Aurelia Butler

A team of researchers at the University of California San Diego has made significant advances in solving some of the most vexing challenges in bioprinting 3D-engineered tissues while meeting the key requirements of high cell density, high cell viability and fine fabrication resolution.
The research led by nanoengineers at the UC San Diego Jacobs School of Engineering was published in the February 22, 2023 issue of Science Advances.
Bioprinting is based on 3D-printing technology, using cells and biopolymer to create biological structures and tissues. 3D-engineered tissues — lab-created yet functional human-like tissues made of living cells and biomaterial scaffolds — have great potential for biomedical applications, including drug testing and development, organ transplants, regenerative medicine, personalized medicine, disease modeling, and more. Their uses could add significant speed and integrity to the process of drug development, as well as helping to mitigate challenges associated with organ-donor shortage and immune rejection.
One of the most promising types of 3D-bioprinting is called digital light processing (DLP) bioprinting. Within this branch of 3D-bioprinting, progress has been impeded by practical and technical impediments. It has proven difficult to print tissues with high cell densities and finely resolved structures.
“After printing, we culture the construct to allow the cells to mature or reorganize into a functional tissue. Therefore, the cell is like a seed, and each cell type has a specific density at which they are most potent to sprout,” said Shaochen Chen, the nanoengineering professor leading the research team.
Using existing approaches, the more dense the presence of cells in bioink, which is a biocompatible polymer used in DLP-based 3D bioprinting, the more the light scatters, hindering printing resolution.

The researchers reduced this light-scattering effect by tenfold, allowing them to print with high cell densities and high resolution thanks to the contrast agent iodixanol, a new ingredient in the bioink.
“Using iodixanol, we developed a refractive index-matched bioink for DLP-based bioprinting to mitigate the light scattering of the cells, concentrating the energy within the user-defined light pattern to improve the printing fidelity,” said Shangting You, a nanoengineering postdoc fellow at UC San Diego, member of Chen’s team and co-first author of the research paper.
For nearly two decades, Chen’s lab has helped steer in the development of DLP-based 3D printing and bioprinting techniques, helping create the foundation for modern 3D biomanufacturing.
How it works
DLP-based 3D bioprinting uses a digital micromirror device (DMD) to project a 2D cross-section of the 3D model to the photo-crosslinkable bioink. When exposed to light, the photocrosslinkable bioink, which can be either synthetic or natural, solidifies. Then, a motorized stage lifts up the bioink by a few tens microns to 200 microns, which allows uncured bioink to refill the gap. When the next cross-section is projected to the bioink, a new layer solidifies and the process repeats.

