HANDHELD 3D BIOPRINTER
A handheld 3D printing apparatus for printing biocompatible materials including stem cells for performing in-situ surgical repairs and comprises one UV curable reagent container and one cell supporting reagent container which are co-axially extruded from a tip and cured to perform in-situ repairs. The extruded material comprises a core material protected by a shell material. The reagents are driven from the containers using an electronic drive train at a constant rate.
- 1-20. -20. (canceled)
- 21. A handheld 3D printing apparatus for extruding multiple reagent compositions, the apparatus comprising:
a housing, comprising; a first reagent container support arrangement which, in use, receives and supports a first reagent container containing a cell supporting reagent; a second reagent container support arrangement which, in use, receives and supports a second reagent container containing a light curable reagent; a power supply; an electric drive train arrangement configured to drive a first reagent piston into a distal end of the first reagent container, and to drive a second reagent piston into a distal end of the second reagent container; an electronic control circuit to control the electric drive train to control extrusion of the reagents from the first and second reagent containers; and a nozzle connected at a distal end of the housing and comprising a co-extrusion tip comprising at least one aperture; a first conduit for receiving the first reagent driven out of a proximal end of the first reagent container and directing the first reagent out of the at least one aperture in the tip; and a second conduit for receiving the second reagent driven out of a proximal end of the second reagent container and directing the second reagent out of the at least one aperture in the tip.
- View Dependent Claims (22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40)
This application is a National Stage Entry of International Patent Application No. PCT/EP2017/079283, filed Nov. 15, 2017, which claims priority from Australian provisional patent application 2017900906, filed Mar. 15, 2017, each of which is hereby incorporate by reference in its entirety for all purposes.
The present disclosure relates to additive manufacturing of biocompatible materials. In a particular form the present disclosure relates to a handheld 3 dimensional (3D) printing of biocompatible materials for surgical biofabrication.
Laboratory studies and prototypes have established the technical feasibility of a handheld 3D printer for surgical biofabrication. In one recent (although not necessarily well known) prototype system UV curable inks containing stem cells and biomaterials are in-situ printed and UV cured to allow a surgeon to biofabricate a tissue structure, for example to directly repair damaged cartilage. In this prototype system two reagent containers separately store the stem cells and biomaterial as hydrogels and a mechanical extrusion system is used to extrude the reagents through 3D printed titanium extruder nozzle, and a UV light source is used to cross-link the hydrogels immediately after extrusion to form a stable structure that encapsulates and supports the stem cells. A foot pedal is used to control reagent extrusion and the rate of extrusion is controlled using an electronic control interface. Each extruder has a circular cross section and is deposited co-axially with a core material containing the stem cells and a shell material which encapsulates and supports the core material
However, while technical feasibility has been established with the above discussed prototype, this prototype has a number of disadvantages, particular to enable cost effective production and reliable use. For example, the prototype device suffers from reliability and consistency issues. The viscosity and thus flow rate of the reagents are sensitive to temperature and the material properties are sensitive to the mixing ratio. This then requires tight control of the extrusion rates. Additionally, the prototype device has limited freedom of movement as it is connected by cables to a foot pedal and an electronic control interface. Further, the nozzle is a 3D printed titanium nozzle which is expensive and unsuitable for volume manufacturing.
There is thus a need to provide an improved handheld 3D printing device, or at least an alternative to existing handheld 3D printing device.
According to a first aspect, there is provided a handheld 3D printing apparatus for extruding multiple reagent compositions, the apparatus including:
a housing having: a first reagent container support arrangement which in use receives and supports a first reagent container containing a stem cell supporting reagent; a second reagent container support arrangement which in use receives and supports a second reagent container containing a light curable reagent; a power supply; an electric drive train arrangement configured to drive a first reagent piston into a distal end of the first reagent container, and to drive a second reagent piston into a distal end of the second reagent container; an electronic control circuit to control the electric drive train to control extrusion of the reagents from the first and second reagent containers; a nozzle connected at a distal end to the housing and including a co-extrusion tip including at least one aperture, and a first conduit for receiving the first reagent driven out of a proximal end of the first reagent container and directing the first reagent out of the at least one aperture in the tip, and a second conduit for receiving the second reagent driven out of a proximal end of the second reagent container and directing the second reagent out of the at least one aperture in the tip.
The extruded material can be cured using an external light source. In another example, the handheld 3D printing apparatus may further include a light source mounted on or in the nozzle and controlled by the electronic control circuit for curing the reagents either just prior or after extrusion from the tip. These and other features will now be described.
