400). A flow cycle pause is a period before (410) or after (440) a pattern of flow where there is no flow to the needle assembly body (122); it is usually where the needle assembly is in the starting or fully withdrawn position. A flow cycle pause has a duration (flow cycle duration (412, 442)). The flow cycle optionally contains a flow cycle pause (410) before the pattern of flow (having a flow pause duration) and optionally contains a flow cycle pause (440) after the pattern of flow (having a flow pause duration). Where a flow cycle pause is present both before and after a pattern of flow, there are two flow cycle pauses.

[0104] Each flow cycle pause may be of the same duration during an administration session, or at least two flow cycle pauses may be different during an administration session.

[0105] A flow cycle pause may provide a time window for displacement of the system between different locations on the skin surface.

[0106] There may be several different flow cycles, each having a different pattern of flow (e.g. selected from a library of 5 to 10 patterns of flow) within an administration session. Each different pattern of flow may have: a different flow pattern duration, and / or a different maximum flow rate and / or different minimum flow rate, and / or a different flow rate variation from the flow pattern start position / time to the flow pattern end position / time.

[0107] Where there are several different flow cycles within an administration session, each having a different pattern of flow, they may be implemented in a defined order or randomly. Where they are implemented in a defined order, the defined order is repeated during the administration session.

[0108] Each flow cycle pause may be of the same duration (flow pause duration) during an administration session, or at least two flow cycle pauses may be of different duration (flow pause duration) during an administration session.

[0109] A flow cycle pause may be used to displace the system between different locations on the skin surface.

[0110] Where there are several different patterns of flow within an administration session, each having a different flow pattern duration, flow cycle pause duration may be adjusted so that the flow cycle duration is constant (and corresponds to the flow cycle frequency set during an administration session)

[0111] A synchronisation between the stroke cycle (300) and the flow cycle (400) may be set by selecting values of parameters of the stroke cycle (300) and selecting values of parameters of the flow cycle (400). FIG. 5 is a schematic illustration of a flow cycle synchronised with a stroke cycle. Different examples of synchronisation between the stroke cycle (300) and the flow cycle (400) are provided below.

[0112] The flow cycle duration (406) is preferably equal to the stroke cycle duration (306).

[0113] The flow cycle frequency is preferably equal to the stroke cycle frequency .

[0114] The flow cycle start (402) and stroke cycle start (302) are preferably at the same time.

[0115] The stroke pattern start time (324) and the flow pattern start time (424) are the same or are more preferably offset in time. Where they are offset, the flow pattern start time (424) is after the stroke pattern start time (324). The offset may be adjustable.

[0116] The flow cycle is synchronised with the stroke cycle such that the flow rate is increasing:

[0117] - during a period of the stroke cycle in which the set (124) of hollow needles (125) is greater than 0% protruding, and - during a period of the stroke cycle in which the needle assembly body (122) is moving in a net direction towards 0% protruding; and

[0118] - after the needle assembly body (122) has reached a fully deployed position.

[0119] The flow cycle is synchronised with the stroke cycle such that the maximum flow rate is maintained:

[0120] - during a period of the stroke cycle in which the set (124) of hollow needles (125) is greater than 0% protruding, and

[0121] - during a period of the stroke cycle in which the needle assembly body (122) is moving in a net direction towards 0% protruding; and

[0122] - and optionally after the needle assembly body (122) has reached a fully deployed position.

[0123] The flow cycle (400) is synchronised with the stroke cycle (300) such that the maximum flow rate is reached during a period of the stroke cycle in which the set of hollow needles is greater than 0% protruding and retracting.

[0124] The flow cycle (400) is synchronised with the stroke cycle (300) such that the maximum flow rate is reached during a period of the stroke cycle in which the set of hollow needles is greater than 50% protruding and retracting.

[0125] The flow cycle (400) is synchronised with the stroke cycle (300) such that the maximum flow rate is reached during a period of the stroke cycle in which the set of hollow needles is greater than 50% protruding.

[0126] The flow cycle is synchronised with the stroke cycle such that the flow rate is greater than zero during a period of the stroke cycle in which the set (124) of hollow needles (125) is below the exterior surface of the skin.

[0127] The flow cycle is synchronised with the stroke cycle such that the flow rate is zero during a period of the stroke cycle in which the set (124) of hollow needles (125) is above the exterior surface of the skin. Where at least one needle or all the needles in the set (124) of hollow needles (125) has a pointed tip that is bevelled, the flow rate is preferably zero during a period of the stroke cycle in which a terminal end of the tip bevel is below the exterior surface of the skin and an opening or a part of the opening of the tip bevel is above the exterior surface of the skin.

[0128] The flow cycle (400) is synchronised with the stroke cycle (300) such that the minimum flow rate is reached during a period in which the needle assembly body (122) is at a fully withdrawn position of the stroke cycle.

[0129] The flow cycle (400) is synchronised with the stroke cycle (300) such that the maximum flow rate is reached during a period of the stroke cycle in which the set of hollow needles is greater than 0% protruding.

[0130] The flow cycle (400) is synchronised with the stroke cycle (300) such that the minimum flow rate is reached during a period in which a proximal most tip of the needle is retracted behind the skin contact surface (126).

[0131] The skin contact surface (126) is a surface configured for making contact with the skin of the subject. It is disposed at a distal (12) end of the system. It comprises at least one, preferably a plurality of needle apertures for passage therethrough of the set (124) of needles (125). The skin contact surface (126) may be planar, or non-planar (e.g. rounded, concave, convex, domed). An axial position of the skin contact surface (126) may be non- adjustable, or may be adjustable (and lockable at a selected axial position). The axial position of the skin contact surface (126) is preferably adjustable by the operator.

[0132] A needle (125) has a length (c / n) as measured from the needle tip to the needle base (128) (FIG. 6). The needle base (128) is where the needle contacts an exterior surface of the needle assembly body (122).

[0133] A majority or all of the needles of the set (124) may have the same length (dn). Typically the majority or all of the needles of the set (124) have the same length (dn) when the skin contact surface (126) is planar. Where all the hollow needles (125) in the set (124) have the same length (dn), a length of the needles from tip to base (128) may be 3 to 10mm, preferably 4 to 5 mm. Some of the needles (125) of the set (124) may have different lengths (dn). Typically the majority or all of the needles of the set (124) have the different lengths when the skin contact surface (126) is non-planar (e.g. rounded, concave, convex, domed) such that a distance from each needle tip to the skin contact surface (126) is the same for all the needles.

