Thesis (S.B.)--Massachusetts Institute of Technology, Dept. of Mechanical Engineering, 2007.Includes bibliographical references (leaf 15).Drug delivery through jet-injection opens the doors to very rapid drug dispersion by eliminating the need for needle sterilization. With this comes the need for a continuous flow of fluids from a large reservoir, currently not available to the single-piston drug delivery systems. A two-piston system in a jet injector enables the use of a cyclic motion of pistons to drive the injected fluids, as opposed to the one-piston design that requires resetting the mechanism. This provides a way to dispense high-volume doses of medication without reloading. In order to test the feasibility of using a two-piston arrangement in jet-injected drug delivery, we have constructed a bench-top version to attempt to achieve the velocities and flow rates needed for jet injection. Using water as the injected fluid, we have found that driving the two pistons with 1800 out-of-phase, 80% symmetric, saw-tooth waveforms and a frequency of 10 Hz is sufficient to inject 900 pIUs of water through the jet and maintain a pressure of more than 2 MPa.by Daniel Cunningham.S.B

Cunningham, Daniel (Daniel P.)

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The Dual-Piston Jet Injector and the Viability of Drug DeliveryByDaniel CunninghamSubmitted to the Department of Mechanical Engineeringin Partial Fulfillment of the Requirements for the Degree ofBachelor of Science at theMassachusetts Institute of TechnologyJune 2007© 2007 Massachusetts Institute of TechnologyAll rights reservedAuthor Signature ........ =... ...... - --- ·--. *"-''-. -- ....- ,..... ."Dep ent of Mechanical EngineeringJune 2007if,,C ertified B y ............................ ............... . ........ ....................................................Ian Hunteratso-ulos Professor of Mechanical EngineeringThesis SupervisorAccepted By .................. ................... .............Prof. John H. Lienhard VProfessor of Mechanical EngineeringChairman, Undergraduate Thesis CommitteeMASSACHUSETTS INSTMIT.1EOF TECHNOLOGYJUN 2 1 2007LIBRARIES~la~cM1~E~~The Dual-Piston Jet Injector and the Viability of Drug DeliveryByDaniel CunninghamSubmitted to the Department of Mechanical Engineering on April 11, 2007in Partial Fulfillment of the Requirements for the Degree of Bachelor of Sciencein Mechanical EngineeringAbstractDrug delivery through jet-injection opens the doors to very rapid drug dispersion byeliminating the need for needle sterilization. With this comes the need for a continuous flow offluids from a large reservoir, currently not available to the single-piston drug delivery systems.A two-piston system in a jet injector enables the use of a cyclic motion of pistons to drive theinjected fluids, as opposed to the one-piston design that requires resetting the mechanism. Thisprovides a way to dispense high-volume doses of medication without reloading. In order to testthe feasibility of using a two-piston arrangement in jet-injected drug delivery, we haveconstructed a bench-top version to attempt to achieve the velocities and flow rates needed for jetinjection. Using water as the injected fluid, we have found that driving the two pistons with 1800out-of-phase, 80% symmetric, saw-tooth waveforms and a frequency of 10 Hz is sufficient toinject 900 pIUs of water through the jet and maintain a pressure of more than 2 MPa.Thesis Supervisor: Ian HunterHatsopoulos Professor of Mechanical EngineeringTable of ContentsAbstract............................................. ...................... .......... 21. Introduction ........................................................................................................ 42. Design ................................................... 52.1. Mechanical Components................................................... 52.1.1. Jet Nozzle..................................................................................................... 52.1.2. The Fluid Pathways...................................................................................... 62.1.3. Pistons ......................................................................................................... 72.1.4. The Lorentz Force Actuators ......................................................................... 82.2. Electrical Components ...................................... ............................................ 93. Theory ........................... ....................................................... 113.1. The Lorentz Force Actuator............................................... 113.2. The Fluidic System ........................................ ................................................. 124 . R esults................................................................................................................. ....... 135. Conclusions .............................................................................. 