When all goes well, a newly formed layer precisely matches the shape of the projected cross-section. However, with existing methods, the incorporation of cells in the bioink can cause severe light scattering, which blurs the projected light in the bioink. As a result, the newly formed layers cannot replicate the fine details of the projected cross-sections.
Tuning the refractive index of the bioink minimizes this scattering effect and significantly improves the fabrication. The Chen Lab’s research shows that a ~50 µm feature size can be achieved in a refractive-index-matched gelatin methacrylate (GelMA) bioink with a cell density as high as 0.1 billion/mL.
This approach introduces a few novel technical innovations, including a hollow organic vascular network embedded in a cell-laden thick tissue, enabling it for perfused and long-term culture, and a snow-flake and spoke shape to showcase the high resolution for both positive and negative features.
The project was not without its challenges. “We have developed various bioink materials and several protocols for handling them,” said Yi Xiang, a nanoengineering PhD student at UC San Diego, member of Chen’s team and co-first author of the research paper. “But with the longer printing time for a larger tissue, any inconsistency and instability in the cells and in the biomaterial was amplified. Therefore, we had to modify and optimize both the material composition and the handling procedures.”
This project marks the first use of iodixanol as a bioink in DLP bioprinting, at a high cell density and with long intervals of exposure. “We performed a series of biological investigations to evaluate this impact and developed some post-printing procedures to sufficientlydissipate the iodixanol,” Xiang said.
With the improved printing resolution mediated by iodixanol, a high cell density, pre-vascularized tissue with an overall size of 17 x 11 x 3.6 mm3 was fabricated.
“In vitro culture of such a thick tissue has been hindered by the limited diffusion of oxygen and nutrients,” Chen said. “We were able to print perfusable vascular lumens embedded in the tissue with diameters ranging from 250 µm to 600 µm, which was interfaced with a perfusion system for long-term culture. We demonstrated that the vascular lumens were endothelialized, and the thick tissue remained viable for 14 days of culture.”
Next steps
The team continues to work on optimizing its materials system and bioprinting parameters for functional thick tissue fabrication and has filed a provisional patent covering this work.
Further next steps Chen suggests include developing precisely structured, high cell-density in vitro tissue models for improved histological and functional recapitulation, with an eye toward high cell-density large-tissue printing for tissue and organ transplants and replacements in human subjects.
Paper: “High Cell Density and High Resolution 3D Bioprinting for Fabricating Vascularized Tissues” in Science Advances
Coauthors include: Shangting You*, Yi Xiang* and Henry H. Hwang, Department of NanoEngineering, University of California San Diego; David B. Berry, Department of Orthopaedic Surgery, UC San Diego; Wisarut Kiratitanaporn, Department of Bioengineering, UC San Diego; Jiaao Guan, Department of Electrical and Computer Engineering, UC San Diego; Emmie Yao, Min Tang and Zheng Zhong, Department of NanoEngineering, UC San Diego; Xinyue Ma, School of Biological Sciences, UC San Diego; Daniel Wangpraseurt, Department of NanoEngineering and Scripps Institution of Oceanography, UC San Diego; Yazhi Sun, Department of NanoEngineering, UC San Diego; Ting-yu Lu, Materials Science and Engineering Program, UC San Diego; and Shaochen Chen, Department of NanoEngineering, Department of Bioengineering, Department of Electrical and Computer Engineering, and Materials Science and Engineering Program, UC San Diego. More

Given the growing importance of graphite in energy storage technologies, a team of Northwestern researchers has conducted a study exploring ways to reduce reliance on imports of the in high-demand mineral, which powers everything from electric vehicles (EVs) to cell phones.
The paper, which published this week in the journal Environmental Science and Technology, is the first natural and synthetic graphite material flow analysis for the U.S., and considers 11 end-use applications for graphite, two waste management stages and three recycling pathways.
“If we want to produce more batteries domestically, we’re going to need to increase our production of graphite,” said Northwestern University chemical engineer Jennifer Dunn. “But the question is, how can we do so in a way that contributes to decarbonization goals?”
Dunn is an associate professor of chemical and biological engineering at Northwestern’s McCormick School of Engineering and director of the Center for Engineering Sustainability and Resilience. The paper was co-authored by Jinrui Zhang, who at the time of the study initiation was a post-doctoral scholar in chemical and biological engineering, and Chao Liang, previously a member of Northwestern’s Institute for Sustainability and Energy (ISEN). Both co-authors are alumni of Dunn’s research group.
The U.S. uses mostly synthetic graphite, which is produced from by-products of the fossil fuel industry and creates a paradoxical relationship between graphite and technologies like electric vehicles (EVs) that aim to remove fossil fuel supply chains from transportation and cut greenhouse gas emissions.
Natural graphite, alternately, is sourced from mines and imported to the U.S. mostly from China. Nearly all the graphite used in the U.S. goes into electrodes for steel manufacturing. As the battery supply chain in the U.S. ramps up, measures like the Inflation Reduction Act seek to incentivize the use of domestically sourced materials — including graphite — in U.S.-made batteries.

