Drug Delivery Mechanisms and Extrusion Systems for

Biomedical Micro-Robots

 

       The need for targeted drug delivery systems is increasing as today’s biomedical technologies request new, innovative systems to replace difficult procedures.   Once such procedure is that of intraocular surgery.  The human eye has many small and delicate components that make it challenging for surgeons to perform various procedures.  By developing a micro-scale delivery system we hope to replace the need for traditional methods and instruments.  Biomedical micro-robots are one possible solution to this and various other medical challenges.  By engineering nano/micro-scale robots that travel throughout the human body we can implement new technologies that re-define conventional processes.  Biomedical robots could be adapted to various procedures such as micro-surgery, targeted drug release, and retrieval.  This emerging concept is becoming a reality with the success and advancement already seen within the research.

     Our research here at the Advanced Micro and Nano-systems Laboratory primarily focuses on the use of in-vivo micro-robots for targeted and controlled drug delivery.  More specifically, we are examining ways to extrude and encapsulate these robots in such a way as to increase the repeatability of a controlled actuation mechanism.  Ultrasound and magnetism are being investigated as potential mechanisms to activate fluidic drug release once the micro-robot has reached its destination.  For these reasons, research can be split up into five main categories:  extrusion, encapsulation, steering/control, actuation and retrieval.  Current research within these categories is outlined and explained below.  

 

                                

 IRIS - Micro-robot on Blood Vessel - Micro-robot structure 

Magnetic Steering System   

         

     This steering system was developed by our collaborators at the Institute of Robotics and Intelligent Systems within the Swiss Federal Institute of Technology.  The system they have developed uses two coaxial pairs of magnetic field generating coils in Helmholtz and Maxwell configurations respectively.  The Helmholtz configuration creates a uniform magnetic field at the center of the coils.  This field induces a magnetic torque on the micro-robot, forcing it to align itself with the field. This part of the system works like a steering wheel by pointing the robot in the desired direction of movement.  The Maxwell configuration creates a constant gradient field that induces a force on the robot in the direction of increasing magnetic field.  This portion of the system works like the engine by providing movement in the desired direction.  A motor is used to control the orientation of the coils and the current in each coil can be adjusted to vary the magnitude of each effect.  This system has been used to effectively guide a micro-robot through a small fluidic maze. 

 

                          For more information visit IRIS (http://www.iris.ethz.ch/msrl/research/micro/bulletin.php) 

 

The Micro-robot Extrusion System

            The micro-robot extrusion system is a coaxial fluidic channel used to extrude alginate droplets in an oil phase.  These alginate droplets are the medium that contains and carries the drug.  By controlling the flow rates of both the alginate stream and the oil phase we are able to vary the size and frequency of the droplets.  This works by altering the shear force acting on the alginate droplet by the oil phase thus effecting when the droplet is pulled out of the capillary.  The picture below shows the basic layout and design of the extrusion manifold.  The larger cylinder contains the oil flow whereas the much smaller capillary tube dispenses the alginate-drug complex. 

 

         

              Fluidic manifold with an inner capillary 

            This system allows us to entrap micro-robots within these droplets by feeding them into the capillary tube.  Upon droplet formation the micro-robot enters the droplet and is extruded from the system.  By fine-tuning the flow rates of the oil and alginate-drug complex we are able to create droplets that surround the micro-robots almost perfectly.  This is beneficial because it gives us a smooth, clean encapsulated robot.  Before the development of this system, encapsulation methods included dip-coating, larger droplet encapsulation, and chemical soaking.  These methods would create inconsistent droplets and would limit the potential amount of drug that could be contained within each robot.  The figures below compare droplets from older methods to those created using this new process. 

                             

                               Robots extruded using this new system.                                             Robot encapsulation prior to this system. 

        We are working to improve this system in order to increase repeatability and ease of extrusions.  We find that the robot-weighted droplets often sink through the oil to the bottom of the extrusion tubes causing deformation to sometimes occur.  Also, we are working to fine tune the flow rate settings to determine the best droplet size for efficient robot encapsulation.  We would also like to clean up the system and upgrade it in such a way as to allow for multiple extrusions.  These are all areas improvement that we are examining to increase the efficiency of our new micro-robot extrusion system.

                                         

The Robot Encapsulation Process

            This portion of the research is devoted to the skin formation around the extruded robot.  It is important to incorporate a skin barrier around the alginate-drug complex in order to keep the drug from diffusing while we are transporting or locating the robot.  In other words, we want to trap the drug inside the robot until we activate the release.  This involves a number of chemical soaks that create a durable protective surface skin around the robot. 