In a further aspect, there is provided the use of the handheld 3D printing apparatus for extruding radiation curable reagent compositions. The radiation curable reagent composition may additionally be cured by using the handheld 3D printing apparatus.
Embodiments of the present disclosure will be discussed with reference to the accompanying drawings wherein:
In the following description, like reference characters designate like or corresponding parts throughout the figures.
According to a general embodiment of the present invention, the handheld 3D printing apparatus has a nozzle connected at a distal end to the housing and comprising a co-extrusion tip comprising at least one aperture, and a first conduit for receiving the first reagent driven out of a proximal end of the first reagent container and directing the first reagent out of the at least one aperture in the tip, and a second conduit for receiving the second reagent driven out of a proximal end of the second reagent container and directing the second reagent out of the at least one aperture in the tip. This means, that the two reagents are contacted, for example mixed, prior to being extruded from the nozzle tip.
In one embodiment, the handheld 3D printing apparatus has a nozzle comprising a core aperture and an annular aperture in a coaxial arrangement, and a first conduit for receiving the first reagent driven out of a proximal end of the first reagent container and directing the first reagent out of the core aperture in the tip, and a second conduit for receiving the second reagent driven out of a proximal end of the second reagent container (9) and directing the second reagent out of the annular aperture in the tip. Referring to
The rear housing 4 comes in a an upper section 41 and a lower section 42 and houses a power supply 6, such as alkaline, lithium ion or other batteries (e.g. 3 AAA alkaline batteries or any other number of batteries), an electric drive train arrangement 7 which is configured to drive a first reagent piston 84 into a distal end 81 of the first reagent container 8, and to drive a second reagent piston 94 into a distal end 91 of the second reagent container 9. An electronic control circuit 5 is used to control the electric drive train 7 to control extrusion of the reagents from the first and second reagent containers 8 and 9.
An embodiment of the nozzle 2 is shown in
The nozzle 2 comprises a manifold housing 21 which comprises a first conduit that receives the first reagent driven out of the proximal end of the first reagent container 8 and directs the first reagent out of the core aperture 23 in the tip 22. A second conduit 26 receives the second reagent driven out of a proximal end of the second reagent container 9 and directs the second reagent out of the annular aperture 25 in the tip 22. The reagents are thus extruded as a coaxial bead of material with the first reagent forming the core material and the second reagent forming a shell material which surrounds, protects and supports the core material. The first or core reagent material may comprise stem cells and support media in a hydrogel or paste. The second or shell reagent material will typically have a different composition in line with providing a protecting and structural support role for the core material, and may or may-not comprise stem cells. The second reagent material may be provided as a hydrogel or paste. The hydrogels may be comprised of a hyaluronic acid, methacrylic anhydride, agarose, methylcellulose, gelatine or the like.
The nozzle in this embodiment is suitable for manufacture using plastic injection moulding and the internal structure of an embodiment of the nozzle is shown in more detail in
As shown in the embodiment of
In this embodiment the light source 24 is a UV LED mounted externally on the nozzle to cure the reagents after extrusion from the tip. As shown in
Further embodiments of the nozzle 2 are illustrated in
The handgrip portion 3 is shown in greater detail in
The main elongated body of the handgrip 3 further comprises a first viewing aperture 38 for viewing the first reagent in the first reagent container, and a second viewing aperture 39 for viewing the second reagent in the second reagent container. In this way a user can observe how much reagent has been used or is remaining in each reagent container. An aperture 34 is also provide for a start/stop (or on/off) button 34 which engages with a toggle switch (or actuator) 33 fitted in or below the aperture 34 and connected to the electronic control board 5 (and power supply 6).
The upper housing is shown in more detail in
The housing 4 also houses the drive train arrangement 7, which is configured to drive the first reagent piston 84 into or from a distal end 81 of the first reagent container 8, and to drive the second reagent piston 94 into or from the distal end 91 of the second reagent container 9.
The drive train arrangement 7 is controlled by the electronic control circuit 5 to control extrusion of the reagents from the first and second reagent containers 8 and 9 by controlling the speed of the stepper motors. Activation of the stepper motors by the electronic control circuit 5 drives rotation of the jack spur gear which in turn drives the jack screw forward to drive the reagent pistons 84 and 94 from a distal to a proximal position and force extrusion of reagents from the proximal (nozzle) end of the reagent containers 8 and 9. Prior to use a start-up purging operation can be performed to start flow through the tip to prepare it for surgical operation.
