Ultrasound-Guided Bioprinting: The New Frontier in Precision Medicine

The healthcare and medical system has come a long way over the last century. In early times, humans depended on medicinal plants. But of course, they lacked consistency and specificity in the delivery of the drug.

Then, pills and capsules became popular for storing pharmaceuticals. They dissolve when they come in contact with gastrointestinal fluids, permeate the gut wall, and are then absorbed into the bloodstream through blood capillaries with no control over the drug release. 

The use of coating on drugs to mask their bitter taste further altered the drug’s rate of release. Over time, the coating materials evolved from gold and silver to pearl, sugar, and enteric coatings.

Enteric coating is an outer polymer coating on oral medication. This barrier prevents the drug from getting dissolved in our stomach’s gastric environment, thus allowing for controlled release. Further advancements in these coatings over the years have made drug delivery even better.

The first nanoparticle therapeutic in the form of polymer-drug conjugate was then reported in the 1950s, while the first nanotechnology, known as liposome, wasn’t discovered until the 1960s. Both marked the origin of nanocarriers.

Over time, smart polymers and hydrogels were developed to stabilize drug delivery systems, while efforts were made to develop targeted nanotechnology drug delivery systems.

In recent years, significant progress has been made toward the successful development of localized drug delivery devices that allow for precise control over drug release. Techniques like micelles, hydrogels, liposomes, and nanoparticles offer a sustained release of therapeutic agents at specific locations.

These approaches enhance treatment effectiveness while minimizing tissue toxicity by avoiding the systemic circulation of the therapeutic agents. 

Implantable drug delivery devices, in particular, effectively deliver drugs into localized regions. These devices are made of biocompatible and biodegradable components and can be designed to release drugs with different dosages and for continuous and intermittent delivery. 

A specific focus is on noninvasive deep-tissue implants, also known as smart implants or minimally invasive implants. These devices, designed to monitor bodily functions, deliver medication, or even help with tissue regeneration, are placed in the body without extensive surgical procedures.

Now, a team of Caltech scientists has made significant progress toward the ultimate goal of providing physicians with the ability to precisely print miniature capsules that can deliver cells required for tissue repair in the exact location, such as inside a beating heart.

For this, they have built the deep tissue in vivo sound printing (DISP) platform. The new imaging-guided in vivo 3D-printing technique¹ has been published in the journal Science.

DISP: Imaging-Guided Sound Printing for Deep-Tissue Therapeutics

Three-dimensional (3D) printing or additive manufacturing is gaining a lot of traction thanks to its versatility, ability to create complex designs, and customization options.

Under this manufacturing process, 3D objects are created from a digital file by laying down layers of material. This allows for quick prototyping, reduced manufacturing costs, and personalized products, which have driven its widespread adoption, particularly in fields like manufacturing, healthcare, and even fashion. 

In healthcare, 3D printing is revolutionizing medical implant production. It has become a highly valuable tool for generating patient-specific implants, both externally and directly inside the body.

However, this promise of customized implants faces the limitations of the need for invasive surgical procedures. Implants for the inside of the body are further restricted by the need for precursor materials and a polymerization method safe for use in a human body that can be activated with precision from outside the body. To address these problems, scientists are turning to ultrasound printing.

For instance, in a study² last year, researchers from the Technion Faculty of Biomedical Engineering presented a noninvasive technique for bioprinting tissues and cells deep within the body through external sound wave irradiation emitted from an external ultrasonic transducer.

Now, the team of scientists from the California Institute of Technology has built a platform that leverages imaging-guided ultrasound printing, which is capable of going much deeper than other methods.

Instead of traditional 3D printing, which has nozzles, in this study, there are focused beams of sound that generate controlled temperature spikes to initiate a printing-like process.

Funded by the National Institutes of Health, the American Cancer Society, the Heritage Medical Research Institute, and the Challenge Initiative at UCLA, the study combines ultrasound with low-temperature liposomes (LTSLs) loaded with crosslinking agents. 

Liposome or a lipid vesicle is a small closed structure found in living cells that contain lipids, which are a group of compounds such as fats, waxes, monoglycerides, and diglycerides that perform a variety of functions in our body, including storing energy, signaling, absorbing vitamins, making hormones, and acting as structural components of cell membranes.

These vesicles are used in various applications, including drug targeting, drug delivery, and in vitro studies of cell membrane dynamics. 

The liposomes in the study are immersed in a polymer solution that contains the monomers of the desired polymer and the cargo to be delivered, such as a therapeutic drug.

The polymer is an imaging contrast agent that divulges when crosslinking has occurred. In the study, gas vesicles are used for this purpose. Through real-time monitoring, gas vesicle (GVs)- based ultrasound imaging enables customized pattern creation in live animals. 

GVs are air-filled protein nanostructures that act as imaging and therapeutic agents for ultrasound, magnetic resonance, and optical techniques. They are increasingly used as contrast agents in ultrasound imaging due to their unique properties that allow them to generate nonlinear contrast under ultrasound. GVs can be genetically encoded and engineered, making them versatile imaging agents.