        In order to better understand the encapsulation procedure it’s important to have a basic idea of the chemistry behind the composition of the droplets. Sodium Alginate was selected as a drug entrapment matrix because it is easy to process and there is evidence supporting successful magnetic modulation of drug release. Sodium Alginate is categorized as a linear polysaccharide.  This is a cellulose fiber found in many plant cells known for its high strength and durability.  It is primarily comprised of mannuronic acid (M) and guluronic acid (G) residues chained in a repeating pattern.

GG-GM-MM-…

 

 

                    

                                                                                                 Sodium Alginate Molecular Structure 

          Once the micro-robots are extruded they are immediately put through a series of chemical baths to construct a tough surface skin that entraps the drug within the robot.  The first of these chemical baths is that of Calcium Chloride.  Soaking the alginate-based droplet (containing the micro-robot) in this salt causes the calcium chloride to crosslink with the Sodium Alginate thus forming a tough, solid droplet.  The droplets are then rinsed and transferred into a Polyethylenimine (PEI) solution where the droplets form a thin protective surface coating.  After this skin develops the droplets are again rinsed and transferred into their final soaking in Poly-l-Lysine solution.  This solution is hypothesized to soak through the PEI skin and leak into the cross-linking thus strengthening the integrity of the droplet.  These three soakings comprise the process of micro-robot encapsulation used to prepare the robot for tests and simulated medical procedures. 

        

                                                                                          Robot Encapsulation and Skin Formation 

 

Drug Release and Actuation Mechanisms

         This section of the project deals with innovative release mechanisms used to actuate the micro-robot once it has been successfully guided to the targeted area.  We are analyzing ultrasonic stimulation and magnetic pulsing as potential candidates for this release process.  This area of research is interesting because it deals with wireless, insensible methods for controlled drug release. 

Magnetic Pulsing

        This possible means of excitation and triggered release involves the use of a pulsing magnetic field to stimulate the micro-robot structure thus allowing drug to diffuse out of the weakened droplet skin.  One specific experiment used two permanent magnets on opposite ends of a rotating rod.  The rotational velocity of the rod directly relates to the period of oscillation for the magnetic field.  The samples containing the micro-robots are positioned in the center of these spinning magnets.  This experiment showed some successful drug release but not in the manner we expected.  The release patterns were somewhat sporadic and reflected the oscillatory motion of the magnetic field.  This can be observed in the graph below showing drug release with respect to time. 

 

                                                                

                                                                             Experimental Setup for Permanent Magnet Experiment 

 

                                     

                                                                                            Release Curves for Permanent Magnet Experiment 

       Other ideas involving the use of oscillating magnetic fields are currently being considered.  Some ideas involve the use of a stronger magnetic pulse, higher-frequency oscillations, or robots engineered to respond mechanically to a pulsing B-field.  These ideas may be candidates for upcoming research experiments. 

Ultrasound and Ultrasonic Cavitation

     This potential mechanism primarily focuses on the use of ultrasound as a means for stimulating fluidic drug release.  Ultrasound could be used to cause resonance in the micro-robot thus causing the robot droplet to rupture and release stored drug.  It can also be used to induce ultrasonic cavitation (the rapid formation and deformation of micro-scale gas bubbles) to deplete the robots protective skin and allow drug to diffuse outwards into the surrounding fluid.   

     At this point, only the latter has been experimentally studied.  The use of ultrasound to induce ultrasonic cavitation in the fluid surrounding the droplet has shown accelerated depletion of the protective surface skin and thus accelerated release kinetics.  This experimental study analyzed not only the release rate of such a mechanism but also the effect of the skin along with the influence of a ferrite powder and micro-robot core.  

Comparative release curves for Drug Release related experiments are shown below.  

                

                                                              Comparative HRP Drug Release Curves

      These curves verify that Ultrasonic cavitation has a significant effect on the HRP release rate over the prior diffusion method.  This can be observed in the sudden increase in slope, representing release rate, noticed post ultrasound activation.  It can also be concluded that a micro-robot core amplifies this effect and further increases the rate of skin depletion, thus offering enhanced release kinetics.  

     These results confirm that ultrasound, as a proposed release mechanism, significantly enhances micro-robot release kinetics over past diffusion methods.  

     Other experiments to further advance ultrasound as a release mechanism include testing the micro-robots at various sound frequencies, designing a robot structure that responds mechanically to a certain frequency, and studying potential resonance within the nickel structures.  These are all areas of future research interest.