despite the general use and success of systemic therapies , there has always been an interest in maximizing drug availability in target tissues and minimizing adverse reactions . as a result , many simple , local , and highly effective drug treatments have been developed including drops for eyes and ears , puffers for the respiratory tract , sprays for the sinuses , creams for skin and mucosa , central nervous system shunts and other implants .
local therapy , where appropriate , allows maximum bioavailability in target tissues while minimizing systemic interactions and allowing for the lowering of drug dosages needed for therapeutic effectiveness .
interest in the development of new drugs is therefore balanced by the increasing emphasis placed on novel delivery systems ( 1,2 ) .
such technologies have been subject to intense development over the past decade and now occupy a multibillion dollar per annum industry in the united states ( 1 ) .
in particular , polymers capable of controlled pharmaceutical release are of significant interest and offer to expand the range of diseases amenable to more localized treatment .
the most classic systems rely upon temperature , ph , magnetic fields , light , mechanical force , or ultrasound ( as in the presently described system ) to cause a change that facilitates drug release by diffusion ( 3,4,5,6 ) . such " smart polymers " often work well in vitro but demonstrate severe limitations when constrained to more physiological conditions . as a simple alternative
, we propose a drug delivery vehicle based upon calcium carbonate powder suspended in particles of a calcium alginate hydrogel matrix .
alginate hydrogels are soft and non - toxic polymers traditionally used as food thickeners , but have more recently found applications in both industrial and medical encapsulation technologies for controlled release ( 7 ) .
calcium carbonate powder is insoluble , non - toxic , and known to be susceptible to ultrasound ( 8) .
the combination of these two inexpensive materials produces a medically useful hydrogel matrix that can be disintegrated with high intensity sound waves .
so far as the authors are aware , this is the first attempt to combine these materials for the purposes of creating an ultrasound activated drug delivery device .
a co - axial airflow encapsulation nozzle was constructed as described by fiszman et al ( 7 ) .
the authors varied the flow rates described below until macroscopic particles of desirable diameter were attained .
it was thought that a 1 mm spherical diameter offered balance between a small enough object to theoretically inject and yet large enough to work with on a macroscopic scale .
briefly , a 16 gauge needle , connected to a peristaltic pump via lab tubing , was passed through a  inch " t " junction and secured in place , thus plugging one of the t 's three ports .
to the horizontal inlet was attached an air hose and pump such that air could be forced around the 90 degree bend and over the needle tip . via a procedure modified from yang ( 9 ) ,
a 1% ( m / v ) algin solution was prepared by dissolving 1000.0 mg of sodium alginate ( sigma ) in 100.0cc of distilled water with intense agitation via vortex for 30min .
preparations were made including 50 g , 75 g and 100 g of calcium carbonate ( sigma ) in the sodium alginate solution to create final 50% , 75% and 100% ( m / v ) mixtures .
suspension was forced through the needle by a peristaltic pump at a rate of 8cc / min while air flowed around the tip at 4l / min , creating enough shear force to convert the liquid stream into fine droplets .
these fell 10 cm into a 4% ( m / v ) cacl22h20 hardening solution below .
four hours were allowed for full polymerization of the particles before they were spun out of solution by gentle centrifugation and re - suspended in normal saline after three washes .
spheres produced by the above method measured approximately 1 mm in diameter and were of an opaque white color .
three particles of each final calcium carbonate concentration were separated into each of three plastic centrifuge tubes and used for the sonication trials .
the tubes were subjected to bursts of ultrasound at 85 watts , one second on and one second off , until fully disintegrated .
similarly , an identical set of three tubes , three alginate spheres per tube , were agitated by vortex for a period of twenty minutes to gain a rough assessment of the product 's mechanical stability without the use of ultrasound disruption .
using the same parameters of three particles per plastic tube and 85 watt ultrasound bursts of 1 second on / off , the time necessary to disintegrate the particles was found as a function of calcium carbonate concentration in the initial encapsulation mixture ( see table 1 ) .
disintegration of the spheres was determined qualitatively by viewing the attained product under a microscope .
similarly , three spheres of each of the three calcium carbonate concentrations were subjected to three trials of agitation by vortex . in each case , no signs of particle disintegration could be observed after thirty minutes ( see table 2 ) .
it is clear that an increasing concentration of calcium carbonate leads to a decrease in the time necessary for particle disintegration .
increasing the concentration of calcium carbonate both raises the amount of material in each sphere sensitive to ultrasound and reduces the relative concentration of alginate .
we experimented with a range of values before running final trials at 50% , 75% and 100% calcium carbonate . using calcium carbonate concentrations of less than 50% drastically increased the time necessary for ultrasound disruption , while concentrations greater than 100% increased viscosity of the mixture and made extrusion through the needle very difficult .
time - dependent diffusion of substances through an alginate matrix has been previously demonstrated , with diffusion times varying over minutes to hours depending upon the weight of the molecule in question and the initial concentration of sodium alginate used to make an encapsulation polymer ( 10 ) . while we may reasonably conjecture that the particles generated in this study would share diffusion characteristics with those published , our initial goal was to dry particles in order to create a hard external calcium carbonate diffusion barrier .
drying particles in an incubator , however , generated a product that adhered too firmly to the drying surface to be removed without damage .
. limitations of this study include the lack of a quantitative method to determine the rate of sphere disintegration as a function of the number of ultrasound bursts to which they were subjected .
second , a method to quantify the amount of agitation delivered would be helpful so that the maximum mechanical disruption tolerated by spheres can be identified . finally ,
although the coaxial airflow technique described in this study is a simple and widely used system of generating even micro - scale hydrogel particles , we found the reproducibility of particle shape and size to be limited from batch to batch .
there are techniques available which offer greater reproducibility of product and smaller sphere size , albeit at much greater cost ( 11 ) .
we have demonstrated a process by which routinely available and non - toxic materials can be used to create particles of encapsulated calcium carbonate in a calcium alginate hydrogel .
the resulting product is easily disrupted with ultrasound and yet retains structural integrity under agitation by vortex for an extended period .
there are logical implications for these particles to be injected into a target tissue under image guidance and subsequently identified via fluoroscopy or ct scan .
destruction of particles with therapeutic ultrasound and the controlled release of encapsulated drugs is a reasonable future experimental goal .
our next set of experiments will involve a system to dry spheres while they are simultaneously agitated .
it will thus be possible to quantify the diffusion characteristics and parameters of ultrasound disruption on dried particles .
we are also working with microscopes that can photograph particles , the disruption products , as well as potentially measure the reduction of particle radius as a function of ultrasound delivery .
 a calcium carbonate suspension , encapsulated within particles of calcium alginate hydrogel , is proposed as a drug delivery device susceptible to ultrasound disruption . 
 spheres approximately 1 mm in diameter were prepared by the coaxial airflow method from mixtures of 1% sodium alginate ( m / v ) and each of 50% , 75% and 100% calcium carbonate ( m / v ) in distilled water . 
 this product was subjected to cycles of 85 watt ultrasound in 1 second on / off bursts via a lab sonication system until fully disintegrated , a process requiring between 8 and 20 minutes depending upon initial calcium carbonate concentrations . 
 the spheres subjected to vortex did not demonstrate any signs of mechanical degeneration after 30 minutes . 
 before use as a model implant , further work is required to develop a method of drying the particles to make them impermeable to drug diffusion before the time of their disruption with ultrasound . 
INTRODUCTION
METHODS
RESULTS
DISCUSSION
CONCLUSION