[0134] Where some of the hollow needles (125) in the set (124) have different lengths (dri), a length of the longest needle from tip to base (128) may be 3 to 10 mm. Where some of the hollow needles (125) in the set (124) have different lengths, a length of the shortest needle from tip to base may be 3 to 7 mm.

[0135] A guard distance (dg) is a distance between the skin contact surface (126) and the tip of a needle (125) when the needle assembly body (122) in the fully withdrawn position (FIG. 6). More in particular, it is a distance along an axis of movement of the needle, between a tip of the needle (125) and a proximal (10) side of skin contact surface (126) when the needle assembly body (122) in the fully withdrawn position. The guard distance (c / g) is preferably the same for all needles. An adjustment to the axial position of the skin contact surface (126) causes a change in the guard distance. The guard distance (c / g) may be 1 mm up to 10mm. The needle gauge may be 22 to 34.

[0136] Number of needles in the set (124) is 1 or more, or 2 more, preferably 5, 10, 15 or 20 needles.

[0137] The set (124) of hollow needles (125) is preferably arranged in one or more linear rows. According to one aspect, there are multiple linear rows, each and every row has the same quantity of needles.

[0138] According to another aspect, there are multiple linear rows, and within a first portion of rows of the multiple linear rows each and every row has a first quantity of needles; optionally within a second portion of rows of the multiple linear rows each and every row has a second quantity of needles different from the first quantity of needles.

[0139] According to another aspect, there are multiple linear rows, each and every linear row has the same spread pattern of needles.

[0140] According to another aspect, there are multiple linear rows, and within a first portion of rows of the multiple linear rows each and every row has the same first spread pattern of needles; optionally within a second portion of rows of the multiple linear rows each and every row has the same second spread pattern of needles, wherein the second spread pattern of needles is different from the first spread pattern of needles.

[0141] According to another aspect, according to one spread pattern, the needles are evenly separated.

[0142] As mentioned elsewhere herein, the set of hollow needles may be protruding by a defined percentage. The percent protruding is a percentage of an axial distance of tips of the set (124) of hollow needles (125) from (the distal (12) side of) the skin contact surface (126) during the stroke cycle compared with the axial distance of tips of the set (124) of hollow needles (125) in the fully deployed position, 100% protruding being in the fully deployed position, and 0% protruding meaning none of the tips of the set (124) (124) of hollow needles (125) protrude (distally) beyond the skin contact surface (126). 0% protruding may or may not be when the needle assembly body (122) is in the fully withdrawn position. The percent protruding as a function of the stroke cycle frequency is affected by the guard distance (dg).

[0143] The needle assembly (120) may be configured such that all the hollow needles (125) in the set (124) protrude equally when the percent protrusion is 100%. In such configuration, all the hollow needles (125) in the set (124) may have the same length. The length of the needle is defined as a distance in an axial direction between a distal (12) surface (128) of the assembly body (122) and the distal (12) needle tip. Alternatively, some of the hollow needles may have different lengths and the distal (12) surface (128) of the needle assembly body (122) is adapted (e.g. provided with compensating indents and / or protrusions) so that all the hollow needles (125) in the set (124) protrude equally when the percent protrusion is 100%. The needle assembly (120) may be configured such that some the hollow needles (125) in the set (124) protrude differentially when all the needles protrude from the skin contact surface (126). In such case, only most protruding needle(s) of the set (124) considered for determining the percent protruding of the set (124).

[0144] According to one aspect, liquid only flows from the set of needles during a period of the stroke cycle (300) in which the set (124) of hollow needles (125) is equal to or greater than 20% to 100% protruding. According to one aspect, liquid only flows from the set of needles during a period of the stroke cycle in which the set (124) of hollow needles (125) is 100% protruding.

[0145] According to one aspect, liquid only flows from the set of needles during a period of the stroke cycle in which the set (124) of hollow needles (125) is being withdrawn.

[0146] According to one aspect, liquid only flows from the set of needles during a period of the stroke cycle in which the set (124) of hollow needles (125) is 100% to 50% protruding and is being withdrawn.

[0147] 100% protruding preferably corresponds to a distance in a range 1 to 5 mm. The distance is the axial distance of tips of the set (124) of hollow needles (125) from (the distal (12) side of) the skin contact surface (126). The distance may be determined by the position of the needle assembly body (122) in the fully deployed position and / or by the guard distance.

[0148] A liquid supply system (900) is provided configured to contain (e.g. in a reservoir) a supply of liquid for the dosing element (800). The supply of liquid may or may not be held under positive (hydrostatic) pressure. The liquid outputted from the liquid supply system (900) may or may not have a positive (hydrostatic) pressure. The liquid supply system (900) may be comprised in a syringe pump.

[0149] The dosing element (800) comprises one of

[0150] - a volumetric pump, or

[0151] - a controlled valve.

[0152] Both are configured for creating an accurate intermittent flow. Both are configured for producing a dose of liquid to the needle assembly (300) according to the flow cycle frequency (Hz) of > 5 Hz, preferably >10, most preferably >20 Hz. The flow cycle frequency is most preferably <25 Hz.

[0153] The dosing element (800) may or may not be comprised within the cartridge (200). Where it is comprised within the cartridge, it is comprised within the needle assembly body (122) of the cartridge (200).

[0154] The dosing element (800) may comprise a controlled valve, and a primary (valve) control unit configured to regulate the controlled valve such that flow rate specified within the flow pattern and flow cycle frequency is met. The valve control unit may be integrated into the primary control unit. In other words, the dosing element (800) may comprise a controlled valve, and a primary control unit configured to regulate the controlled valve such that flow rate specified within the flow pattern and flow cycle frequency is met.

[0155] The controlled valve may be rotary (e.g. ball valve, cylinder valve) or displacement (e.g. plunger / needle valve, membrane valve) operated.

[0156] The regulation of the controlled valve may be achieved mechanically, for instance, being linked to the stroke cycle. The regulation of the controlled valve may be achieved electronically, for instance, using timing signals that are also used to control the stroke cycle.

[0157] Where the dosing element (800) comprises a controlled valve, the liquid supply system (900) comprises a separate pump for supplying the liquid under positive pressure to the controlled valve at a definable and preferably constant flow rate. The aforementioned flow rate is determined according to variation in amplitude of the flow cycle. The separate pump may be any kind of pump configured for providing liquid from the supply of liquid to the controlled valve, for instance, a peristaltic pump, a diaphragm pump, a syringe pump, or a piston pump.

