Fat tissue holds the key to 3D printing layered living skin and potentially hair follicles, according to researchers who recently harnessed fat cells and supporting structures from clinically procured human tissue to precisely correct injuries in rats. The advancement could have implications for reconstructive facial surgery and even hair growth treatments for humans.&nbsp;The team’s findings published today (March 1) in&nbsp;<a href="https://doi.org/10.1016/j.bioactmat.2023.10.034" target="_blank">Bioactive Materials</a>. The U.S. Patent and Trademark Office granted the team a patent in February for the bioprinting technology it developed and used in this study.&nbsp;“Reconstructive surgery to correct trauma to the face or head from injury or disease is usually imperfect, resulting in scarring or permanent hair loss,” said Ibrahim T. Ozbolat, professor of engineering science and mechanics, of biomedical engineering and of neurosurgery at Penn State, who led the international collaboration that conducted the work. “With this work, we demonstrate bioprinted, full thickness skin with the potential to grow hair in rats. That’s a step closer to being able to achieve more natural-looking and aesthetically pleasing head and face reconstruction in humans.”While scientists have previously 3D bioprinted thin layers of skin, Ozbolat and his team are the first to intraoperatively print a full, living system of multiple skin layers, including the bottom-most layer or hypodermis. Intraoperatively refers to the ability to print the tissue during surgery, meaning the approach may be used to more immediately and seamlessly repair damaged skin, the researchers said. The top layer — the epidermis that serves as visible skin — forms with support from the middle layer on its own, so it doesn’t require printing. The hypodermis, made of connective tissue and fat, provides structure and support over the skull.“The hypodermis is directly involved in the process by which stem cells become fat,” Ozbolat said. “This process is critical to several vital processes, including wound-healing. It also has a role in hair follicle cycling, specifically in facilitating hair growth.”The researchers started with human adipose, or fat, tissue obtained from patients undergoing surgery at Penn State Health Milton S. Hershey Medical Center. Collaborator Dino J. Ravnic, associate professor of surgery in the Division of Plastic Surgery at Penn State College of Medicine, led his lab in obtaining the fat for extraction of the extracellular matrix — the network of molecules and proteins that provides structure and stability to the tissue — to make one component of the bioink.Ravnic’s team also obtained stem cells, which have the potential to mature into several different cell types if provided the correct environment, from the adipose tissue to make another bioink component. Each component was loaded into one of three compartments in the bioprinter. The third compartment was filled with a clotting solution that helps the other components properly bind onto the injured site.“The three compartments allow us to co-print the matrix-fibrinogen mixture along with the stem cells with precise control,” Ozbolat said. “We printed directly into the injury site with the target of forming the hypodermis, which helps with wound healing, hair follicle generation, temperature regulation and more.”They achieved both the hypodermis and dermis layers, with the epidermis forming within two weeks by itself.“We conducted three sets of studies in rats to better understand the role of the adipose matrix, and we found the co-delivery of the matrix and stem cells was crucial to hypodermal formation,” Ozbolat said. “It doesn’t work effectively with just the cells or just the matrix — it has to be at the same time.”They also found that the hypodermis contained downgrowths, the initial stage of early hair follicle formation. According to the researchers, while fat cells do not directly contribute to the cellular structure of hair follicles, they are involved in their regulation and maintenance.“In our experiments, the fat cells may have altered the extracellular matrix to be more supportive for downgrowth formation,” Ozbolat said. “We are working to advance this, to mature the hair follicles with controlled density, directionality and growth.”According to Ozbolat, the ability to precisely grow hair in injured or diseased sites of trauma can limit how natural reconstructive surgery may appear. He said that this work offers a “hopeful path forward,” especially in combination with other projects from his lab involving printing bone and investigating how to match pigmentation across a range of skin tones.“We believe this could be applied in dermatology, hair transplants, and plastic and reconstructive surgeries — it could result in a far more aesthetic outcome,” Ozbolat said.“With the fully automated bioprinting ability and compatible materials at the clinical grade, this technology may have a significant impact on the clinical translation of precisely reconstructed skin.”Ravnic and Ozbolat also are affiliated with the Huck Institutes of the Life Sciences and the Penn State Cancer Institute. Ozbolat has additional affiliations with the Penn State Materials Research Institute and the Department of Medical Oncology at Cukurova University in Turkey, where he is currently on sabbatical leave. Other contributors include Yogendra Pratap Singh, postdoctoral scholar, and Mecit Altan Alioglu, graduate student, both in the Penn State Department of Engineering Science and Mechanics; Youngnam Kang and Miji Yeo, both researchers, and Irem Deniz Derman, graduate student, in the Huck Institutes of the Life Sciences; Yang Wu, Harbin Institute of Technology in China; and Jasson Makkar and Ryan R. Driskell, College of Veterinary Medicine at Washington State University. Kang, Yeo, Singh, Alioglu and Derman also are affiliated with Penn State Department of Engineering Science and Mechanics.

Miji Yeo, a postdoctoral researcher at Penn State, checks the bioink cartridges on a 3D printer developed to intraoperatively print layers of skin. Credit: Michelle Bixby/Penn State. All Rights Reserved.