146. References .................................................................................................... 151. IntroductionMost automatic needle-free drug delivery systems currently in use are single-dosagedispensers, relying on springs or compressed air to actuate the delivery [1]. By eliminating theneed for single-dosage containers through the use of multi-shot dispensers, the cost per dosecould be reduced. We believe that using a two-piston driving system can provide the followingbenefits over a single piston system:* Draw multiple doses from a single dosage source* Eliminate the need for resetting the injection mechanism* Provide more controllable injection waveforms through interlocking driving signalwaveformsA two-piston system could be used in a needle-assisted or a needle-free drug delivery systemwith very few modifications to the existing system. As long as the pressure supplied by thepistons is sufficiently high, the drugs could be delivered with or without needle assistance.If used in a needle-free system, the multi-shot design would allow the rapid dispensing ofvaccinations without the need of reloading the doses or sterilizing the injector. In a needle-assisted device, the multi-shot capacity would reduce the between-shot time by eliminating thesingle-dosage loading.In order to test the validity of a continuous-drive drug delivery system, we show that a multi-piston system is able to provide a source of constant pressure high enough to inject a standarddosage within a reasonable amount of time.2. DesignTo test the feasibility of a multi-pistondrug delivery system, we designed andbuilt a bench-top model, utilizing a two-piston, upright, vertical injector. Thedesigns for this system were developedthrough over a year of testing iterations.2.1. MechanicalComponentsThe design of our drug injector hasfour main components: the jet nozzle, the, .-1dlul pathways, me pistons, ana the Figuresolenoid drivers. Each component is alongsimodularly designed as separate systems, with theinteractions between the being as minimal aspossible.2.1.1. Jet NozzleFor simplicity, our design adapts thecommonly-used InjexTM-brand injectors into ourneedle-assisted/needle-free drug delivery system.These "Ampules" provide a sterile injectionNozzleFluidPathsistonsioid1 - The four main components are highlighted here,de the fluid reservoir and piping.Figure 2 - The InjexTM needle tip jet orifice has a160 Am opening.~jiz~·a~i~Ichamber, a precisely defined jet orifice, and are available in large quantities. These come as twocomponents: a 0.3 mL chamber with a 160 Am jet orifice (as shown in cross-secion in Figure 2),and a piston with a rubber-seal head. The chamber/orifice has a threaded base that we use tomate with the top of the fluid pathway.Removing the plastic and rubber piston, we add a rubber o-ring to the threads of the"Ampule", under a bottom plate. We then add PTFE plumbers' tape to the threads for added sealintegrity. The "Ampule" is screwed into a receiving tap at the end of the fluid pathway.2.1.2. The Fluid PathwaysThe flow of the fluid through the system is much like that of a traditional pump; two checkvalves regulate the flow as the pistons pump the liquid in one direction. Broadly, our system issimply two dual action reciprocating pumps that draw fromthe same reservoir and also recombine in an upper chamberto flow out the same jet. The difference is that our pumpsare rapid and the piston trajectories are highly controllable.It took many iterations before we came up with thisfinal design; initial tries had perpendicular fluidthroughways, but bubble-collection became a problem.This was an issue because any build-up of compressiblefluids within in the system acts as a pressure damper, andmuch of the motion of the pistons go into compressing thebubbles before it increases the pressure of the liquid.LI reservoir We currently use an upright, side-by-side pistonFigure 3 - The hydraulic diagram of configuration (similar to that shown in Figure 3) wherethe fluid passages is much like a configuration (similar to that shown in Figure 3) wheresimple pump with two paths. both pistons draw from the same reservoir, in this case alarge oral syringe. To remove any residual air is in the system, the plunger is inserted in thesyringe and liquid is forced through the system until the pathways are sufficiently clear of air.The check valves used in the system would ideally have low cracking pressure, and wouldallow no backflow before closing. Because of their small size, we initially tried BeswickEngineering's miniature metric check-valves (0.5 mm profile, less than 20 mm long, and about 3kPa cracking pressure). We found that these used rubber nipples to regulate the flow, and inhigh-pressure situations this rubber flexed beyond what was acceptable (much like an additionalcompressible fluid in the line, this added damping). Looking slightly larger, we found moredurable check valves that utilized a