[0158] Where the dosing element (300) comprises a controlled valve, the conduit (910) between the liquid supply system (900) and the controlled valve (800) may comprise a region of volumetric elasticity. The region of volumetric elasticity may be implemented in an elastically expandable wall (part or complete) of the conduit and / or by presence of an expansion chamber in fluid connection with the conduit having elastically expandable wall. This allows the conduit (910) to act as a buffer. In other words, the connection (conduit (910)) between the liquid supply system (900) and controlled valve (800) has a region of volumetric elasticity and is configured to act as a fluid buffer to reduce variation over time of a (hydrostatic) pressure at an inlet to the controlled valve (800). For instance, if liquid flows from the liquid supply system (900) at a rate of Q1 , and liquid flows from the controlled valve (800) at a rate of Q2, and temporarily Q1 >Q2 during a flow cycle, then the region of volumetric elasticity starts to expand, thereby buffering the excess liquid caused by the momentary Q1 >Q2. To the contrary, if temporarily Q2>Q1 during a flow cycle, then region of volumetric elasticity starts to contract, thereby releasing the excess liquid caused by the momentary Q2>Q1.

[0159] Thus, during a cycle, variations of flow rate from an outlet of the liquid supply system (900) may be tolerated without affecting the desired flow rate from an outlet of the controlled valve (800) according to the flow cycle. It is preferred that a flow rate over a flow cycle from the outlet of the liquid supply system (900) equals the average desired flow rate over a flow cycle at the outlet of the dosing element (800).

[0160] Where the dosing element (800) comprises a controlled valve and the liquid supply system (900) comprises a separate pump that is a syringe pump, a flow rate setting of the syringe pump is preferably adjusted responsive to the flow cycle dose i.e. a total volume of liquid outputted by the set (124) of one or more hollow needle(s) (125) in one flow cycle. The flow rate setting of the syringe pump is preferably constant during the flow cycle (400).

[0161] Where the dosing element (800) comprises a controlled valve and the liquid supply system (900) comprises a separate pump that is a syringe pump, the syringe pump may be actuated at a speed such that an outflow from the syringe pump per cycle period (per flow cycle 400 in FIG. 4 or per stroke cycle 300) equals the flow cycle dose More preferably, an average of the outflow from the syringe pump per cycle period over a period is equals the flow cycle dose over the same period. The speed of the syringe pump is preferably constant during the flow cycle (400).

[0162] Pressure (hydrostatic pressure) between in a conduit (910) between the liquid supply system (900) and the controlled valve (800) may be controllable, responsive to the flow cycle dose i.e. total volume of liquid outputted by the set (124) of one or more hollow needle(s) (125) in one flow cycle. This is particularly the case when the liquid supply system is held under positive pressure (e.g. is a syringe pump). The pressure (hydrostatic pressure) is controllable by adjusting an output flow rate of the liquid supply system (e.g. of the a syringe pump).

[0163] A (hydrostatic) pressure sensor may be disposed at an inlet to the dosing element (800), at an outlet of the liquid supply system (900), between an outlet of the liquid supply system (900) and an inlet to the dosing element (800), or in a conduit (910) between the liquid supply system (900) and the controlled valve (800). This is particularly the case when the liquid supply system is held under positive pressure (e.g. is a syringe pump) or an output of the liquid supply system has a positive pressure . The pressure measured by the pressure sensor may be used to regulate a flow rate setting of the liquid supply system (900). For instance, the pressure measured by the pressure sensor may regulate the flow rate setting of the liquid supply system in a closed feedback loop system. Where the pressure is above a threshold, the flow rate setting of the liquid supply system is reduced. Where the pressure is below a threshold, the flow rate setting of the liquid supply system is increased. The threshold is preferably determined by the flow cycle dose i.e. total volume of liquid outputted by the set (124) of one or more hollow needle(s) (125) in one flow cycle. Where the flow cycle dose is increased, the threshold is increased. Where the flow cycle dose is decreased, the threshold is decreased. The pressure measured by the pressure sensor may be used to limit a flow rate setting of the liquid supply system (900) where an over-pressure is detected.

[0164] A force sensor may be disposed within the liquid supply system (900) configured for determining an applied force on an actuator of the liquid supply system (900). The actuator is a part of the liquid supply system (900) that induces movement of the liquid pressure. For instance, where the liquid supply system comprises a syringe, the force sensor may be placed at a position for measurement of a force (e.g. from an motorized arm) applied to a plunger of the syringe. One position of the force sensor may be between the arm and the plunger thumb rest; another position of the force sensor may be between the barrel and barrel stop. Alternatively, the force sensor may measure force level of the (motor) actuator or by measuring the motor force. Measurements from the force sensor are reflective of the (hydrostatic) pressure in a conduit (910) between the liquid supply system (900) and the controlled valve (800). The force sensor is preferably present when the liquid supply system is held under positive pressure (e.g. is a syringe pump) or an output of the liquid supply system has a positive pressure. The force measured by the force sensor may be used to regulate a flow rate setting of the liquid supply system (900). For instance, the force measured by the pressure sensor may regulate the flow rate setting of the liquid supply system in a closed feedback loop system. Where the force is above a threshold, the flow rate setting of the liquid supply system is reduced. Where the force is below a threshold, the flow rate setting of the liquid supply system is increased. The threshold is preferably determined by the flow cycle dose i.e. total volume of liquid outputted by the set (124) of one or more hollow needle(s) (125) in one flow cycle. Where the flow cycle dose is increased, the threshold is increased. Where the flow cycle dose is decreased, the threshold is decreased. The force measured by the pressure sensor may be used to limit a flow rate setting of the liquid supply system (900) where an over- force is detected.

[0165] A flow rate setting of the liquid supply system (900) that is under positive pressure (e.g. is a syringe pump) may be adjusted according to the total volume of liquid outputted by the set (124) of one or more hollow needle(s) (125) in one flow cycle. Where the flow cycle dose is increased, the flow rate setting of the liquid supply system (900) is increased. Where the flow cycle dose is decreased, the flow rate setting of the liquid supply system (900) is decreased. The flow rate setting of the liquid supply system (900) that is under positive pressure (e.g. is a syringe pump) is preferably adjusted such that it matches the total volume of liquid outputted by the set (124) of one or more hollow needle(s) (125) in one flow cycle.

[0166] The dosing element (800) may comprise a volumetric pump. Examples of volumetric pump include:

[0167] - a peristaltic pump,

[0168] - a diaphragm pump or membrane pump, or

[0169] - a piston pump or plunger pump.

[0170] Where the dosing element (300) comprises a volumetric pump (800), the liquid in the liquid supply system (900) may be held under positive pressure. The positive pressure may be constantly applied; positive pressure may be applied, for instance, using a spring, piston, motor / spindle drive. The liquid supply system (900) may be comprised within a syringe pump. Where the dosing element (300) comprises a volumetric pump (800), the controlled valve (800’) may be absent.