Bioengineered advancement may have implications for more natural-looking reconstructive surgery outcomes, according to international research team

3D-printed skin closes wounds and contains hair follicle precursors

<h2 id="isPasted">What is silver/silver chloride ink?</h2>‍Silver/silver chloride (Ag/AgCl) is a conductive ink typically used to print electrodes for biomedical applications. It’s a non-toxic, environmentally friendly ink with stable electrochemical potential used to create disposable on-skin medical electrodes for biosensors, like "ECG, EEG and TENS electrodes; defibrillator pads; transdermal drug delivery; biomedical sensors and reference electrodes," according to <a href="https://www.creativematerials.com/products/ag-agcl-inks/" target="_blank">Creative Materials</a>.&nbsp;‍<img src="https://s3-us-west-1.amazonaws.com/wevolver-project-images/froala%2F1709524616616-63d022dacfb6e86a1a3cf1c4_ffhgM2WgWmVRDuIv4GtMPtOgJnNsHrpU0DlhQb2hw9DhzCZ4C7IujXkmI6-Wb1oQkcFbDkFukxQI-6qOCSdGzc-RG3ihBfYeMomcrtZXFV6dX66qBWO6I56fjNV7IngcIVg4ZVpc3em72_ZUQ7XEEeOsDnoXYJ3UkXIu4GSpT1uTJ1njEsNQKtcxJaKNC.png" style="width: 100%px;" class="fr-fic fr-dib">Source: Henkel<h3 id="isPasted">Features:</h3><ul><li>Silver-to-silver chloride ratios can be adjusted and blended to achieve different resistance values and sensitivity levels.&nbsp;</li><li>The ink has a smooth surface finish with excellent adhesion and crease resistance when printed onto polyester and plastic substrates.&nbsp;</li><li>Silver/silver chloride is compatible with screen printing and direct-ink-writing printing technology.&nbsp;</li></ul><h2>Smart health patches</h2>‍Used in both healthcare and athletics applications, smart health patches deliver new capabilities in monitoring. These devices can continuously measure heart rate, brain activity, movement, and other body functions. <a href="https://www.quad-ind.com/smart-health-patches-to-run-smart/" target="_blank">Quad Industries’ Smart Health Patch</a>, designed to optimize training for ultra-runners, is made using Henkel’s silver/silver chloride ink.<img src="https://s3-us-west-1.amazonaws.com/wevolver-project-images/froala%2F1709524652661-63d022daa5cbee3ab018e3e7_8VgrqoubKIfwaL1zITpxMMjBjwZ0pwQdx2p_UCyq48yZIDh9jqqb281s3xO3BjQ7xTJO1oM0xUcUoKoQ6506xXmB2AnVlUENl_QzrSiBiDSWsE25qMLNrOtCmqt1c8hxKm-xZMRmZoxMabvNRQA6Udn9Q6RByf0cqbC_Dy22HfbQWYy4S7Tu8SvzcJjw9.png" style="width: 100%px;" class="fr-fic fr-dib">Source: Quad Industries<img src="https://s3-us-west-1.amazonaws.com/wevolver-project-images/froala%2F1709524667591-63d022dac9c95f5daebb1936_7x7-GMmj24mLom3wqW-nHmMi9PeRUDPwS6Pv5tYsxw_QONplpV8Uyxc6qzd6FJCo3t4G_uNybUwFGiJohdDlYNlrqbXxN0Dv3g1kujpKAT8hPn5BLnvSYClXC0DZIMi8kvIL44HJyqEZwq3CgivP2w_SNr8UElf52dxJI3B_k1N1qiwnP6yNkXgmyRzOe.png" style="width: 100%px;" class="fr-fic fr-dib"><figure data-rt-type="image" data-rt-align="center" id="isPasted"><figcaption>Source: Quad Industries‍</figcaption></figure>‍Silver/silver chloride ink is also used to print glucose sensors for continuous glucose monitoring (CGM) patches like Freestyle Libre.CGM patches are being widely adopted for diabetes management. Rather than pricking a finger several times a day to monitor glucose levels, the CGM continuously measures glucose in the blood and interfaces with a reader device or smartphone app. This allows patients to monitor glucose levels throughout the day and refine the timing for their insulin injections.<img src="https://s3-us-west-1.amazonaws.com/wevolver-project-images/froala%2F1709524688181-63d022da3ae9a36f914066d5_hHSjbJgZWS36H1qokZ_5LN2coCJiIs7H9b7Uw6TUm0o7Qbss4LCqngtZB53W-wdG_sMiMR7KnUMKSRcuX3OhSHY_ngYl7SoPJEe1ZVD_LTrvMQfALXzmxpZAVSwQMxAkHLrVb_SZ0MxJqfYS9fmmN_cH8CSOwUOq1YLmYLEZqfyrDEwgtp1lhSBGSFLoV.png" style="width: 100%px;" class="fr-fic fr-dib">Source: Healthline<img src="https://s3-us-west-1.amazonaws.com/wevolver-project-images/froala%2F1709524702228-63d022da3916c36e5646942d_QdXGhsRpN4wtDyT6VosSkgxf0n4hxX7QICaxkDGbyBOM1Ar0t7ehDpr8ZQoIHzbhKxWRzY8_0G1bBz20I3Yi61Pf0pI0vCZ-6Bd6a7TGwEZp6waSXE0_Ascb-h8PVZQsQcwqcIt5-SUFVGauo6chHPNjqTfZa3hUNWCJfkaXF0WyMdRWn0TQdMiYLySC.jpeg" style="width: 100%px;" class="fr-fic fr-dib">Source: Advanced Technologies and Polymer Materials