Given the growing importance of graphite in energy storage technologies like lithium-ion batteries, the team carried out this analysis to characterize the major production routes of the mineral, its main uses and opportunities to reduce consumption through recycling. Data from 2018 — the most recent period with sufficient data for this type of analysis — was used for the study.
Most of the graphite consumed in the U.S. in 2018 was synthetic graphite, with 63% of this graphite produced domestically. Production of synthetic graphite emits more greenhouse gases than mining natural graphite (Natural graphite has between 62% and 89% lower greenhouse gas emissions). Synthetic graphite is also more expensive. However, the U.S. does not mine natural graphite but imports it, predominately from China.
As the only material that conducts electricity besides metal, the main use of graphite is for electrodes in steel making. As demand for low-carbon steel increases, more graphite may be consumed in electrode production. During steel making, graphite burns and dissipates — much like how graphite pencils start to disappear as you write with them. Though it is not impossible to recover dissipated graphite, it rarely is, diminishing opportunities to recover the mineral through recycling. Technologies to recover graphite from lithium-ion batteries are increasing in maturity but not yet common.
Dunn said that part of the focus on domestic sources and recycling of graphite-containing products like lithium-ion batteries is based on the current supply chain’s potential instability and projected increasing demand.
“You can recover some graphite from recycling lithium-ion batteries, but batteries last a while, so it may be a decade before you can get graphite back from EVs that reach the end of their life,” Dunn said. “However, we are also building the bioeconomy in the U.S., and that can include making graphite from biomass. This opens up another supply option beyond making graphite from fossil fuel industry by-products or mining.”
With the passage of the Inflation Reduction Act of 2022, more funding will move toward the use of domestically sourced and recycled graphite, and Dunn said the U.S. needs to be ready to make the shift.
The study, “Graphite flows in the U.S.: Insights into a key ingredient of the energy transition,” was supported by the National Science Foundation’s Future Manufacturing Program (NSF CMMI-2037026). More

Imagine you can open your fridge, open an app on your phone and immediately know which items are expiring within a few days. This is one of the applications that a new technology developed by engineers at the University of California San Diego would enable.
The technology combines a chip integrated into product packaging and a software update on your phone. The phone becomes capable of identifying objects based on signals the chip emits from specific frequencies, in this case Bluetooth or WiFi. In an industrial setting, a smartphone equipped with the software update could be used as an RFID reader.
The work harnesses breakthroughs in backscatter communication, which uses signals already generated by your smartphone and re-directs them back in a format your phone can understand. Effectively, this technique uses 1000 less power than state of the art to generate WiFi signals These advances have enabled very low-power communication between components of the Internet of Things and hardware such as WiFi or Bluetooth transceivers, for applications such as on-body sensors or asset trackers.
The custom chip, which is roughly the size of a grain of sand and costs only a few pennies to manufacture, needs so little power that it can be entirely powered by LTE signals, a technique called RF energy harvesting. The chip turns Bluetooth transmissions into WiFi signals, which can in turn be detected by a smartphone with that specific software update.
The team will present their work at the IEEE International Solid-State Circuits Conference in San Francisco on Feb. 20, 2023.
Currently, state of the art backscatter modulation requires two external devices: one to transmit and one to receive and read the signals. This conference paper presents the first backscatter integrated circuit that can enable wireless communication and battery-less operation coming from a single mobile device.

“This approach enables a robust, low-cost and scalable way to provide power and enable communications in an RFID-like manner, while using smartphones as the devices that both read and power the signals,” said Patrick Mercier, one of the paper’s senior authors and a professor in the Department of Electrical and Computer Engineering at the University of California San Diego.
The technology’s broader promise is the development of devices that do not need batteries because they can harvest power from LTE signals instead. This in turn would lead to devices that are significantly less expensive, last longer, up to several decades, said Dinesh Bharadia, a professor in the UC San Diego Department of Electrical and Computer Engineering and one of the paper’s senior authors.
“E-waste, especially batteries, is one of the biggest problems the planet is facing, after climate change,” Bharadia said.
How it works
The researchers achieved this breakthrough by harvesting power from LTE smartphone signals and buffering this power onto an energy storage capacitor. This in turn activates a receiver that detects Bluetooth signals, which are then modified into reflected WiFi signals.