[0171] Where the dosing element (800) comprises a peristaltic pump, a volume in a tube lumen (of a flexible tube) held between adjacent rollers compressing the tube lumen is less than a liquid volume delivered during the stroke cycle.

[0172] Where the dosing element (800) comprises a diaphragm pump or membrane pump, a diameter of the diaphragm or membrane is preferably equal to or less than five times a displacement distance of the diaphragm or membrane during a period of positive flow from the pump. The displacement distance is a distance moved by the diaphragm or membrane between one extreme end of its motion and the other extreme end of its motion.

[0173] Optimally the diameter is equal to or less than two times said displacement distance.

[0174] Where the dosing element (300) comprises a piston or plunger pump, a diameter of the piston is preferably equal to or less than five times a displacement distance of the piston during “injection” (forwards) during a period of positive flow from the pump. The displacement distance is a distance moved by the piston between one extreme end of its motion and the other extreme end of its motion.

[0175] Optimally the diameter is equal to or less than two times said displacement distance.

[0176] The system may further comprise a movement inducer configured to induce movement in the needle assembly body (122) (according to the stroke cycle or needle stroke cycle).

[0177] The movement inducer preferably comprises a motor (e.g. stepper motor, servo motor, continuously-rotating motor, or a linear motor). Where the movement inducer comprises a stepper motor or servo motor, the stepper motor or servo motor may be controlled to move between a certain angle range that reflects a distance moved by the needle assembly body (122) between the fully withdrawn position and the fully deployed position, at the stroke cycle frequency (Hz). The angular (rotational) motion of the stepper motor or servo motor may be transformed into a sliding motion using any known element, such as, for instance, a transmission bar, and / or rack and pinion.

[0178] Where the movement inducer comprises a continuously-rotating motor, the continuously- rotating motor a mechanism is included to transform the continuous rotary motion in a sliding (back and forth) motion using any known element, such as for instance, a slider crank mechanism.

[0179] The stroke cycle is a cycle of slidable movement (over time) of the needle assembly body (122) within a stroke cycle period in which the needle assembly body (122) undergoes one complete pattern of motion. The slidable movement is with respect to the skin contact surface (126). The movement is linear (i.e. forwards and / or backwards). The needle stroke cycle is defined as slidable movement (over time) of the set (124) of hollow needles (125) relative to the skin contact surface (126) within a stroke cycle in which the needle assembly body (122) undergoes one complete pattern of motion. The needle stroke cycle is identical to the stroke cycle, except: for an offset caused by length of the needle(s), and a lower amplitude of the motion may be clipped by the skin contact surface (126). The extent (quantity) of clipping is determined by a guard distance. The greater the guard distance the greater the clipping of the lower amplitude of the motion. The guard distance may be between 0.5 to 3 mm (depending on the shape of the proximal (10) side of the skin contact surface (126)) to avoid skin damage (scratching) during repositioning of the system.

[0180] The liquid delivered to the subject’s skin may be any. For instance, the liquid may be any suitable for treatment of one or more psoriasis, burns, skin-related (pre-)malignancies, alopecia, striae, cellulite, hyperhidrosis, pigmentation disorders, scarring (e.g. traumatic, burn), wounds, age- or sun-induced skin damage. The liquid may be any suitable for a cosmetic treatment such as skin rejuvenation or mesotherapy.

[0181] The liquid may comprise one or more of hyaluronic acid, vitamins and minerals, amino acids, coenzymes L-carnitine, Growth factors, peptides, caffeine, botulinum toxin, autologous fat, corticoid, 5-fluorouracil. The liquid may comprise one or more of fat derivatives, blood-derivatives, autologous or allogeneic acellular fractions from bodily fluids and tissues as the acellular fraction from fat tissue or separated extracellular vesicles.

[0182] For the skin rejuvenation or mesotherapy, the liquid may contain one or more skin rejuvenation agents such as hyaluronic acid, vitamins and minerals, amino acids.

[0183] According to a preferred aspect, system further comprises a primary control unit (700). The primary control unit (700) is configured to control at least the flow cycle (400), the stroke cycle and their synchronisation. An example of a configuration of the presently-disclosed system (100) including a primary control unit (700) is shown in FIG. 11. The stroke cycle (300), and the flow cycle (400) and their synchronisation are controlled by a primary control unit (700). The dosing unit (800) and movement inducer (140) are each operatively connected to the primary control unit (700). The primary control unit (700) is configured to generate and output signals (electronic) for controlling the dosing unit (800) and the movement inducer (140) according to the flow cycle (400) and the stroke cycle (300) respectively, and is configured to control their synchronisation.

[0184] Signals (electronic) from the primary control unit (700) are received by the dosing unit (800) and movement inducer (140) in order to control the dosing unit (800) and movement inducer (140) respectively. In particular, signals (electronic) outputted from the primary control unit (700) are received by the dosing unit (800) and movement inducer (140) in order to control the flow cycle (400), the stroke cycle (300), respectively, and their synchronisation.

[0185] Where a parameter is described as being adjustable by the operator, the operator may input a desired parameter value into the primary control unit (700), and the primary control unit controls the stroke cycle (300), the flow cycle (400) and their synchronisation according to the operator input. The adjustment by the operator may be dynamic; in other words, one or more parameter values may be adjusted during the administration session.

[0186] According to one aspect, the primary control unit may receive an input from an operator of a selection of a pre-prepared program, and the primary control unit controls the stroke cycle (300), the flow cycle (400) and their synchronisation according to the selected pre-prepared program. The pre-prepared program may be downloadable into the primary control unit.

[0187] According to a preferred aspect, the primary control unit is configured to adjust dynamically the stroke cycle (300), and the flow cycle (400) and their synchronisation. The dynamic adjustment may be responsive to an operator input and / or to a sensor input.

[0188] The primary control unit may be configured to control the (slidable) movement of the needle assembly body (122) according to the stroke cycle (300). The primary control unit may be configured to control a movement inducer configured to induce movement in the needle assembly body (122) according to the stroke cycle. More specifically, the primary control unit may be configured to control the movement inducer such that the slidable movement of the needle assembly body (122) induced in the needle assembly body (122) is according to the stroke cycle.

[0189] The primary control unit may be configured to control one or more, a plurality, or all of the parameters of the stroke cycle (300).