for Surgical Sutures<img src="https://s3-us-west-1.amazonaws.com/wevolver-project-images/froala%2F1709524715190-63d022dad7285c542dc110f7_YSW1DtYARgBxTI1OcJYkuL_bHjR4eAI01NARpWowdleL1PdML6EBfQ_ksZ3d9jS4o9G6m6beeDeroNPsSs1OxRiOhx7wZA7-ws935lrFJZpgSVoHFMf49r1TYDTgE-eP-sOOrhR3C15nlwi19GzLEiqP-VQNR-vhQo7fOW3MlwK5SiBN7Uh-ltI3qhHSP.png" style="width: 100%px;" class="fr-fic fr-dib">Source: HenkelIn recent years, CGMs also have become a tool for athletic performance. Endurance athletes use CGMs to monitor for dips in glucose during training, and then methodically dial in their fuel strategy and nutrition plan accordingly. The <a href="https://www.supersapiens.com/" target="_blank">Supersapiens</a> glucose monitoring system is being leveraged by athletes like Crossfit Games champion Samantha Briggs, olympic triathlon gold medalist Kristian Blummenfelt, and endurance obstacle course world champion Ryan Atkins.&nbsp;<img src="https://s3-us-west-1.amazonaws.com/wevolver-project-images/froala%2F1709524734463-63d022dabc5f8813d838b2d8_x7tSiD3dwvioNowEvZUasv-THGBtHupPy1ikaI29n8xyFH_LLcNtG0P3YC-ZncS2A82C9caDVwLeK1aHPlWYoN5ex_AI4YwzcVdOPMuK5d9AG7Os9XvLz1v68Xk56Uu_Q_DKjbceQ84tf8ZoTsFuLDn4GvyU6fWrkS92eL7nrIRSUA7ehMEgPfYecPW2F.png" style="width: 768px;" class="fr-fic fr-dib">Source: SupersapiensSilver/silver chloride ink can also be paired with TPU used to print stretchable interconnections for constructing <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6163896/" target="_blank">medical sensor textiles</a> and <a href="https://journals.sagepub.com/doi/abs/10.1177/00405175211005039" target="_blank">smart textile garments</a>. Commercialization has been limited due to lack of cost-effective, standard fabrication processes that can be applied to a large variety of fabrics, but companies like <a href="https://softmatter.io/" target="_blank">Softmatter</a> and <a href="https://www.memtronik.com/printed-electronics/smart-clothing/" target="_blank">Memtronik</a> now offer customized smart-garment design and fabrication.<hr><h2>I want this ink. Where do I start?</h2><h4>‍Henkel Adhesive Technologies</h4>If you work in the engineering world, you’re probably familiar with Loctite, a line of products by Henkel Adhesive Technologies. Loctite EDAG 7019 E&amp;C is a silver/silver chloride conductive ink, formulated to provide excellent adhesion to the wide variety of substrates used in the manufacture of electrically conductive medical devices.&nbsp;Read the datasheet here: <a href="https://tds.henkel.com/tds5/Studio/ShowPDF/?pid=EDAG%207019%20EC&format=MTR&subformat=HYS&language=EN&plant=WERCS&authorization=2" target="_blank">LOCTITE EDAG 7019 E&amp;C Technical Data Sheet </a>Henkel also sells a&nbsp;<a href="https://print-your-electronics-with-loctite.com/LOCTITE-SENSOR-DEMONSTRATOR" target="_blank">Loctite sensor demonstrator kit</a> with twelve dry adhesive electrodes for medical research and technical material validation. Henkel Adhesive Technologies have developed a wide portfolio of innovative solutions in adhesives, sealants, inks, and functional coatings.&nbsp;<h4>Dupont</h4>‍Another option is Dupont 5874 silver/silver chloride, which is designed for screen printing on polyester, and is suitable for a wide variety of biomedical applications. Dupont is an industry leader in materials development, combining scientific and applications development expertise to accelerate innovation. Read the datasheet here: <a href="https://www.dupont.com/content/dam/dupont/amer/us/en/mobility/public/documents/en/EI-10086-DuPont-5874-Ag_AgCI-Composition-Data-Sheet.pdf" target="_blank" data-lf-fd-inspected-kn9eq4roawkarlvp="true">Dupont 5874 silver/silver chloride composition for screen printing</a><h4>Kayaku Advanced Materials‍</h4>Kayaku Advanced Materials also offers a silver/silver chloride conductive ink, designed for screen printing medical EEG and EKG sensors. Kayaku develops and manufactures innovative specialty materials to push the latest innovation trends. Read the datasheet here: <a href="https://kayakuam.com/wp-content/uploads/2020/03/agcl-675-silver-chloride-ink.pdf" target="_blank" data-lf-fd-inspected-kn9eq4roawkarlvp="true">AGCL-675 SILVER/SILVER CHLORIDE INK&nbsp;</a>