The microcontroller comprises embedded software for monitoring the state of the on/off switch 32, and controls the speed of the stepper motors (and thus extrusion rate) based on changes in detected changes in state. For a simple on/off embodiment with a constant (fixed) extrusion rate, the microcontroller stores a fixed speed (which may be stored as a frequency, voltage or a current level) for each stepper motor. The speed may be the same for each stepper motor, in which case the reagents are extruded at the same rate, or different speeds may be used for each stepper motor, in which case the reagents are extruded at different rates. This choice will depend upon the material or chemical properties of the reagents, or the desired application. In some embodiments the rate of extrusion of the first and second reagents is a mechanically fixed ratio with 2 jack screws 73 driven by a common motor.
In some embodiments, the user can control the extrusion speed or flow rate via a user interface 51 such as a knob, one or more buttons, or other speed control actuator that allows a user to set or change the rate of extrusion. In the embodiment shown in
In some embodiments, for example for research uses or specialised surgical applications, variable (i.e. continuous or semi-continuous) speed control over a predefined range may be desired. This may be in the form of an analog speed control knob in which the angle of the knob corresponds to a speed over a predefined range (e.g. a rheostat) or a digital system in which the rotation through a defined arc (or angular steps) is detected and corresponds to a fixed speed step change, with the angle of rotation defining the direction of change (increase or decrease) between maximum and minimum limits. Additionally in some embodiments the rate of extrusion of the first and second reagents (and first and second stepper motors) is independently controllable. This may be through providing two speed control actuators or a combination of actuators such as knobs and buttons, for example a button may enable selection of which reagent, and a knob enables selection of speed. Alternatively a button or multiple buttons may be used to select pre-set speeds and or extrusion ratios.
In some embodiments the viscosity of reagents is temperature dependent and thus in some embodiments heating elements and sensors such as a Peltier cell system are provided, for example in the handgrip and the electronic control circuit 5 is used to heat and then maintain the temperature of inserted reagent containers 8 and 9 at a predefined temperature. Control of the temperature can also be used as a form of speed control (or in conjunction with speed control) by enabling control of the viscosity. Alternatively one or more temperature sensors may be included and the control system may vary the extrusion rate (e.g. stepper motor speed) of one or both of the reagents to compensate for changes in viscosity or mixing rate with temperature to ensure consistent application or mixing of the reagents. This may be based on calibration data.
In one embodiment the desired speed control or flow rate setting for a reagent is encoded on the reagent container so that when inserted in the handgrip a sensor reads or detects the encoded speed control or flow rate setting, and sends this information to the microcontroller. The microcontroller can then use this information to set the speed of the corresponding stepper motor. In some embodiment the encoded value may be a voltage or current level which the microcontroller can directly use, or the microcontroller may store sets of predefined speeds/control values each associated with a code, and thus by reading the code on the reagent container the microcontroller can look up the appropriate speed setting. The encoding maybe a physical encoding such as projection in a defined location on the flange which engages a switch, or a barcode or similar code printed on the reagent which is scanned and read by a light sensor in the handgrip housing.
In one embodiment the inventive biopen apparatus is preloaded with batteries and provided in a sterile container as a disposable apparatus. At the time of use, the sterile container is opened, and reagent containers 8 and 9 are loaded into the device. Once the operation is completed the entire device is disposed of Through the use of cheap and long lasting AA(A) batteries, fixed speed/extrusion rate (i.e. simple electronic circuit) and construction using injection moulding techniques the cost of the device can be kept low, whilst also providing a long shelf life (largely depending upon the shelf life of the batteries). In another embodiment the biopen is disposable but additionally allows limited speed control (i.e. 2, 3, or 4 speeds). That is the apparatus is supplied in a sterile condition, and reagents can be loaded and reloaded during use (whilst maintaining sterility), and after use apparatus is disposed of
In other embodiments the biopen could be reusable and sterilisable, or be comprised of disposable parts and sterilisable parts, or segmented between sterilisable (contacts the operator) and non-sterile (isolated from the operator). In one embodiment the nozzle 2 and handgrip 3 (i.e. the parts contacting the patient and operator) is separable from the rear housing 4, and the nozzle 2 and handgrip 3 are either disposable or can be sterilised using radiation or an autoclave, and the rear housing containing the electronics, mechanical components and batteries is sterilised using an alcohol swab or bath (70-85% ethanol). In this case the batteries are replaced and/or recharged between uses. Additionally the reagents can be loaded and reloaded during use (whilst maintaining sterility).