[0190] The parameters of the stroke cycle are mentioned elsewhere herein. The parameters of the stroke cycle are exemplified in FIG. 3. Parameters of the stroke cycle include:

[0191] - the stroke cycle duration (306);

[0192] - the optional (start) stroke cycle pause duration (312) of the optional (start) stroke cycle pause (310);

[0193] - the pattern of motion (320); the stroke pattern start time (324) of the stroke pattern start position (322); the stroke pattern end time (334) of the stroke pattern end position (332); the stroke pattern duration (330); the fully deployed position (329); the fully withdrawn position (328);

[0194] - the optional (end) stroke cycle pause duration (342) of the optional (end) stroke cycle pause (340); and

[0195] - the stroke cycle frequency;

[0196] The primary control unit may be configured to control the variation in flow rate during the flow cycle duration (406) of the flow cycle.

[0197] The primary control unit may be configured to control the dosing element (800) such that the liquid is provided to the set (124) of hollow needle(s) (125) according to a flow cycle (400).

[0198] The primary control unit may be configured to control the dosing element (800) such that the variation in the flow rate during the flow cycle duration (406) is met.

[0199] The primary control unit may be configured to control the controlled valve such that the liquid is provided to the set (124) of hollow needle(s) (125) according to a flow cycle (400). The primary control unit may be configured to control the controlled valve such that the variation in the flow rate during the flow cycle duration (406) is met.

[0200] The primary control unit may be configured to control the volumetric pump such that the liquid is provided to the set (124) of hollow needle(s) (125) according to a flow cycle (400). The primary control unit may be configured to control the volumetric pump such that the variation in the flow rate during the flow cycle duration (406) is met.

[0201] The primary control unit may be configured to control one or more, a plurality, or all of the parameters of the flow cycle (400).

[0202] The parameters of the flow cycle are mentioned elsewhere. The parameters of the flow cycle are exemplified in FIG. 4. Parameters of the flow cycle include:

[0203] - the flow cycle duration (406);

[0204] - the optional (start) flow cycle pause duration (412) of the optional (start) flow cycle pause (410);

[0205] - the pattern of flow (420); the flow pattern start time (424) of the flow pattern start rate (422); the flow pattern end time (334) of the flow pattern end rate (432); the flow pattern duration (430); the maximum flow rate (429); the minimum flow rate (428);

[0206] - the optional (end) flow cycle pause duration (442) of the optional (end) flow cycle pause (440);

[0207] - the flow cycle dose; and

[0208] - the flow cycle frequency.

[0209] The primary control unit may be configured to control a synchronisation between the stroke cycle (300) and the flow cycle (400). A synchronisation between the stroke cycle (300) and the flow cycle (400) may be set by selecting one or more values of parameters of the stroke cycle (300) and selecting one or more values of parameters of the flow cycle (400), for instance:

[0210] -the flow cycle duration (406) is preferably equal to the stroke cycle duration (306); - the flow cycle frequency is preferably equal to the stroke cycle frequency;

[0211] - the flow cycle start (402) and stroke cycle start (302) are preferably at the same time.

[0212] The primary control unit may be configured to control a synchronisation between the stroke cycle (300), and the flow cycle (400) such that the stroke pattern start time (324) and the flow pattern start time (424) are the same or are more preferably offset in time. Where they are offset, the flow pattern start time (424) is after the stroke pattern start time (324).

[0213] The primary control unit may be configured to control a synchronisation between the stroke cycle (300) and the flow cycle (400) such that

[0214] - a maximum flow rate is reached or maintained during a period of the stroke cycle as mentioned elsewhere herein, or

[0215] - a minimum flow rate is reached or maintained during a period of the stroke cycle as mentioned elsewhere herein, or

[0216] - a flow rate greater than zero is reached or maintained during a period of the stroke cycle as mentioned elsewhere herein, or

[0217] - a flow rate of zero is reached or maintained during a period of the stroke cycle as mentioned elsewhere herein.

[0218] The primary control unit is an electronic control unit. It usually comprises a microcontroller, which typically is provided as an integrated circuit (IC) or as a printed circuit board (PCB) comprising a microprocessor (processing unit / calculation unit) as well as other elements such memory, input / output ports, timer(s), interface(s) and the like. The microprocessor runs software loaded into memory of the microcontroller. The primary control unit may include a communication interface allowing communication with the primary control unit e.g. using a control panel, using one or more switches, dials, using a wireless connection to a smart device.

[0219] Examples of suitable microcontrollers include those manufactured by STMicroelectronics (e.g. STM32), Microchip, Texas Instruments, NXP Semiconductors, or any having a requisite specifications including processing speed, quantity of I / O ports, form factor, and the like. The stroke cycle (300), the flow cycle (400) and their synchronisation are adjustable by setting one or more parameter values within software of the primary control unit. The adjustment may be dynamic; in other words, one or more parameter values may be adjusted during the administration session. The adjustment may be by the operator. The adjustment may be automatic e.g. responsive to a sensor, such as a pressure sensor for detecting liquid pressure in the needle assembly, and / or an infra-red sensor for measuring skin depth.

[0220] Provided herein is a cartridge (200) configured for operative attachment to the system described herein. The cartridge (200) comprises a needle assembly (120) comprising a needle assembly body (122) and a set (124) of one or more hollow needle(s) (125) attached to the needle assembly body (122), each needle having a lumen for delivery of the dose of the liquid. A chamber (130) is provided in the needle assembly body (122) for receiving and distributing the liquid to the set (124) of one or more hollow needle(s) (125). An inlet to the chamber (130) is connectable to an outlet of the dosing element (800).

[0221] Provided herein is a method for treatment (medical or cosmetic) of a subject by multiple- repeated deliveries of a dose of a liquid below an exterior surface of a skin of the subject comprising using a device described herein.

[0222] A problem in the art of drug delivery liquid below an exterior surface of a skin of a subject, for an area of the skin exterior surface is accurate delivery of dose to the target. Accurate dosing is critical in many application such as delivery of active agents for treatment of disorders of the skin including psoriasis, burns, skin-related (pre-) malignancies, alopecia, striae, cellulite, hyperhidrosis, pigmentation disorders, scarring (e.g. traumatic, burn), wound healing, age- or sun-induced skin damage.

[0223] Using typical devices of the art, skin is pierced using solid needles, and liquid applied to the skin surface is driven intradermally using an outer surface of the needle. Liquid is hence distributed on the skin surface - which is not the target. Further, liquid is pushed below the surface which relies on several factors (parameters) including liquid viscosity, and elasticity of the subjects skin tissue. The inventors have found that hollow needles provide a more accurate dose and are less wasteful of liquid, since liquid is administer only below the exterior surface of the skin of the subject.