‍Silver/silver chloride (Ag/AgCl) is a conductive ink typically used to print electrodes for biomedical applications.

Materials Feature: Silver or Silver Chloride Ink

In this episode, we talk about a new AI designed catheter that is 100x safer than and how it came to be after a passive conversation about fun facts between two researchers.

Podcast: AI Makes Catheters 100 Times Safer

“Soft robots,” medical devices and implants, and next-generation drug delivery methods could soon be guided with magnetism—thanks to a metal-free magnetic gel developed by researchers at the University of Michigan and the Max Planck Institute for Intelligent Systems in Stuttgart, Germany.The material is the first in which carbon-based, magnetic molecules are chemically bonded to the molecular network of a gel, creating a flexible, long-lived magnet for soft robotics. The study describing the material was published today in the journal Matter.Creating robots from flexible materials allows them to <a href="https://ieeexplore.ieee.org/document/7527653" target="_blank" rel="noreferrer noopener">contort</a> in unique ways, <a href="https://www.pnas.org/doi/10.1073/pnas.2209819119" target="_blank" rel="noreferrer noopener">handle delicate objects</a> and explore places that other robots cannot. More rigid robots would be crushed by the<a href="https://www.nature.com/articles/s41586-020-03153-z" target="_blank" rel="noreferrer noopener">&nbsp;deep ocean’s pressure</a> or could damage sensitive tissues in <a href="https://www.science.org/doi/full/10.1126/scirobotics.abc8191?casa_token=hqd5r3mI-VQAAAAA%3AJVE7YGtecWNWrACNynbQVLZfQCkJE6ngbzcmRnFo7u2Lb2K2oD6suzJvchvjpYa0zj9w4VBjykjmwQ" target="_blank" rel="noreferrer noopener">the human body</a>, for example.“If you make robots soft, you need to come up with new ways to give them power and make them move so that they can do work,” said <a href="https://mse.engin.umich.edu/people/abdon" target="_blank" rel="noreferrer noopener">Abdon Pena-Francesch</a>, assistant professor of materials science and engineering affiliated with the Robotics Institute at the University of Michigan and a corresponding author of the study.<img src="https://s3-us-west-1.amazonaws.com/wevolver-project-images/froala%2F1706103853343-Precursor-material-1.jpg" style="width: 766px;" class="fr-fic fr-dib">Pena-Francesch holds the soft gel before it is treated with chemicals that give the material its magnetic properties. The colorless precursor can be molded into a variety of shapes—such as capsules that could one day be ingested to deliver medicine. Photo credit: Brenda Ahearn, Michigan Engineering.Today’s prototypes typically move with hydraulics or mechanical wires, which require the robot to be tethered to a power source or controller, also limiting where they can go. Magnets could unleash these robots, enabling them to be moved by magnetic fields.<img src="https://s3-us-west-1.amazonaws.com/wevolver-project-images/froala%2F1706103920253-TEMPO_structure.png" style="width: 740px;" class="fr-fic fr-dib">The chemical structure of the organic magnet. Brown lines and black nodes show the general layout of the “cross-linking molecules” that serve as the frame for the gel’s molecular structure and a cage for the TEMPO molecules (shown in red). The TEMPO molecules are bonded directly to the gel structure. Free electrons on the TEMPO oxygen atoms (shown as dots) give the material its magnetic properties. Image credit: Abdon Pena-Francesch, BioInspired Materials Lab, University of Michigan.Conventional, metallic magnets introduce their own complications, however. They could reduce the flexibility of soft robots and be too <a href="https://onlinelibrary.wiley.com/doi/abs/10.1002/jab.770060110" target="_blank" rel="noreferrer noopener">toxic</a> for some medical applications.The new gel could be a nontoxic alternative for medical operations, and further modifications to the magnet’s chemical structure could help it degrade in the environment and human body. Such biodegradable magnets could be used in capsules that are guided to targeted locations of the body to release medicine.“If these materials can safely degrade in your body, you don’t have to retrieve them with another surgery later,” Pena-Francesch said. “This is still pretty exploratory, but these materials could enable newer, cheaper medical operations some day.”The team’s gel consists solely of carbon-based molecules. The key ingredient is TEMPO, a molecule with a “free” electron that is not paired up with another electron inside an atomic bond. The spin of every unpaired TEMPO electron in the gel aligns under a magnetic field, which attracts the gel to other magnetic materials.<img src="https://s3-us-west-1.amazonaws.com/wevolver-project-images/froala%2F1706103947442-BlockM.jpg" style="width: 594px;" class="fr-fic fr-dib">The magnetic gel can be carved and molded into a variety of shapes, including the University of Michigan block M. Photo credit: Abdon Pena-Francesch, BioInspired Materials Lab, University of Michigan.Additional “cross-linking molecules” in the gel act like a frame that connects the TEMPO molecules to a solid network structure while forming a protective cage around the TEMPO electrons. That cage prevents the unpaired electrons from forming bonds, which would remove the gel’s magnetic properties.“Earlier studies soaked these small, magnetic molecules into a gel, but they could leak out of the gel,” said Zane Zhang, a doctoral student in materials science and engineering and co-author of the study. “By integrating the magnetic molecules into the cross-linked gel network, they are fixed inside.”Locking the TEMPO molecules inside the material ensures that the gel does not leak potentially harmful TEMPO molecules into the body and allows the material to retain its magnetic properties for more than a year.While weaker than metallic magnets, the TEMPO magnets are strong enough to be pulled and bent with another magnet. Their weaker magnetism also has some upsides—TEMPO magnets can be photographed by an MRI, unlike stronger magnets that can&nbsp;<a href="https://med.stanford.edu/bmrgroup/Research/mri-near-metal.html" target="_blank" rel="noreferrer noopener">distort MRI images</a> to the point of uselessness.“Medical devices using our magnets could be used to deliver drugs to target locations and measure tissue adhesion and mechanics in the GI tract under MRI imaging,” said Metin Sitti, former director of the Physical Intelligence Department at Max Planck Institute for Intelligent Systems and a corresponding author of the study.<iframe width="640" height="360" src="https://www.youtube.com/embed/NTAWzVN5pNg?&amp;wmode=opaque&amp;rel=0&amp;enablejsapi=1&amp;origin=https://www.wevolver.com" frameborder="0" allowfullscreen="" class="fr-draggable" data-gtm-yt-inspected-9="true" data-lf-form-tracking-inspected-kn9eq4roawkarlvp="true" data-lf-yt-playback-inspected-kn9eq4roawkarlvp="true" data-lf-vimeo-playback-inspected-kn9eq4roawkarlvp="true"></iframe>Designing Non-Metallic Squishy Magnets to Power Soft Robots