In one embodiment the embedded software performs additional functions such as reloading or error detection. This may include detecting an empty reagent container condition (or full extension of the jack screw) in which case extrusion is ceased and the user is alerted to replace the reagent. Similarly the software could detect an input from a user to change reagents and automatically shuts off the light source and retracts the piston actuators to allow reloading. The software could also be used to control an initial purge to ready the device for operation. The software could also monitor the drive arrangement or flow through the tip and detect an extrusion error (e.g. blocked extruder or blocked tip) in which case operation is ceased and the user alerted. The software could also detect failure of the light source in which case extrusion is ceased and the user is alerted. The software could also detect a low battery voltage and alert the user. The user could be alerted using one or more externally visible LED'"'"'s located on the housing and turned on or strobed when an error condition is detected. In one embodiment the electronic control circuit comprises a wireless communications chip to allow wireless control of the apparatus. The software may perform the above tasks by turning on an acoustic signal instead of using visible LED'"'"'s. In one embodiment a combination of acoustic and light signals may be used.
Other variations can be used to drive the reagent pistons 84 and 94. For example the drive train arrangement could comprise a stepper motor drive with a worm gear, rack and guide or a linear stepper motor with a leadscrew/jackscrew guide. In one embodiment a brushed DC motor drive is used with a jack screw, jackscrew guide, and a double worm reduction gear set to transmit torque from the motor to the jack screw at a much reduced speed, with a ratio in the range of 80-300:1, and a worm gear with provision for a magnet to facilitate sensing of the motor shaft to regulate motor speed. In one embodiment the drivetrain is a brushless DC motor drive with a jack screw, jack screw guide and a gear set to transmit torque from the motor to the jack screw.
Other embodiments include a side loading embodiment, shown in exploded isometric view in
As can be seen in these embodiments, the apparatus comprises a frame 10 which in turn supports the nozzle assembly 2, reagent containers 8 and 9 (not shown) in cavities 18, 19, drive assembly 7, control module 5 and power supply 6. The housing surrounds the frame and comprises an upper housing 41, a lower housing 42, and a rear motor cover 714. In this context relative locations such as upper, lower, forward or proximal, and rear or distal are referenced with respect to the nozzle tip when held by a user. The upper housing 41 has a cradle shape and comprises clips on the inside surfaces to allow the housing 10 to be clipped into the lower housing 42. The nozzle assembly 2 projects forward of the proximal (or forward) ends of the upper housing and lower housings 41 and 42. The lower housing 42 is connected to the rear motor cover 714 using a hinge 36 that allows the upper housing 41 to hinge upwards and rearward as shown in
The housing is moulded so that the biopen apparatus can be comfortably held by a user'"'"'s hand with the upper housing 41 comprising a bump near the palm and a depression near the fingertip region of the handgrip portion 3. A start/stop button 32 is located on the proximal side of the lower housing 42 which engages with actuator 33 to allow a user to control extrusion of material from the biopen. The start/stop button is formed as an extrusion button in the side of the lower housing 42. In one embodiment a user interface 51 as shown in
The drive assembly comprises two jack screw (shafts) that pass through apertures in the rear wall 17 of the frame 10 and end in jack spur gears 74 which is held in place by a retainer 712, which is mounted to the frame 10 and rear motor cover 714 via screws 49. The retainer 712 also supports the stepper motors 79. Plunger actuators 840 are mounted on the jack screw such that rotation of the jack screw moves the plunger actuators 840 forward (or rearward) to drive the plungers of the syringes (located in the forward or handgrip portion) to extrude material.
In this embodiment the power supply comprises three 1.5V AAA type batteries which are located in a battery compartment on the underside of the frame 10, and above the PCB circuit board on which is mounted control electronics including a microprocessor and power circuits to respond to user interface signals and to control the operation of the apparatus. Wires 63 run from the PCB on the underside of the frame 10 to the start/stop button 32, and wires 65 run from the PCB to the stepper motors 75 to control extrusion. A UV LED 240 is mounted on the top surface of the PCB, and a light pipe 242 directs the UV light to the tip of the nozzle 2 to provide a UV light source 24 to cure extruded material.