The software update is simply a bit sequence that turns the Bluetooth signal into something that can be more easily turned into a WiFi signal.
In addition, most lower power wireless communications require custom protocols, but the device the researchers developed relies on common communication protocols: Bluetooth, WiFi and LTE. That’s because smartphones are equipped with both a Bluetooth transmitter and a WiFi receiver.
The device has a range of one meter-about one yard. Adding a battery would boost the tag’s range to tens of meters, but also increase costs. The device, which is half a square inch in size, costs just a few cents to manufacture.
Next steps
Next steps include integrating the technology in other research projects to demonstrate its capabilities.
The team also hopes to commercialize the device, either through a startup or through an industry partner.
The work was supported by the National Science Foundation under Grant 1923902 and the UC San Diego Center for Wearable Sensors.
An LTE-harvesting BLE-to-WiFi Backscattering Chip for Single-Device RFID-like Interrogation
Shih-Jai Kuo*, Manideep Dunna*, Hongyu Lu, Akshit Agarwal, Dinesh Bharadia, Patrick Mercier, Department of Electrical and Computer Engineering, University of California San Diego
*co-primary authors More

In recent years, wearable devices such as smartwatches and rings, as well as smart scales, have become ubiquitous — “must-haves” for the health conscious to self-monitor heart rate, blood pressure, and other vital signs. Despite the obvious benefits, certain fitness and wellness trackers could also pose serious risks for people with cardiac implantable electronic devices (CIEDs) such as pacemakers, implantable cardioverter defibrillators (ICDs), and cardiac resynchronization therapy (CRT) devices, reports a new study published in Heart Rhythm, the official journal of the Heart Rhythm Society, the Cardiac Electrophysiology Society, and the Pediatric & Congenital Electrophysiology Society, published by Elsevier.
Investigators evaluated the functioning of CRT devices from three leading manufacturers while applying electrical current used during bioimpedance sensing. Bioimpedance sensing is a technology that emits a very small, imperceptible current of electricity (measured in microamps) into the body. The electrical current flows through the body, and the response is measured by the sensor to determine the person’s body composition (i.e., skeletal muscle mass or fat mass), level of stress, or vital signs, such as breathing rate.
“Bioimpedance sensing generated an electrical interference that exceeded Food and Drug Administration-accepted guidelines and interfered with proper CIED functioning,” explained lead investigator Benjamin Sanchez Terrones, PhD, Department of Electrical and Computer Engineering, University of Utah, Salt Lake City, UT, USA. He emphasized that the results, determined through careful simulations and benchtop testing, do not convey an immediate or clear risk to patients who wear the trackers, but noted that the different levels emitted could result in pacing interruptions or unnecessary shocks to the heart. Dr. Sanchez added, “our findings call for future clinical studies examining patients with CIEDs and wearables.”
The interaction between general electrical appliances, and more recently smart phones, with CIEDs has been subject to study within the scientific community over the past few years. Nearly all, if not all, implantable cardiac devices already warn patients about the potential for interference with a variety of electronics due to magnetic fields — for example, carrying a mobile phone in your breast pocket near a pacemaker. The rise of wearable health tech has grown rapidly in recent years, blurring the line between medical and consumer devices. Until this study, objective evaluation for ensuring safety has not kept pace with the exciting new gadgets.
“Our research is the first to study devices that employ bioimpedance-sensing technology as well as discover potential interference problems with CIEDs such as CRT devices. We need to test across a broader cohort of devices and in patients with these devices. Collaborative investigation between researchers and industry would be helpful for keeping patients safe,” noted Dr. Sanchez Terrones. More