Strong enough to move soft robots and medical capsules, weak enough to not ruin MRI images

Squishy, metal-free magnets to power robots and guide medical implants

MIT engineers have developed a robotic replica of the heart’s right ventricle, which mimics the beating and blood-pumping action of live hearts.The robo-ventricle combines real heart tissue with synthetic, balloon-like artificial muscles that enable scientists to control the ventricle’s contractions while observing how its natural valves and other intricate structures function.The artificial ventricle can be tuned to mimic healthy and diseased states. The team manipulated the model to simulate conditions of right ventricular dysfunction, including pulmonary hypertension and myocardial infarction. They also used the model to test cardiac devices. For instance, the team implanted a mechanical valve to repair a natural malfunctioning valve, then observed how the ventricle’s pumping changed in response.They say the new robotic right ventricle, or RRV, can be used as a realistic platform to study right ventricle disorders and test devices and therapies aimed at treating those disorders.“The right ventricle is particularly susceptible to dysfunction in intensive care unit settings, especially in patients on mechanical ventilation,” says Manisha Singh, a postdoc at MIT’s Institute for Medical Engineering and Science (IMES). “The RRV simulator can be used in the future to study the effects of mechanical ventilation on the right ventricle and to develop strategies to prevent right heart failure in these vulnerable patients.”Singh and her colleagues report details of the new design in an open-access&nbsp;<a href="https://www.nature.com/articles/s44161-023-00387-8" target="_blank">paper appearing today in&nbsp;Nature Cardiovascular Research</a>. Her co-authors include Associate Professor Ellen Roche, who is a core member of IMES and the associate head for research in the Department of Mechanical Engineering at MIT; along with Jean Bonnemain, Caglar Ozturk, Clara Park, Diego Quevedo-Moreno, Meagan Rowlett, and Yiling Fan of MIT; Brian Ayers of Massachusetts General Hospital; Christopher Nguyen of Cleveland Clinic; and Mossab Saeed of Boston Children’s Hospital.<h2>A ballet of beats</h2>The right ventricle is one of the heart’s four chambers, along with the left ventricle and the left and right atria. Of the four chambers, the left ventricle is the heavy lifter, as its thick, cone-shaped musculature is built for pumping blood through the entire body. The right ventricle, Roche says, is a “ballerina” in comparison, as it handles a lighter though no-less-crucial load.“The right ventricle pumps deoxygenated blood to the lungs, so it doesn’t have to pump as hard,” Roche notes. “It’s a thinner muscle, with more complex architecture and motion.”This anatomical complexity has made it difficult for clinicians to accurately observe and assess right ventricle function in patients with heart disease.“Conventional tools often fail to capture the intricate mechanics and dynamics of the right ventricle, leading to potential misdiagnoses and inadequate treatment strategies,” Singh says.To improve understanding of the lesser-known chamber and speed the development of cardiac devices to treat its dysfunction, the team designed a realistic, functional model of the right ventricle that both captures its anatomical intricacies and reproduces its pumping function. &nbsp;The model includes real heart tissue, which the team chose to incorporate because it retains natural structures that are too complex to reproduce synthetically.“There are thin, tiny chordae and valve leaflets with different material properties that are all moving in concert with the ventricle’s muscle. Trying to cast or print these very delicate structures is quite challenging,” Roche explains.<h2>A heart’s shelf-life</h2>In the new study, the team reports explanting a pig’s right ventricle, which they treated to carefully preserve its internal structures. They then fit a silicone wrapping around it, which acted as a soft, synthetic myocardium, or muscular lining. Within this lining, the team embedded several long, balloon-like tubes, which encircled the real heart tissue, in positions that the team determined through computational modeling to be optimal for reproducing the ventricle’s contractions. The researchers connected each tube to a control system, which they then set to inflate and deflate each tube at rates that mimicked the heart’s real rhythm and motion.To test its pumping ability, the team infused the model with a liquid similar in viscosity to blood. This particular liquid was also transparent, allowing the engineers to observe with an internal camera how internal valves and structures responded as the ventricle pumped liquid through.They found that the artificial ventricle’s pumping power and the function of its internal structures were similar to what they previously observed in live, healthy animals, demonstrating that the model can realistically simulate the right ventricle’s action and anatomy. The researchers could also tune the frequency and power of the pumping tubes to mimic various cardiac conditions, such as irregular heartbeats, muscle weakening, and hypertension.“We’re reanimating the heart, in some sense, and in a way that we can study and potentially treat its dysfunction,” Roche says.To show that the artificial ventricle can be used to test cardiac devices, the team surgically implanted ring-like medical devices of various sizes to repair the chamber’s tricuspid valve — a leafy, one-way valve that lets blood into the right ventricle. When this valve is leaky, or physically compromised, it can cause right heart failure or atrial fibrillation, and leads to symptoms such as reduced exercise capacity, swelling of the legs and abdomen, and liver enlargement.The researchers surgically manipulated the robo-ventricle’s valve to simulate this condition, then either replaced it by implanting a mechanical valve or repaired it using ring-like devices of different sizes. They observed which device improved the ventricle’s fluid flow as it continued to pump.“With its ability to accurately replicate tricuspid valve dysfunction, the RRV serves as an ideal training ground for surgeons and interventional cardiologists,” Singh says. “They can practice new surgical techniques for repairing or replacing the tricuspid valve on our model before performing them on actual patients.”Currently, the RRV can simulate realistic function over a few months. The team is working to extend that performance and enable the model to run continuously for longer stretches. They are also working with designers of implantable devices to test their prototypes on the artificial ventricle and possibly speed their path to patients. And looking far in the future, Roche plans to pair the RRV with a similar artificial, functional model of the left ventricle, which the group is currently fine-tuning.“We envision pairing this with the left ventricle to make a fully tunable, artificial heart, that could potentially function in people,” Roche says. “We’re quite a while off, but that’s the overarching vision.”This research was supported, in part, by the National Science Foundation.