The user interface is configured to allow a user to control the rate of extrusion of the reagents from the first and second reagent containers, and select between at least two operating modes (for example manual and automatic). As shown in the embodiment of
In one embodiment, the “on” state is indicated by the presence of at least one illuminated light. The biopen apparatus can be configured so that the illuminated light cycles clockwise or counter clockwise and cycles back to the starting position once the end is reached. The default configuration is to cycle clockwise starting in the purge Shell position. By default:
The curing lamp is not illuminated during purging;
The curing lamp is on low power during extrusion to facilitate a pre-cure, configurable to any pattern and/or percentage of full power (set at the factory);
The light is applied at any configurable percentage or pattern (set at the factory) in light only mode. No other functions are active;
The curing light is illuminated in time limited periods to facilitate control over light dose/curing of materials.
In other embodiments the curing lamp may be applied intermittently during extrusion to create desirable mechanical properties in the extruded material.
Both the cap portion 271 and nozzle portion 272 are designed to be formed using injection molding processes with the ability to control tolerances to a high level. The cap 271 is moulded and stripped from the undercut in the tool while still hot permitting a peripheral clip retention feature 274 to be formed. The nozzle portion 272 is moulded over the hypodermic tube 23 in a single operation. Specialised tooling is required for holding the tube in place during moulding. The nozzle portion 272 forms the mechanical interface with the frame 10 and seals to the syringes via a Luer slip interface.
The cap portion 271 is a clip/interference fit on the nozzle portion 272 forming a fluid tight seal once pressed into position negating the need for any additional sealing method. The cap portion 271 also forms a fluid manifold 229 guiding the shell material from the syringe to a concentric ring 230 around the hypodermic tube 23 thus forming a coaxial extrusion. In other embodiments the nozzle assembly is sealed with an o-ring and fastened with one or more screws.
The nozzle assembly (2) may be integrated into the housing, i.e. may be permanently fixed so that it cannot be removed from the biopen. In one embodiment, the nozzle assembly (2) is removable from and attachable to the housing. This allows to attach different types of nozzle assemblies (2) to the biopen depending on the application for which the biopen should be used. For example, by replacing the nozzle assembly (2) it is possible to have differing blend system, such as the first reagent being extruded throughout a core aperture (23) and the second reagent being extruded through an annular aperture (25), whereas by replacing the nozzle assembly (2) the first reagent may be extruded throughout an annular aperture (25) and the second reagent may be extruded through an a core aperture (23). The possibility of replacing the nozzle assembly may also allow to replace defect or clogged nozzles assemblies.
The nozzle assembly 2 is an example of a separate assembly to the frame 10 to permit changing of the nozzle assembly if damaged, or at a device level, refinement of the nozzle assembly design for alternate applications. Alternate configurations may include side by side extrusion, different geometric shapes, different length nozzles, different diameter nozzles, different geometric ratios etc. The rear of the nozzle portion 272 comprises a rear shoulder, which as shown in
The biopen as described in the embodiments above may be further modified to include additional reagent containers and to co-extrude these additional reagents. In these embodiments the previously described reagent support arrangements and the electric drive train arrangement is further configured to drive each additional reagent piston into a distal end of the additional reagent container, and the nozzle is further configured to receive the additional reagent driven out of a proximal end of each additional reagent container and co-extrude each additional reagent with the first and second reagents. In such embodiments, the biopen may comprise at the distal end of each reagent container a flange with a unique profile shape, and each reagent container support arrangement may comprise a cut-out portion matching the unique profile shape.
In this embodiment the central syringe 133 delivers the core material, and the two outermost syringes 131 and 132 (each adjacent to the central syringe) deliver the outer and intermediate shell materials respectively.
The tubes 121, 122 and 123 are sized to permit nesting and the construction of the tri-axial (or N axial) bead of extruded material. The stacked assembly uses die plates with three fine wires between each nested tube to maintain the coaxial alignment. For example as shown in exploded view 14C and section views 14J and 14K, cap die plate 125 is located on the inner (distal) sides of cap manifold 124 and receives spacing guide wires 185 which spaces apart intermediate tube 122 and outer tube 121, and similarly intermediate die plate 127 is located on the inner (distal) sides of intermediate manifold 126 and receives spacing guide wires 187 which spaces apart core tube 123 and intermediate tube 122. In another embodiment the tubes can have a trilobular profile to facilitate coaxial location. In another embodiment the tubes can have additively manufactured location features integrated onto the tubes.