brass seat held with a small return spring. This provided uswith a sensitive-enough check valve that did not increase the pressure damping of the system.2.1.3. PistonsUtilizing the InjexTM injector's supplied pistons with rubber-seal heads, we developed apiston chamber of the same dimensions of the original "Ampule" chamber. This allowed us toattach the original piston and rubber head to our solenoid coil and drive the fluids in a way verysimilar to that which InjexTM intended.A smooth and clean surface finish is critical fora good seal between the piston orifice and therubber head. Machining this 3.5 mm diameter holewas difficult, but after many manufacturingiterations we developed a consistent procedure.This included undersized drilling with only 2 mm-deep pecks, and chip clearance on each peck.,which ensured a consistently clean surface forcutting. This process was then repeated using a 3.5 Figure 4 - The pistons shown here are taken fromthe original InjexTM needle and adapted for our use.mm straight machining reamer.Interfacing the base of the needle piston with our solenoid coil was a simple matter ofconcentrically threading the end of the piston to mate with a tapped hole in the middle of thecoil. Initially there were some concentricy issues due to threading the piston at an angle, whichincreased the mechanical resistance between the piston and the chamber walls. To solve this, atool was developed for a milling machine in order to hold the piston and threading dyeconcentric, ensuring a straight thread.2.1.4. The Lorentz Force ActuatorsExtensive prior art exists on a type of linear actuator utilizing a Lorentz force driver. Thesehave been used previously in various single-shot needle-less injectors created in MIT'sBioInstrumentation Lab [2, 3].The solenoid coils are wound with a machine we developed. Our primary coils consist ofmore than 600 wraps of 350 Am (28 gauge) enamel-coated copper wire with a layer of adhesive,but a special application coil was developed that used 120 wraps of 500 tm (20 gauge) enamel-coated wire. The adhesive on our current wire is activated after the coil is wound, to helpprevent loop-jumps or breaks during operation. During normal use, these coils carry more than100 A of current and so would normally get very hot, but the time that it carries this current issmaller than the time constant in heating the wires.The magnets used within the coil to provide a strong, stable magnetic field are 0.4 MN/m2(50 MGOe) NdFeB magnets specially purchased for this application. They have an extremelystrong magnetic field (approx 0.6 T at the coil location), and are made with a 6.35 mm (/4") boredown the longitudinal axis. This allows us to run an alignment pin down the center of themagnet and into the housing, ensuring that the coil is perfectly concentric and is as close aspossible to the strongest areas of the magnetic field.Electrical Components10 KO Linear PotR20-8VFigure 5 - The electrical diagram isThe system's electrical design is rather simple, with theprimary component being the Op-Amp control circuit, detailedbelow. The basic feedback loop is completed between thesolenoid driver and the op-amp circuit by a linear slidingpotentiometer attached to the solenoid coil. The coil is driven byan Agilent 33220A signal generator providing the desiredwaveform. The Power Amplifier (a Techron 8803 Power SupplyAmplifier) increases theR1amperage supplied tothe solenoid coil.The Op-Amp circuitwe constructed uses a741 Op Amp and a 10kta LinearPotentiometer. We setL 71-up the /741 into a systemthat subtracts twoa basic subtraction op-amp with a gain.2.2.Civoltages, with a gain. The first voltage is the supplied input voltage from the signal generator;the second is the voltage coming from the linear potentiometer, driven by the location of thesolenoid.R1Resistances R1 and R2 were chosen to provide an ample gain (defined as -) in order toR2provide sufficient power to the solenoid through the power amplifier.By subtracting the current voltage (position) from the desired voltage (position) wedetermine the magnitude the solenoid needs to move to be at the goal location. The gain in thesystem is the proportionally-increased voltage that will be supplied to the solenoid coil, whichwill cause a force in the desired direction.The internal pressure is measured by a Kistler 211B Miniature Pressure Sensor (with apressure range of 0-7 MPa), which supplies a voltage proportional to the pressure detected byway of a standard voltage mode IEPE (Integral Electronic PiezoElectric) power supply/coupler.This pressure (as well as position voltage, signal waveform, etc) is recorded by Tektronics TDS3012B digital oscilloscope.3. TheoryThe two major systems to model are the Lorentz Force actuator and the fluid dynamicswithin the system. The Lorentz Force actuator provides the link from the electronic signal tomoving the fluid, and the dynamics dictate the fluid's response to the piston's motion, producinga