A new bio-robotic model developed by MIT engineers simulates the function of the heart’s lesser-known right ventricle (illustrated here in cross-section, as seen from a front view, on the left). Soft, balloon-like “muscles” (in blue) wrap around and contract the ventricle, mimicking its real pumping action. The model could help to test new implants and devices to treat a range of cardiac disorders. Credit: Courtesy of the researchers

The realistic model could aid the development of better heart implants and shed light on understudied heart disorders.

MIT engineers design a robotic replica of the heart's right chamber

<h2 dir="ltr" id="isPasted">FDA's Approach to Digital Health Solutions</h2>The United states Food and Drug Administration (FDA) strategy towards digital health solutions is function-based, focusing on the device's functions rather than hardware or software components. This approach allows for a more flexible and efficient regulatory process.Digital therapeutics are categorized as either class one or class two medical devices, depending on the level of risk they pose. They often follow a 510K pathway for approval, streamlining the process compared to traditional hardware-based medical devices. The speed of clearance through this pathway depends on the intended use and the risk to the patient.The FDA assesses digital health products based on the risk level to the patient, irrespective of whether the product is software or hardware. This risk-based categorization ensures that the appropriate approval pathway is applied.The Digital Medicine Society (DiMe) has developed resources to aid entrepreneurs and engineers in digital therapeutics companies. These resources include an interactive tool and flow chart that consolidate over 30 guidances and multiple policies, simplifying the navigation through regulatory landscapes.Artificial Intelligence (AI) and Machine Learning (ML) algorithms are increasingly being utilized in digital therapeutics, extending beyond radiology to the prevention and management of diseases. These technologies are proving to be crucial in enhancing efficiencies and clinical applications across the healthcare sector.<h3 dir="ltr">Innovations in Medical AI</h3>A notable example of innovation in medical AI is Caption Health's cardiac AI software, which was the first of its kind to be granted approval early this year. This breakthrough demonstrates the significant potential for innovation and evolution in the field of medical AI.In conclusion, the podcast with Dr. Smit Patel offered valuable insights into the dynamic world of digital therapeutics. It underscored the importance of regulatory adaptability, the growing role of AI and ML in healthcare, and the resources available to those venturing into this promising field.&nbsp;<a href="https://www.wevolver.com/article/the-tech-between-us-podcast-the-rise-of-digital-therapeutics/draft" target="_blank" rel="noopener noreferrer">Listen to part 1 here. </a>

In part II of the Mouser podcast episode, Dr. Smit Patel continued discussing the evolving landscape of digital therapeutics and its impact on healthcare highlighting several key insights into how digital solutions are reshaping medical treatments and the regulatory environment surrounding them.

The Tech Between Us Podcast: The Rise of Digital Therapeutics Part II.