The incorporation of LTSLs loaded with crosslinking agents into bio ink enables the new platform to offer rapid and precise cross-linking of diverse functional biomaterials on demand using focused ultrasound.

The team validated their platform by successfully printing near the cancerous areas in the mouse bladder and deep within the rabbit’s leg muscles in vivo. 

Using the DISP platform to print polymers loaded with a chemotherapeutic drug (doxorubicin) near a bladder tumor in mice, the team was able to achieve far more tumor cell death for several days than those who received the drug through direct injection of drug solutions.

Safety, Precision, and Biocompatibility: DISP’s Clinical Potential

The Caltech team has developed a technique for 3D printing polymers at specific locations deep within living animals. Elham Davoodi, an assistant professor of mechanical engineering at the University of Utah, is the study’s lead author, who completed it while a postdoctoral scholar at Caltech.

This method utilizes sound for localization. Already, it has been used to print glue-like polymers to seal internal wounds and polymer capsules for selective drug delivery.

Scientists previously used infrared light to activate polymerization, the process where small units called monomers are linked together to form larger molecules called polymers, within living animals.

However, infrared has very limited penetration. “It only reaches right below the skin,” noted Wei Gao, professor of medical engineering at Caltech and a Heritage Medical Research Institute Investigator.

In contrast, the new technique can reach deep tissue and can also print different materials for a broad range of applications while “maintaining excellent biocompatibility.”

To realize deep tissue in vivo printing, the team turned to ultrasound, a platform widely used in biomedicine for this purpose. 

But they needed a way to activate the binding of monomers, or crosslinking, at a specific location and only when desired.

So, the team introduced a new way, combining ultrasound with (LTSLs) loaded with cross-linking agents and then embedded in a polymer solution containing polymer monomers and the cargo. More components, like cells and conductive materials such as silver or carbon nanotubes, can also be included here. The resulting bioink was then injected directly into the body.

Now, to initiate printing, scientists used focused ultrasound, which increased the temperature in a targeted area by a few (about 5) degrees. This causes the liposomes to release their contents, so that polymer printing can begin in a precise location. According to Gao:

“Increasing the temperature by a few degrees Celsius is enough for the liposome particle to release our crosslinking agents. Where the agents are released, that’s where localized polymerization or printing will happen.”

The gas vesicles, which are derived from bacteria and used as an imaging contrast agent here, tell us that everything is working as intended by showing up strongly in ultrasound imaging. They are sensitive to chemical changes that take place when the liquid monomer solution crosslinks to create a gel network.

When the transformation takes place, the vesicles change contrast, which is identified by ultrasound imaging. This enables scientists to easily detect when and precisely where the polymerization crosslinking happened, allowing them to modify patterns being printed in live animals.

Besides bioadhesive gels and polymers, the study also details the use of the technique for printing bioelectric hydrogels, polymers with embedded conductive materials used for internal monitoring of physiological vital signs. 

Now, the verification of the DISP platform through successful experiments in mice and rabbits without any signs of inflammation or tissue damage showcases the platform’s potential for localized drug delivery, tissue replacement, and bioelectronics. With the body clearing unpolymerized ink within a week, it further highlights the platform’s safety profile.

Moreover, its ability to print cell-laden, drug-loaded, bioadhesive, and conductive materials shows its versatility for various medical applications. But of course, for it to be translated into clinical use, the platform needs further refinements.

“It’s a new research direction in the field of bioprinting. Our next stage is to try to print in a larger animal model, and hopefully, in the near future, we can evaluate this in humans.”

– Gao

The team aims to enhance the ability of the DISP platform to localize precisely and apply focused ultrasound through machine learning.

“In the future, with the help of AI, we would like to be able to autonomously trigger high-precision printing within a moving organ such as a beating heart.”

– Gao

Investing in 3D Bio-Printing

An early player in the 3D printing industry, 3D Systems (DDD -26.67%) is one of the leading names to watch as this space evolves. The company provides comprehensive 3D printing and digital manufacturing solutions, including 3D printers for metals, materials, and plastics, software, and services. From dental labs and automotive manufacturers to semiconductor designers and medical device makers, it designs software and develops printers for all kinds of industries and materials.

3D Systems (DDD -26.67%)

3S Systems operates through two segments: Healthcare Solutions, which serves dental, regenerative medicine, medical devices, and personalized health services, and Industrial Solutions, which serves transportation, aerospace, defense, and general manufacturing. 

In 2021, it acquired Allevi to expand its regenerative medicine initiative by accelerating growth in pharmaceutical research laboratories. As the company notes on its website, 3D bioprinting has advanced the development of animal-free preclinical models and 3D disease modeling through iterative bioprint designs and its ability to recapitulate in vivo human biology.