velocity and flow rate, as well as the pressure behind the injection.3.1. The Lorentz Force ActuatorThe common Lorentz Law states that a charged particle moving within a magnetic fieldcreates a force perpendicular to both the field's and particle direction's vectors [4]. By inducingan electric current in a coil of wire around a static magnetic field, a force can be produced alongthe length of the core of the coil. This is the mechanism behind voice coils, commonly found indigital speakers.We use this method to drive a coil with high current in a strong magnetic field, creatingforces upward of 200 N. As mentioned before, our coils have more than 600 hand-wound turnsof 350 ltm-diameter enamel-coated copper wire. Lorentz Law states thatF = nDnI x B, [1]where F is the force in Newtons, I is the current in Amperes, n is the number of turns, D isthe diameter of the coil, and B is the magnetic field at the coil. In the case of a coil of wirearound a circular magnetic field, the cross product is equal to the simple product.The force from the coil is transferred to the fluid through the piston, where the force isconcentrated over the small area of the head to make pressures on the order of megapascals.From there, the energy in the system is dictated by fluid dynamics.3.2. The Fluidic SystemBernoulli's principle states that when there is an area of high pressure connected to an area oflow pressure, there will be a fluid flow with velocity proportional to the square root of thepressure difference divided by the fluid density [5, 6]. In our case of incompressible, inviscidflow, Bernoulli equation simplifies to2PS= , [2]where P is the gauge pressure and p is the fluid density. By controlling the pressure within thepiston chamber, we can control the fluid velocity out of the jet injector, as long as we are dealingwith fluids of known density.Also, because the opening diameter of the jet injector is known, the volumetric flow rate ofthe injector can be obtained by simply multipling the area of the jet and the velocity of the fluid.4. ResultsInitially we tested the pistons separately, with good results. After eliminating any residual airin the system, with step input signals to the individual pistons we were able to get 2.5 MPaspikes of pressure, which was above the target constant pressure.5420I £IL0. 32n.-1372-3-8-130 0.2 0.4 0.6Time (s)0.8We initially tested 8-signal bursts of an 80% symmetricone piston with a signal 1800 out of phase from the other.more than 2 MPa for as long as the bursts were sustained.0 0.2 0.4 0.6Time (s)saw tooth wave at 10 Hz, triggeringThis successfully held a pressure at0 0.1 0.2 0.3 0.4 0.5Time (s)0.6 0.7 0.8 0.9--A a-SA A A AAj I I II I--E I~;*i;·I I ILater tests proved that as long as the waveforms were maintained, the pressure wouldaverage out to more than 2 MPa. Further, we found that higher frequencies generated higherpressure-spikes, but were more sporadic between those spikes, even dropping down below 1MPa. Nevertheless, the pressure averaged over each period was greater than 2 MPa.5. ConclusionsA multi-piston injection system utilizing high-power Lorentz force actuators can sustainmore than 2 MPa of pressure within the fluid chambers, creating volumetric flow rates out of theInjexTM 160 /m jet orifice sufficient to providing standard doses in a reasonable amount of time.The possibility for hundreds of doses to be injected before dosage refilling is highly beneficial toapplications involving large-scale or frequent injections. Further work would includeminiaturizing our current system to allow for hand-held applications, as well as developing away to better design the driving waveforms to facilitate more controllable needle-less injections.6. References[1] R. A. Hingson and J. G. Hughes, "Clinical studies with jet injection: A new method ofdrug administration," Anesth. Analg. Cleve., vol. 26, pp. 221-230, 1947.[2] Taberner, A.J., N.B. Ball, N.C. Hogan, I.W. Hunter, "A Portable Needle-free Jet InjectorBased on a Custom High Power-density Voice-coil Actuator," Proc. 28th Conference of theIEEE Engineering in Medicine and Biology Society, 2006.[3] Tabemer, A.J., N.B. Ball, N.C. Hogan, I.W. Hunter, "A Portable Needle-free Jet InjectorBased on a Custom High Power-density Voice-coil Actuator," Proc. 28th Conference of theIEEE Engineering in Medicine and Biology Society, 2006.[4] Cornille, P., "On the difference between the Lorentz and Amp'ere force law inmagnetostatics," J. of Physics A: Math. and Gen., Vol. 22, p. 4075, 1989[5] White, F.M., "Fluid Mechanics," McGraw-Hill Companies; 5th edition, 2002[6] Baker, A. B. and Sanders, J. E. "Fluid mechanics analysis of a spring-loaded jet injector,"IEEE Trans. Biomed. Engng, February 1999, 46(2), 235-242.

The dual-piston jet injector and the viability of drug delivery

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The dual-piston jet injector and the viability of drug delivery

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