<section id="isPasted">The first glucose self-monitoring system created in 1970 weighed three pounds, was initially designed only for physicians’ offices and needed a large drop of blood for a reading. Over 50 years later, researchers at Texas A&amp;M University are working to create a fully injectable continuous glucose monitor (CGM) so small it rivals a grain of rice and can be used with an external optical reader to measure sugar levels at any given time.While CGMs have advanced over the last 25 years, current models can still be a nuisance to the user and the required upkeep may discourage use. To address this issue, two faculty members from the Department of Biomedical Engineering have received a National Science Foundation (NSF) grant to fund a multidisciplinary project to develop an injectable, grain-of-rice-sized glucose biosensor and wearable device enabling user-friendly, minimally-invasive continuous monitoring.“CGMs are commercially available, but most of them are indwelling, meaning there is a needle in the skin connected to a patch on the arm,” co-principal investigator and Regents Professor Dr. Gerard Coté said. “There is one CGM that is totally implantable, but it is much bigger than ours and requires a doctor to surgically implant it with an incision.”The NSF grant is backed by the biosensing program, a part of the engineering biology and health cluster of the NSF Chemical, Bioengineering, Environmental and Transport Systems (CBET) Division. The division aims to support trailblazing research and education in these areas.<h2>Using autofluorescence to read blood sugar&nbsp;</h2>Coté and his lab are designing the injected sensor’s chemistry and developing the watch-type reader device. The sensor is put under the skin and analyzed using light from the watch-like device to determine the glucose concentration. The reader sends the signal to a cell phone and the patient can share the results with their health provider.“The chemical assay in the injectable sensor is used to determine the concentration of the glucose within the tissue, and the watch device sends in light and measures the fluorescence from the sensor to give the sugar concentration,” Coté said.Aside from its unique size and injectability, the sensor and wearable reader employ an optical sensing technology that addresses the challenges associated with biosensing for populations of darker skin tones.&nbsp;“We use chemistry that has a fluorescent color that emits in the red and infrared range rather than green light, which works better for the darker skin tones,” Coté said.</section><section><h2>Protecting the sensor</h2>Co-principal investigator Dr. Melissa Grunlan, Charles H. and Bettye Barclay Professor in Engineering, is working with her lab to wrap the sensing chemistry in a membrane that makes it more compatible within the body.<img src="https://s3-us-west-1.amazonaws.com/wevolver-project-images/froala%2F1701821831800-BMEN-news-biosensor-sleeve-16Nov2023.jpg" style="width: 300px;" class="fr-fic fr-dib">The size and injectability of the biosensor makes for a less invasive method of monitoring blood glucose. | Image:&nbsp;<cite id="isPasted">Courtesy of Dr. Melissa Grunlan</cite>“When you implant something, the body thinks, ‘This does not belong here,’ and it tries to seal it off,” Grunlan said. “When that happens, that sensor can't work because there's no glucose getting into it. Our membrane is a hydrogel, similar to the material used for contact lenses, but this is a special hydrogel that is thermoresponsive.”The thermoresponsive nature allows the sensor to sit subtly in the body. The surface actively swells and shrinks just enough to keep cells and proteins from sticking to the sensor and forming obstructive scar tissue around it.Grunlan and Coté recently had a patent issued on the membrane technology and are considering different devices it could be used with, particularly to sustain the lifetime of medical devices.“The membrane could be applied to assorted devices that are prone to adhesion processes in the body,” Grunlan said. “It could be used on maybe a catheter to prevent thrombosis and infection by preventing the accumulation of proteins, cells, and organisms.”<h2>Multidisciplinary research in biomedical engineering</h2>The project culminates nearly two decades of research and collaboration between Coté’s biosensing expertise and Grunlan’s biomaterial expertise.“Working together as a team with complementary expertise is the key to developing complicated technologies such as this one,” Coté said. “Being able to collaborate with an expert like Dr. Grunlan in designing and developing biocompatible materials and bringing our experience in optical biosensor design is needed and gives us hope for success.”Although the grant is new funding, Grunlan and Coté have been preparing for this stage of their project for some time now and feel confident in the device’s outcome.“Dr. Coté and I have done extensive research in the past together that has led up to this study and this particular grant,” Grunlan said. “We've done some preclinical studies to assess the membrane's biocompatibility. He's done extensive work developing the sensing chemistry. What’s great about this grant is now we can prove our idea, and we’re in a really good position to do that.”</section>

Researchers receive funding to develop injectable grain-of-rice-sized continuous glucose monitor technology.

