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Ramaswamy K et al, 2015: Targeted Microbubbles: A Novel Application for Treatment of Kidney Stones

Ramaswamy K, Marx V, Laser D, Kenny T, Chi T, Bailey M, Sorensen M, Grubbs R, Stoller M
Department of Urology, University of California, San Francisco, 400 Parnassus Ave, Suite A610, San Francisco, CA 94122.

Abstract

Kidney stone disease is endemic. Extracorporeal shock wave lithotripsy (EWL) was the first major technologic breakthrough where focused shock waves were used to fragment stones in the kidney or ureter. The shockwaves induced the formation of cavitation bubbles, whose
collapse released energy at the stone, and the energy fragmented the kidney stones into pieces small enough to be passed spontaneously. Can the concept of microbubbles be used without the bulky machine? The logical progression was to manufacture these powerful microbubbles ex-vivo and inject these bubbles directly into the collecting system. An external source can be used to induce cavitation once the microbubbles are at their target; the key is targeting these microbubbles to specifically bind to kidney stones. Two important observations have been established: 1) bisphosphonates attach to hydroxyapatite crystals with high affinity; and 2) there is substantial hydroxyapatite in most kidney stones. The microbubbles can be equipped with bisphosphonate tags to specifically target kidney stones. These bubbles will preferentially bind to the stone and not surrounding tissue, reducing collateral damage. Ultrasound or another suitable form of energy is then applied causing the microbubbles to induce cavitation and fragment the stones. This can be used as an adjunct to
ureteroscopy or percutaneous lithotripsy to aid in fragmentation. Randall's plaques, which also contain hydroxyapatite crystals, can also be targeted to preemptively destroy these stone precursors. Additionally, targeted microbubbles can aid in kidney stone diagnostics by
virtue of being used as an adjunct to traditional imaging modalities - especially useful in high risk patient populations. This novel application of targeted microbubble technology not only represents the next frontier in minimally invasive stone surgery, but a platform technology for other areas of medicine. 

BJU Int. 2014 Nov 17. doi: 10.1111/bju.12996. [Epub ahead of print]

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Comments 1

Hans-Göran Tiselius on Thursday, 26 February 2015 09:19

This is an extremely interesting discussing article from University of California in San Francisco. The authors have formulated a number of relevant and exciting questions on the possible role of targeted micro-bubbles in stone treatment as well as in some other urological conditions.

The basic idea is to create disintegrating power similar to that occurring during SWL by collapse of cavitation bubbles at the stone surface. Micro-bubbles with di-phosphonate tags are produced in order to accomplish adherence of the bubbles to hydroxyapatite in calcium stones. The bubbles can be delivered to the stone surface by retrograde or antegrade techniques. Once attached to the target the bubbles can be expanded by electromagnetic, ultrasound or piezoelectric pulses with ensuing stone disintegration. The minimal invasiveness by using ureteral catheters for retrograde bubble delivery might enable stone disintegration without general or regional anaesthesia.

Micro-bubbles containing contrast medium can also have a place in stone diagnosis and treatment by making stones with poor or no radio-density, such as those composed of uric acid, cystine or drug components, clearly visible during fluoroscopy. Such a method might also enable identification of stones on MRI-examination.

The problem by using di-phosphonate as binding tag is that although calcium phosphate (hydroxyapatite) is a component of a large fraction of calcium oxalate stones, the calcium phosphate content is usually rather small. Ideally a tag for calcium oxalate should be sought.

The authors also mention the possibility to attach micro-bubbles to the subepithelial deposits that we recognize as Randall’s plaques. These deposits are entirely composed of calcium phosphate. The idea is intriguing as a way to eliminate the basis for formation of many calcium oxalate stones. My personal view is, however, that with the close relationship between calcium phosphate, interstitial tissue and urinary macromolecules it is unlikely that these deposits can be eliminated in this way.

One attractive possibility would be to target residual stone fragments in the lower calyx and by combining further disintegration, by expansion and collapse of micro-bubbles, with inversion therapy, low-invasive improved fragment elimination might be possible. Further reports of this technique are anticipated with excitement.

I have selected this article as a top-publication despite lack of essential experimental support, because the authors present a quite new possible approach to stone disintegration.

This is an extremely interesting discussing article from University of California in San Francisco. The authors have formulated a number of relevant and exciting questions on the possible role of targeted micro-bubbles in stone treatment as well as in some other urological conditions. The basic idea is to create disintegrating power similar to that occurring during SWL by collapse of cavitation bubbles at the stone surface. Micro-bubbles with di-phosphonate tags are produced in order to accomplish adherence of the bubbles to hydroxyapatite in calcium stones. The bubbles can be delivered to the stone surface by retrograde or antegrade techniques. Once attached to the target the bubbles can be expanded by electromagnetic, ultrasound or piezoelectric pulses with ensuing stone disintegration. The minimal invasiveness by using ureteral catheters for retrograde bubble delivery might enable stone disintegration without general or regional anaesthesia. Micro-bubbles containing contrast medium can also have a place in stone diagnosis and treatment by making stones with poor or no radio-density, such as those composed of uric acid, cystine or drug components, clearly visible during fluoroscopy. Such a method might also enable identification of stones on MRI-examination. The problem by using di-phosphonate as binding tag is that although calcium phosphate (hydroxyapatite) is a component of a large fraction of calcium oxalate stones, the calcium phosphate content is usually rather small. Ideally a tag for calcium oxalate should be sought. The authors also mention the possibility to attach micro-bubbles to the subepithelial deposits that we recognize as Randall’s plaques. These deposits are entirely composed of calcium phosphate. The idea is intriguing as a way to eliminate the basis for formation of many calcium oxalate stones. My personal view is, however, that with the close relationship between calcium phosphate, interstitial tissue and urinary macromolecules it is unlikely that these deposits can be eliminated in this way. One attractive possibility would be to target residual stone fragments in the lower calyx and by combining further disintegration, by expansion and collapse of micro-bubbles, with inversion therapy, low-invasive improved fragment elimination might be possible. Further reports of this technique are anticipated with excitement. I have selected this article as a top-publication despite lack of essential experimental support, because the authors present a quite new possible approach to stone disintegration.
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