The new technology of “telegastric” is expected to realize targeted treatment of tumors

“Telescopic” has always been a human dream, and this sci-fi superpower is now realized by ultrasound technology and is expected to be used to treat diseases and save people.

On June 6, the team of researcher Zheng Hairong, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences (hereinafter referred to as “Shenzhen Advanced Institute”), developed a phased array holographic acoustic tweezers control technology, which successfully realized the non-invasive precise control and efficient enrichment of airbag-containing bacterial groups in organisms and bloodstream, and realized the application of tumor targeted therapy in animal models. The results were published in Nature Communications, a journal of Nature. In this study, Shenzhen Advanced Institute is the only communication unit for papers.

Schematic diagram of phased array holographic acoustic forceps system and in vivo manipulation cell aggregation Photo courtesy of the research team

It is understood that the phased array holographic acoustic tweezer system generates tunable three-dimensional bulk sound waves based on the high-density surface array transducer, and successfully controls the balloon-containing bacterial clusters by accurately regulating the spatial sound field in complex environments such as living blood vessels, so that it can accurately move to the target area and play a therapeutic function, which is expected to provide an ideal means for targeted drug delivery and cell therapy of tumors.

Acoustically manipulate cells and “telene” them in blood vessels

Physical means such as light, acoustics, electromagnetism and other physical means are considered to be possible ways to achieve “telescopic” non-contact manipulation of objects. For example, optical tweezers (2018 Nobel Prize in Physics) control technology has demonstrated precise advantages in micro-nanoscale particle manipulation, but its penetration depth in opaque organisms is very limited. In addition, magnetic forceps manipulation technology generally requires the binding adhesion of magnetic particles, which limits cell activity and affects the therapeutic effect.

“In contrast, acoustic tweezers designed based on high-frequency acoustic gradient sound fields have the unique advantages of high force, high penetration, high control flux and no need for labeling in biological systems.” Zheng Hairong, the corresponding author of the paper, said that if acoustic methods can be used, without intervention, drugs and therapeutic cells can be accurately transported to the site of biological lesions like “telescopic”, which will solve a major problem in clinical treatment.

Based on the above problems, Professor Zheng Hairong led the medical imaging team of Shenzhen Advanced Institute after more than ten years of accumulation of sound manipulation technology, based on the principle of ultrasonic radiation, using high-density two-dimensional planar array and multi-channel programmable electronic system, combined with three-dimensional sound field modulation, ultrasonic imaging and time inversion algorithms, proposed and constructed the theory, technology and instrument system of programmable phased array holographic acoustic tweezers, laying the foundation for precise sound control in complex environments such as organisms.

Schematic diagram of phased array holographic acoustic tweezers system (Research, 2021) Courtesy of the research team

The team analyzed the radiation response characteristics of particles with different acoustic properties, pioneered the use of time inversion to correct the distortion generated by sound waves passing through non-uniform media, and combined ultrasonic imaging with three-dimensional acoustic manipulation to realize self-navigating three-dimensional acoustic tweezers in non-transparent and non-uniform media, taking the lead in breaking through the bottleneck problem of acoustic manipulation in complex environments. The team continued to cultivate in the field of phased array holographic acoustic tweezers, promoted the miniaturization of two-dimensional high-density ultrasonic arrays, fused microscopic imaging, initially realized the verification of ex vivo three-dimensional acoustic manipulation of cells and microorganisms, and further combined with gene editing and other technologies, focusing on promoting the key applications of programmable phased array holographic acoustic tweezers in various fields. This time, the team has made a breakthrough in biomedical applications by promoting the high-precision and high-throughput control technology of phased array holographic acoustic forceps, and has taken the lead in realizing the targeted therapy of solid tumors by bacteria in body acoustic manipulation.

Schematic diagram of phased array holographic acoustic forceps system in vivo manipulation cells (Nature Communications, 2023) Photo courtesy of the research team

The paper’s peer reviewers said that the study achieved sound-modifying genetically engineered bacteria in vivo, and the study was carried out in blood vessels with normal blood flow, which is a very important step, because blood flow is an extremely challenging environmental factor. The fact that they successfully sonically manipulate vesicle bacteria in blood vessels opens the door to biomedical applications, such as acoustic manipulation of targeted drug delivery. Therefore, the study describes and introduces the combination of acoustic forceps with targeted therapy techniques that will be widely studied and applied in the coming years.

Invisible “tweezers” to achieve targeted tumor therapy

The internal environment of organisms is extremely complex, affected by environmental factors such as tissues and organs, bones, blood vessels, blood flow, etc., in such a complex environment, how should acoustic means be used to “catch” bacteria that can produce the effect of treating tumors, and make them effective, so as to achieve “telescopic extraction”?

Research team member Ma Teng said that the complex environmental factors in living organisms have great challenges to the establishment of sound field and the anti-interference of ultrasound. From the theoretical research level, the research team proposed the discrete expression and calculation theory of acoustic radiation force in complex sound field environment, solved the bottleneck problem of arbitrary structure particles being forced, and explored the dynamic behavior of manipulation targets under the action of spatial sound field in complex environment. From the level of engineering research and development, through long-term technical exploration and accumulation, the team has overcome the problems of sound field design and manufacturing process in the development of high-density acoustic tweezers transducer, successfully developed a two-dimensional high-density ultrasonic transducer array, and realized the generation of strong gradient sound field and the spatiotemporal dynamic regulation of complex sound field by using the method of holographic element construction and time multiplexing, combined with multi-channel high-precision time inversion ultrasonic excitation.

“The strong gradient sound field formed by the two-dimensional high-density ultrasonic transducer array is like an invisible ‘tweezers’, establishing a holographic stereo field at the lesion, and controlling the bacteria to accurately follow the preset route to the lesion site.” Ma Teng said.

From the level of biomedical application, researchers Yan Fei and others in the research team used gene editing technology to produce submicron gas vesicles in bacterial cells, and the existence of the air sacs significantly improved the acoustic sensitivity of genetically engineered bacteria, so that they could be aggregated into clusters under the guidance of radiation in the sound field. In particular, by constructing animal models, combining microscopy imaging with phased array holographic acoustic forceps, overcoming the influence of complex organism tissue structure and high-speed blood flow, these bacterial clusters can successfully flow counterflow or as needed into the preset blood vessels of living mice, demonstrating excellent spatiotemporal manipulation accuracy. In addition, high-throughput phased array holographic acoustic forceps manipulation technology can significantly improve the aggregation efficiency of engineered bacteria in tumors, and combined with the tumor cytotoxicity of bacteria, it can significantly delay the growth of tumors and greatly extend the survival time of tumor-bearing mice.

Researcher Zheng Hairong said that the study proved that the phased array holographic acoustic forceps instrument system can be used as a new tool for non-contact precise manipulation of cells in vivo. With phased array holographic acoustic forceps as a means and functional cells and cell spheres as carriers, it has exciting application potential in immunotherapy, tissue engineering, targeted drug delivery, etc., such as acoustic manipulation of CAR-T and CAR-M cells to break through the solid tumor barrier; Customized sound assembly of stem cells and organoids in vivo; The sound aggregation of drug-loaded cells at the lesion has important transformation value in ultrasound therapy, ultrasound administration and neuromodulation. (Source: China Science News, Diao Wenhui)

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