[0224] Certain devices use hollow needles, however, the speed and deposition efficiency of these devices is low. Deposition efficiency refers to an amount of liquid that is dispensed from the set of hollow needles compared with an amount of liquid that is absorbed on or below the skin. In such art devices of the art, flow liquid to the needles is continuous when the set of needles is both fully deployed and fully withdrawn. Liquid is both dispensed below the skin surface and onto the skin surface. Such devices require time for the liquid provided in the fully withdrawn position that is delivered onto the skin surface to be absorbed (if at all) into the holes. Efficiency of such devices is reasonable at low cycle frequency (< 1 Hz), however, treating a large area is time consuming, expensive, and is still wasteful of liquid that is not absorbed.

[0225] By employing a dosing element (300) configured for providing the liquid to the set of hollow needles according to the flow cycle, deposition of liquid on the skin surface can be avoided, absorption times are reduced, and cycle frequency can be increased by a factor 5 to 10 which reduces treatment time and costs. Speed is increased while fluid deposition efficiency is maintained. This is the case whether the set of hollow needles contains 2, 10, 20, or more hollow needles.

[0226] The reduction in time improves patient comfort since the treatment is painful for the subject, even when anesthetic cream is used. Having a flow cycle synchronized to the stroke cycle reduces waste because liquid flow can be minimized in parts of the stroke cycle where the set of needles is not below the skin surface.

[0227] By employing a dosing element (300) configured for providing the liquid to the set of hollow needles according to the flow cycle, a speed of the stroke cycle can be increased, for instance to >5 Hz. The dosing element allows for an accurate intermittent flow at higher stroke cycle frequency s compared with, for instance, a syringe pump-only arrangement which does not have a capacity for a flow start-stop rate, which places a limit on the volume of liquid that can be controllably dispensed during faster stroke cycle frequency. Shown in FIG. 7 is a comparison of using the dosing element compared with using the syringe pump- only; with a conventional syringe pump, a high flow rate cannot be achieved for an intermittent flow at higher injection speeds (stroke cycle > Hz).

[0228] The inventors have further found that dosing accuracy is affected when liquid is administered during movement of a needle towards the deployed position. Without being bound to any theory, it is thought that a resistance to flow liquid is created, namely forward pressure of the liquid from the lumen of the needle is countered by a back pressure formed at the outlet of the needle lumen during advancement of the needle below the exterior surface of the skin of the subject. Heterologous resistance to flow between different needles causes an unpredictable dose to different needles with each injection. The inventors have found that by imposing a cyclic forward flow that reduces or stops liquid flow during movement to the deployed position compared with movement to the withdrawn position, the actual quantity of liquid delivered more closely matches the expected quantity of liquid delivered per needle. In other words, dose of liquid to needles of the set of needles is more homogenous.

[0229] The inventors have found that a short stroke cycle duration (e.g. stroke cycle frequency >5 Hz) has an advantage of improving equal flow distribution through the different needles resulting in a more homogenized delivered fluid volume through every needle. FIG. 8 shows an exemplary equivalent schematic for the flow resistance in the fluid path of the present system.

[0230] Rn indicates the flow resistance element in the circuit, Pn indicates a pressure measured and Q represents a volumetric flow rate. The pressure drop (AP (Pna. - Pnb)) over a flow resistance element can be calculated as the flow resistance multiplied by the volumetric flow rate (see formula (1)).

[0231] AP = R * Q (1)

[0232] For laminar flow the flow resistance R may be determined with the Hagen-Poiseuille equation: 128 * * L (2)

[0233] Wherein: • L is the length of pipe,

[0234] • p is the dynamic viscosity,

[0235] • D is the inner diameter of the channel.

[0236] In FIG. 8, the fluid is supplied by the fluid supply unit (800) and delivered to the dosing unit (800). The conduit connecting both has a flow resistance described by Rsuppiy (which is low by design resulting in Pr« P2) The elastic expansion of the region of volumetric elasticity in the conduit connecting the fluid supply unit (800) to the dosing unit (800) is represented by the buffer with flexibility kCOnnection hose The dosing unit (800) is further connected to the needle assembly body (122) and a set (124) of one or more hollow needle(s) where the flow is distributed to all needles. The connection between the dosing unit and the needle assembly body (122) is represented by Rconnect (which is low by design resulting in P3« P4). The flow resistance of the fluid path to and through each needle is represented by Rneedie 1 to n with n the number of needles. When dispensing liquid through the needles when the needles are in the skin, there is a counterpressure Ptissue 1 to n that has to be overcome to dispense the fluid from the needle into the skin.

[0237] Flow averaged over one cycle in the first part of the system is equal as the same fluid volume passes through every element and resistance elements have no impact on the flow distribution through the different needles:

[0238] Qi=Q2=Q3=Q4 (3)

[0239] The volumetric fluid outflow through these needles is to be equalised: ?5.1=?5.2=?5.3 (4)

[0240] The flow entering the chamber (130) splits the fluid flow, which is equal to the sum of flow leaving the seperate needles:

[0241] Q4=Qs.l + Qs.2 + ?5.3 (5)

[0242] The counterpressure created by the soft tissue is dependent on the permeability of the local tissue structure and is thus slightly different for each needle.

[0243] The flow distribution through the different needles is determined by the formula’s (6) below in combination with formula (5).

[0244] By construction the internal flow path in the needle assembly body (122) for each needle is designed to be equal:

[0245] Pneedle 1—Pneedle 2—Pneedle 3 (7)

[0246] To equalize the flow through the needles ((25.1, (25.2 and Q5 3) the terms P4- Ptissue n have to be equalized. This may be done by increasing P4to reduce the impact of inequality between the terms Ptissue nonthe fluid flow. This will create a higher pressure drop over the needles and a higher momentary volumetric flow. As the injected volume is fixed, a shorter injection period (e.g. stroke cycle frequency >5 Hz) will equalize the flow through the needles.

[0247] The second way to homogenize the fluid flow is to equalize the soft tissue counterpressure Ptissue n- This can be realized by performing the fluid injection during retraction of the needle as explained in the next section.

[0248] When the needles advancing towards the fully deployed position and penetrating the skin, soft tissue is pressed against the needle opening due to the needle insertion. When fluid is injected during this period, the fluid flow (602) into the compressed soft tissue (600) through the small area of the needle opening as shown in FIG. 9 Panel A resulting in a high counterpressure. Furthermore, due to the heterogeneous structure of the dermis, the counterpressure is different for every needle. As described in formulas above, a high and heterogenous counterpressure results in a less equal flow distribution through the different needles.