The same year, it also acquired Additive Works GmbH, a German software firm, to expand its simulation capabilities for rapid optimization of industrial-scale 3D printing processes.

The company’s shares are currently trading at $1.94, down 22.26% YTD. At this price level, 3D Systems’ shares have experienced a significant decline from their peak of about $48.60, which was hit in early 2021, much like many other stocks in the market. 

3D Systems has achieved a market cap of $345.6 million, and its EPS (TTM) is -1.93, and a P/E (TTM) is -1.32.

As for company financials, they show that in the first quarter of 2025, 3D Systems recorded a revenue of $94.5 million, which was a decline of 8% from the same quarter last year due to lower materials sales.

Healthcare Solutions revenue accounted for $41.3 million, while $53.2 million belonged to Industrial Solutions.

This, CEO Dr. Jeffrey Graves said, reflects “a continuation of challenging top-line pressures as many customers are delaying their capital investments” to get greater clarity around potential tariff impacts in addition to the ongoing geopolitical and broader macroeconomic uncertainty.

Gross profit margin for the period was 34.6%, and non-GAAP gross profit margin was 35% because of lower volumes and unfavorable prices. Net loss, meanwhile, was $37 million. At the end of March 2025, its cash and cash equivalents were $135 million, and total debt, net of deferred financing costs, was $212.3 million.

However, the company is working on a $50 million cost savings initiative, which will be completed by mid-2026. It is also projected to get breakeven on an EBITDA basis in the last quarter of this year.

Furthermore, its balance sheet strengthened as a result of the sale of the Geomagic portfolio, providing over $100 million post-tax increase to cash reserves to $250 million as of April 30, 2025.

The positive aspects of 3D systems as an investment option are that the company is seeing steady growth in the Aerospace and Defense markets, and its newest hardware systems have recorded growth in sales. Also, AI infrastructure is another area 3D Systems is focusing on to drive its progress.

“Our deliberate preservation of R&D investments over the last few years has yielded a significant wave of new technology introduction across the entirety of our product portfolio, including both our polymer and metal platforms.”

– Gravel

He noted that while this negatively impacts profitability in the short term, strong customer interest means “our new systems are increasingly preferred for high-quality/high-reliability component manufacturing, for applications within the human body, and in advanced industrial systems.” Multiple new products are now entering the critical phase of commercialization.

This year, so far,  3D Systems has collaborated with the leading commercial vehicle manufacturers Daimler Truck to facilitate remote spare part printing. The on-demand printing is to overcome supply chain bottlenecks and reduce delivery time by 75%. 

Its clinically validated NextDent 3D printing resins are reported to now address over 30 applications, including those focused on repairing teeth. The company also announced the first 3D-printed PEEK facial implant at its point-of-care additive manufacturing solution in partnership with the University Hospital Basel.

At a recent event, 3D Systems also unveiled multiple new products, such as QuickCast® Diamond™ and PSLA 270, and a new module for large-format EXT Titan Pellet Extrusion printers. It also introduced a high-throughput, precision Figure 4® 135 3D printer and Figure 4 Tough 75C FR Black material to reduce the cost of high-mix, low-volume manufacturing. 

Latest on 3D Systems

Conclusion

The healthcare system has gone through a massive transformation over the last few decades. This journey from herbal concoctions to sophisticated nanomedicine shows that the evolution of drug delivery has been marked by technological innovation. 

Now, the latest development by Caltech scientists is a remarkable step forward in the world of medical revolution. By using the very same sound waves that are currently used to look inside the body for imaging purposes, the DISP platform is able to penetrate much deeper into tissues. A bespoke blend of solution (bioink) and focused ultrasound (FUS) transducer, meanwhile, is enabling the precise printing.

As the technology makes its advancement toward larger animal models and human trials, DISP, with its biocompatibility, precision, and adaptability, holds the promise of redefining drug delivery and internal healing.

Click here for a list of the top 3d bioprinting stocks.

1. Davoodi, E., Li, J., Ma, X., Najafabadi, A. H., Yoo, J., Lu, G., Sani, E. S., Lee, S., Montazerian, H., Kim, G., Williams, J., Yang, J. W., Zeng, Y., Li, L. S., Jin, Z., Sadri, B., Nia, S. S., Wang, L. V., Hsiai, T. K., Weiss, P. S., Zhou, Q., Khademhosseini, A., Wu, D., Shapiro, M. G., & Gao, W. (2025). Imaging-guided deep tissue in vivo sound printing. Science, 388(6747), 616–623. https://doi.org/10.1126/science.adt0293

2. Debbi, L., Machour, M., Dahis, D., Shoyhet, H., Shuhmaher, M., Potter, R., Tabory, Y., Goldfracht, I., Dennis, I., Blechman, T., Fuchs, T., Azhari, H., & Levenberg, S. (2024). Ultrasound mediated polymerization for cell delivery, drug delivery, and 3D printing. Small Methods, 8(6), 2301197. https://doi.org/10.1002/smtd.202301197