Cap 124, intermediate manifold 126 and nozzle base manifold 128 when stacked form the fluid manifolds to each respective tube and sealing faces. As shown in exploded view 14C and section views 14J and 14K, cap manifold 124 comprises a outer channel 181 located on the inner (proximal) side of the cap manifold 124 leading from the outer syringe 131 (via aperture in the nozzle base manifold 128) and intermediate manifold 126 comprises a intermediate channel 182 located on the inner (proximal) side of the intermediate manifold 126 leading from intermediate syringe 132 (via aperture in the nozzle base 128). Additional sealant, glue or gaskets may be applied in some embodiments.
In other embodiments the present system could be extended to add additional syringe assemblies to extrude N-axial beads of material. i.e. using 4, 5, 6, 7 or even more syringes. Generally, N materials and N associated syringes and drive assemblies may be used, wherein N is an integer, for example from 1 to 10. In other embodiments, other geometrical layouts could be used such as distributing the syringe and driver arrangements around a central axis (e.g. at 0°, 120° and 240°) and redesigning the manifolds (or fluid delivery channels) in the nozzle 120.
Thus, the of the invention may generally be used for extruding radiation curable reagent compositions. The radiation curable reagent composition may additionally cured by using the handheld 3D printing apparatus, for example using a light source which is part of the biopen. In one embodiment the light source may be an external light source.
Embodiments of the handheld 3D printing apparatus or biopen have a number of surgical and research uses. For example the biopen can be used for repairing defects of an mammalian body. Such defect may be, but not limit to, tissue defects or bone defects. In one embodiment, the repair relates to biological materials which are unable to self-repair such as cartilage or corneal tissue. In such applications the biopen can be used to directly write 3D living cells onto the damaged area for tissue or bone regeneration. For example cartilage is unable to self-repair and can become damaged through physical activities, wear, trauma or degenerative conditions. A biopen loaded with appropriate stem cells can be used to perform in-situ repair, and current surgical interventions are of limited effectiveness. It is also possible to use the biopen for cell types capable of repair, such as skin or bones. In such cases the biopen could be used to directly print or write living cells onto damaged tissue to assist with the repair process. For example bone stem cells and bone growth factors could be printed on fractures or in other bone surgery such as spinal fusions to stimulate bone growth. Similarly keratinocytes and other skin cells could be directly printed onto cuts, abrasions or burns to stimulate skin repair and minimise scar tissue formation.
In one embodiment the handheld 3D printing apparatus or biopen may be mounted to a robot or robot arm.
Embodiments of the handheld 3D printing apparatus or biopen have a number of advantages. First the biopen is suitable for cost effective production using high volume manufacturing techniques and processes. For example the nozzle, handgrip and housings can be cheaply manufactured using high throughput techniques such as injection moulding using thermoplastic and/or thermosetting polymers. In particular the nozzle has been carefully designed to ensure consistent flow of materials whilst also being suitable for cheap and easy construction. Additionally the system features improved reliability through the use of drive system using a micro-controlled electronic (DC) jack screw. Additionally the microcontroller can be used to tightly control the temperature of the reagent containers to ensure consistent flow rates. The apparatus is an all-in-one unit, featuring an internal power supply, and is ergonomically designed to fit easily in the hand giving the user greater freedom of movement and ease of use. The apparatus is designed to allow easy and fool-proof reagent loading through the use of a hinged opening with different shaped loading bays to ensure that each reagent is loaded (and can only be loaded) into the correct bay. In one embodiment the biopen can be cost effectively manufactured as a single purpose disposable item which delivers a specific reagent at a constant rate without requiring any control by the user (other than on/off control). In other embodiments more sophisticated control system can be incorporated for the biopen allowing the user greater control over the extrusion of the reagents.
Throughout the specification and the claims that follow, unless the context requires otherwise, the words “comprise” and “include” and variations such as “comprising” and “including” will be understood to imply the inclusion of a stated integer or group of integers, but not the exclusion of any other integer or group of integers.
The reference to any prior art in this specification is not, and should not be taken as, an acknowledgement of any form of suggestion that such prior art forms part of the common general knowledge.
It will be appreciated by those skilled in the art that the disclosure is not restricted in its use to the particular application or applications described. Neither is the present disclosure restricted in its preferred embodiment with regard to the particular elements and/or features described or depicted herein. It will be appreciated that the disclosure is not limited to the embodiment or embodiments disclosed, but is capable of numerous rearrangements, modifications and substitutions without departing from the scope as set forth and defined by the following claims. Thus, it will be appreciated that there may be other variations and modifications to the compositions described herein that are also within the scope of the present invention.