[0249] Alternatively, the fluid may be injected during needle retraction as shown in FIG. 9 Panel B. This approach has a two-step advantage to homogenize the fluid flow and fluid delivery through all needles. By inserting the needle in the soft tissue, a cavity (604) is created which can be filled during needle retraction. For filling this cavity (604) no flow needs to be absorbed by the soft tissue yet thus creating a low and highly equal backpressure resulting in equalized flow through the different needles. As in the first stage of the injection the volume of the cavity (604) is filled, the complete outer surface of the filled cavity (fluid boundary) provides a significantly increased contact area between the fluid and the soft tissue to allow for fluid absorption by the soft tissue. This increase of contact area reduces the flow resistance of the soft tissue for absorbing fluid thus resulting in a reduced counter pressure. The reduced counter pressure results again in a more homogenized fluid flow.

[0250] Deposition efficiency is dependent on several factors, including a viscosity of the liquid, a liquid flow rate, an injection depth, and also skin type. Concerning skin type, there may be local variations in absorption capacity and tissue structure (e.g. elasticity or rigidity, toughness). Where a dose is only partially absorbed, excess liquid seeps from the injection channel (wasteful), and the quantity absorbed is far less than intended meaning the subject is underdosed.

[0251] Being able to adjust one or more parameter values (e.g. one or more flow cycle parameter values, and / or one or more stroke cycle parameter values, and / or one or more synchronisation parameter values adjusted by the primary control unit) prior to or during an administration session means that the same system can be adapted, including dynamically, according to the skin type so as to maximise deposition efficiency. For example, in a treatment of keloids and hypertrophic scars, corticosteroids are administered intradermally in the scar tissue to reduce inflammation and collagen overproduction. Non-wasteful dosing is desirable owing to expense. Further, an uneven distribution, overdosing and / or underdosing may lead to skin atrophy or incomplete scar regression. The inventors have found that material properties (such as skin flexibility, toughness, strength) can be highly variable across a single region of scar tissue. A dynamic control of one or more of the aforementioned parameters by the operator or automatically results in improved deposition efficiency during the administration session. For example, the operator might choose to prolong the period of time in which the needle assembly body (122) is in the fully deployed position (329) in portions where the skin is tough to enable absorption, and conversely to reduce the period time in the fully deployed position (329) where the skin is less tough. This dynamic adjustment leads to a more even distribution across the across scar tissue for the same subject. Delay in the actual fluid flow through the needles compared to the desired fluid flow as a result of liquid properties such as viscosity can be compensated by adjusting the offset of the flow cycle and / or adjusting the offset between the flow cycle and the stroke cycle.

[0252] Because the primary control unit outputs electronic control signals, the one or more flow cycle parameters, and / or one or more stroke cycle parameters, and / or one or more synchronisation parameters can be more accurately adjusted. The range of adjustment is large (e.g. wide range of motion, wide range of flow rates, wide variety of pattern variability). The electronic control signals can be adjusted dynamically e.g. responsive to operator or sensor input; the dynamic adjustment is near-instantaneous and without interruption to the treatment session, allowing a continuous treatment session that is shorter and hence less painful for the subject.

[0253] Example 1

[0254] A system was prepared as described herein, wherein the dosing element (800) provided the liquid to the set of hollow needle(s) according to a flow cycle, wherein each flow cycle comprised a period of maximum flow rate and a period of a minimum flow rate (intermittent flow) and was synchronised with the stroke cycle such that liquid was injected into an ex-vivo human skin sample only while the needle was below the surface of the sample. This was compared with a system of the prior art in which liquid was provided to the set of hollow needle(s) continuously. The results are shown in Table 1.

[0255] Table 1. Results showing efficiency and material loss for a system having synchronised stroke and flow cycle with intermittent flow, compared with a system having continuous flow. Efficiency was measured by comparing change in mass after injection with change of mass after injection and removing surface excess. Example 2

[0256] FIG. 10 depicts an exemplary system (100) described herein. The system (100) had a proximal (10) and distal (12) end. The system (100) comprised a liquid supply system (900) having a syringe, a conduit (910) connecting the liquid supply system (900) to the dosing element (not shown), a dismountable cartridge (200) having a set of needles (124). A housing (160) of the system was provided with a flow cycle volume adjustment dial (162), a stroke cycle frequency adjustment dial (164), and a power on / off button (166).

[0257] Example 3

[0258] A system was prepared as described herein, wherein the stroke cycle, flow cycle and their synchronisation were controlled by a primary control unit, such that liquid was injected into an ex-vivo human skin sample only while the needle was below the surface of the sample. Trials 1 to 5 (Table 2) used such a device.

[0259] As a comparative example (CPEx1 in Table 2) a commercial manually-actuated injector (TURTLEPIN Multi Needle Injector (JM Biotech) having 5 needles, 32G, length needles 2 mm, no ability to adjust stroke cycle, flow cycle and their synchronisation) was used to administer the same liquid into a similar ex-vivo human skin sample while the needle was below the surface of the sample.

[0260] As a further comparative example (CPEx2 to 4 in Table 2) a commercial motorised injector (U225 intradermal injector (Needle concept) having 1 needle, no ability to adjust stroke cycle, flow cycle and their synchronisation) was used to administer the same liquid into a similar ex- vivo human skin sample while the needle was below the surface of the sample.

[0261] This was compared with a system of the prior art in which liquid was provided to the set of hollow needle(s) continuously. The results are shown in Table 2.

[0262] Table 2 Results showing efficiency for a system according to the invention (Trials 1-5), compared with a commercial systems (CPEx1-4). Key: UnC - uncontrolled. Efficiency was measured by comparing change in mass after injection with change of mass after injection and removing surface excess.

[0263] | Aspect | Trial 1 | Trial 2 | Trial 3 | Trial 4 | Trial 5 | CPEx1 | CPEx2 | CPEx3 | CPEx4 |

[0264]

[0265] Present system (Trial 1) cfCPEx2 device: Trial 1 shows a 98±1.6% efficiency, CPEx2 device has 58±25.8% efficiency. This means that present system has an average material loss of 2% while the CPEx2 device has 42% loss.

[0266] Present system (Trial 4) c CPEx4 device: Trial 4 shows a 83±3.6% efficiency, CPEx4 device has 20±12.2% efficiency. This means that present system has an average material loss of 17% while the CPEx4 device has 80% loss.

[0267] Present system (Trial 3) cf CPEx3 device: Trial 3 shows a 87±6.0% efficiency, CPEx3 device has 32±29.2% efficiency. This means that present system has an average material loss of 13% while the CPEx3 device has 68% loss.

[0268] The results show a more efficient deposition using the system as described herein.

[0269] Example 4

[0270] A system was prepared as described herein, wherein the dosing element (800) provided the liquid to the set of hollow needle(s) according to a flow cycle, wherein each flow cycle comprised a period of maximum flow rate and a period of a minimum flow rate (intermittent flow) and was synchronised with the stroke cycle. The stroke cycle frequency and the flow cycle frequency were both 5 Hz. The stroke cycle duration and flow cycle duration were both 200 ms. Diameter of each needle was 3 mm. A quantity of needles was 5. Liquid was injected into an ex-vivo human skin sample. A synchronisation between flow cycle and stroke cycle was adjusted in multiple trials insofar the stroke pattern start time and the flow pattern start time were offset by a different time in each trial. The results are shown in FIG. 12, in which 0% is no delay, and 25% delay equates to a 50 ms delay, 50% delay equates to a 100 ms delay, and the flow pattern start time was after the stroke pattern start time.

Claims

Claims1. A system (100) for multiple-repeated deliveries of a dose of a liquid below an exterior surface of a skin of a subject comprising:- a cartridge (200) comprising:- a needle assembly (120) comprising a needle assembly body (122) and a set (124) of one or more hollow needle(s) (125) attached to the needle assembly body (122), each needle having a lumen for delivery of the dose of the liquid;- a dosing element (800), configured for providing the liquid to the set (124) of hollow needle(s) (125) according to a flow cycle (400), wherein the flow cycle is a variation in flow rate during a flow cycle duration (406) to the set of needles and comprises a period of maximum flow rate and a period of a minimum flow rate; - a liquid supply system (900) having an outlet in fluid connection with an inlet of the dosing element (800);- a movement inducer (140) configured to induce slidable movement in the needle assembly body (122) according to a stroke cycle (300), wherein the stroke cycle (300) contains a pattern of motion (320) of the needle assembly body (122) within a stroke cycle duration (306) and the flow cycle (400) is synchronized with the stroke cycle (300); and- a primary control unit (700) configured to control at least the flow cycle (400), the stroke cycle (300), and their synchronisation.

2. The system (100) according to claim 1 , wherein the flow cycle (400) is synchronised with the stroke cycle (300) such that the minimum liquid flow rate is reached during a period in which the needle assembly body (122) is at a fully withdrawn position of the stroke cycle (300).

3. The system (100) according to claim 1 or 2, wherein flow cycle is synchronised with the stroke cycle such that the maximum flow rate is reached during a period of the stroke cycle in which the set of hollow needles protrudes from a skin contact surface (126), wherein the skin contact surface (126) is configured for making contact with the skin of the subject and provided with a least one needle aperture for passage therethrough of the set (124) of needles (125).

4. The system (100) according to any one of claims 1 to 3, wherein the flow cycle is synchronised with the stroke cycle such that the flow rate is increasing:- during a period of the stroke cycle in which the set (124) of hollow needles (125) is greater than 0% protruding from a skin contact surface (126), the skin contact surface (126) configured for making contact with the skin of the subject and provided with a least one needle aperture for passage therethrough of the set (124) of needles (125), and- during a period of the stroke cycle in which the needle assembly body (122) is moving in a net direction towards 0% protruding from the skin contact surface (126); and- after the needle assembly body (122) has reached a fully deployed position.

5. The system (100) according to claim 4, wherein the primary control unit (700) is configured to control the dosing element (800) such that the variation in the flow rate during the flow cycle (400) is met.

6. The system (100) according to any one of claims 1 to 5, wherein the dosing element (800) comprises one of- a volumetric pump, or- a controlled valve.

7. The system (100) according to claim 6, wherein the dosing element (800) comprises a volumetric pump and the volumetric pump is a peristaltic pump, a diaphragm pump, a membrane pump, a piston pump or plunger pump.

8. The system (100) according to any one of claims 1 to 7, wherein the cartridge (200) is detachable and optionally disposable.

9. The system (100) according to any one of claims 1 to 8, wherein the dosing element (800) is integrated into the cartridge (200).

10. The system (100) according to any one of claims 1 to 9, wherein the primary control unit is configured to control the movement inducer such that the slidable movement of the needle assembly body (122) induced in the needle assembly body (122) is according to the stroke cycle (400).

11. The system (100) according to any one of claims 1 to 10, wherein the dosing element (800) is a controlled valve, and a liquid supply system (900) is provided to supply the controlled valve, wherein the liquid of liquid supply system (900) is outputted under positive pressure.

12. The system (100) according to claim 11 , wherein pressure in a conduit (910) between the liquid supply system (900) and the controlled valve (800) is controllable, responsive to the flow cycle dose that is a total volume of liquid outputted by the set (124) of one or more hollow needle(s) (125) in one flow cycle.

13. The system (100) according to claim 12, where the pressure in the conduit (910) is determined from a pressure sensor in the conduit (910) and / or from a force sensor determining an applied force on an actuator of the liquid supply system (900).

14. The system (100) according to claim 11 , wherein a flow rate setting of the liquid supply system (900) is adjustable responsive to a total volume of liquid outputted by the set (124) of one or more hollow needle(s) (125) in one flow cycle.

15. The system (100) according to any one of claims 11 to 14, wherein a conduit (910)) between the liquid supply system (900) and the controlled valve (800) comprises a region of volumetric elasticity configured to act as a fluid buffer to reduce variation over time of a (hydrostatic) pressure at an inlet to the controlled valve (800).

11. The system (100) according to any one of claims 1 to 10, wherein the dosing element (800) is a controlled valve, and a liquid supply system (900) is provided to supply the controlled valve, wherein the liquid of liquid supply system (900) is outputted under positive pressure.

12. The system (100) according to claim 11 , wherein pressure in a conduit (910) between the liquid supply system (900) and the controlled valve (800) is controllable, responsive to the flow cycle dose that is a total volume of liquid outputted by the set (124) of one or more hollow needle(s) (125) in one flow cycle.

13. The system (100) according to claim 12, where the pressure in the conduit (910) is determined from a pressure sensor in the conduit (910) and / or from a force sensor determining an applied force on an actuator of the liquid supply system (900).

14. The system (100) according to claim 11 , wherein a flow rate setting of the liquid supply system (900) is adjustable responsive to a total volume of liquid outputted by the set (124) of one or more hollow needle(s) (125) in one flow cycle.

15. The system (100) according to any one of claims 11 to 14, wherein a conduit (910)) between the liquid supply system (900) and the controlled valve (800) comprises a region of volumetric elasticity configured to act as a fluid buffer to reduce variation over time of a (hydrostatic) pressure at an inlet to the controlled valve (800).

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