Miniature Device Offers Peace of Mind for Diabetics

Cell-based therapies, which use biological cells to treat diseases or injuries in the body, offer enormous potential from facilitating drug delivery to enabling more effective treatment of obesity, diabetes, and cancer. Generating on-site oxygen is a critical component of activating such therapies, because there is a high metabolic demand on these densely packed cells, and maintaining cell potency becomes a challenge, due to factors like immune response and dissolved oxygen. As part of an ongoing, multidisciplinary collaboration, a group of researchers from Carnegie Mellon University, Northwestern University, Georgia Institute of Technology and Rice University have identified a novel device that makes on-site oxygen for biological cells transplanted inside the body.Every cell is closely situated to tiny blood capillaries due to its need of sufficient oxygen supply to function. Current approaches to generating on-site oxygen for cell-based therapies have drawbacks including size and supply capacity. Some options introduce gaseous oxygen from outside the body to tackle the problem but are bulky; others are limited by supply capacity, like a can of water that cannot be refilled once it’s been emptied. This new device boasts a compact footprint and relies on the abundance of water in the human body, making it an excellent choice for implantation, along with ensuring a sustainable and lasting source of oxygen.<blockquote>Our device uses electricity and water to make oxygen for the cells—it’s as simple as a Chemistry 101 electrolysis experiment we all did as children, but we’re conducting it in a smarter manner.<cite>Tzahi Cohen-KarniProfessor , <cite id="isPasted">Biomedical Engineering and Materials Science and Engineering</cite> </cite></blockquote>“Our device uses electricity and water to make oxygen for the cells—it’s as simple as a Chemistry 101 electrolysis experiment we all did as children, but we’re conducting it in a smarter manner,” said <a href="https://engineering.cmu.edu/directory/bios/cohen-karni-tzahi.html" target="_blank">Tzahi Cohen-Karni</a>, professor of <a href="https://www.cmu.edu/bme/" rel="noopener" target="_blank">biomedical engineeringOpens in new window</a> and <a href="https://www.mse.engineering.cmu.edu//index.html" rel="noopener" target="_blank">materials science and engineeringOpens in new window</a> at Carnegie Mellon University. “We are using unique materials, including iridium oxide to produce oxygen, while avoiding the production of harmful byproducts, such as chlorine or excess hydrogen peroxide. By controlling how much electricity our device uses, we can change how much oxygen it produces.”The biggest advantage and differentiator of the group’s research, recently published in <a href="https://www.nature.com/articles/s41467-023-42697-2" rel="noopener" target="_blank">Nature CommunicationsOpens in new window</a>, is that it bridges the gap between energy science, biomedical engineering, and electronics. Water splitting research, which is geared toward energy conversion and storage, guided exploration of which materials could safely be used for oxygen evolution reaction in the human body, which led to the group incorporating iridium oxide.<img src="https://s3-us-west-1.amazonaws.com/wevolver-project-images/froala%2F1700813771065-1109-em-boosting-oxygenation-1.png" style="width: 766px;" class="fr-fic fr-dib">A schematic illustration of electrocatalytic on-site oxygenation. Source:&nbsp;Tzahi Cohen-Karni lab (CMU Engineering)“Unlike other approaches out there, we are using electrocatalysis, to reduce the energetic cost to generate the oxygen, and we are also tailoring the conditions of our device to provide oxygen without any byproducts, such as bleach,” added Inkyu Lee, materials science and engineering Ph.D. student. “We are also operating our device under conditions that will allow oxygen generation without bubbles that can disrupt the device.”The cells in this study were biologically engineered to produce human leptin, a key component in the body’s mechanism for weight control and regulation of circadian rhythms, which is also being investigated by the group through the <a href="https://engineering.cmu.edu/news-events/news/2021/06/07-circadian-clocks.html" target="_blank">DARPA Normalizing Timing of Rhythms Across Internal Networks of Circadian Clocks (NTRAIN) project</a>. The NTRAIN effort is managed by Jonathan Rivnay from Northwestern University.<img src="https://s3-us-west-1.amazonaws.com/wevolver-project-images/froala%2F1700813803284-1109-em-boosting-oxygenation-2.png" style="width: 766px;" class="fr-fic fr-dib">A representative set of 3D-rendered immunofluorescence images after 21 days in vitro oxygenation.&nbsp;Source:&nbsp;Tzahi Cohen-Karni lab (CMU Engineering)Additionally, some aspects of this published work will be used in the ARPA-H funded&nbsp;<a href="https://engineering.cmu.edu/news-events/news/2023/09/26-cancer-implant-tech.html" target="_blank">Targeted Hybrid Oncotherapeutic Regulation (THOR) project</a>, which is combining the group’s expertise in an effort to develop sense-and-respond technology to treat ovarian, pancreatic and other difficult-to-treat cancers. The THOR projects is managed by Omid Veiseh from Rice University.“We are the pioneers of this electrocatalytic oxygenation technology, and we have concrete plans to translate our devices to clinical practices in the real world,” emphasized Cohen-Karni. “We are not focusing on only one disease but instead, pushing to translate our work to various disease models.”As this work moves forward, the team is concentrating on perfecting highly stable materials that can operate for months in the body and plan to deploy their cutting-edge approaches to treat chronic diseases.The effort was co-led by Tzahi Cohen-Karni (MSE/BME, CMU) and Jonathan Rivanay (NU) and researchers Inkyu Lee (MSE, CMU) and Abhijith Surendran (NU). Other Carnegie Mellon participants involved in the research were Douglas Weber, professor of mechanical engineering; Adam Feinberg, professor of biomedical engineering; Sharon John, research associate; Seonghan Jo and Yingqiao Wang, materials science and engineering Ph.D. students; Tim Schwartzkopff, chemical engineering Ph.D. student; Omar El-Refy, physics Ph.D. student; and Ian Gimino, chemical engineering undergraduate student.

To advance cell-based therapies, researchers have identified a novel device that makes on-site oxygen for biological cells transplanted inside the body.

Boosting oxygenation for transplanted cell-based therapies

Synthetic biology holds the promise of enhancing and modifying biological systems into innumerable new technologies for the benefit of society. This engineering approach to biology has already reaped benefits in the fields of drug delivery, agriculture, and energy production. In a paper published in Nature Chemical Biology, EPFL researchers at the Laboratory of Protein Design and Immunoengineering (<a href="https://www.epfl.ch/labs/lpdi/" target="_blank">LPDI</a>) at the School of Engineering have taken an important step in designing more performative biological systems. By observing complex self-regulating behavior in cells and taking inspiration from electrical engineering, they have engineered a sophisticated biological switch using modified proteins as the hardware.<blockquote>We use a number of approaches in terms of protein design, more specifically computational protein design, in order to engineer new molecular hardware.<footer>Professor Bruno Correia, head of LPDI</footer></blockquote>The goal of LPDI is to develop biological functions that imitate and even go beyond what nature has provided over millions of years of evolution. “We use a number of approaches in terms of protein design, more specifically computational protein design, in order to engineer new molecular hardware,” says Bruno Correia, head of LPDI and lead author the paper. This new biological hardware—in the form of engineered proteins—can then be placed in living cells and respond to stimuli that the engineer can closely control.The lab’s methodology begins by observing how cells function and imitating or adapting these functions for other uses. One of the things that nature does extremely well is self-regulation. When a cell needs more ions, for example, it activates mechanisms that allow for the ions to flow into the cell. Once the cell’s needs are met and it has reached a certain equilibrium known as homeostasis, it can then turn off the ion flow.This biological mechanism can be conceptually likened to the selective nature of a bandpass filter in electronics. While a bandpass filter discriminates signals based on a specific range of frequencies, allowing only those within a designated band to pass through, the cell selectively permits ions to enter or exit based on its current needs. Although the comparison is a simplification, as the biological process is governed by complex biochemical feedback rather than binary signals, it similarly achieves selective permeability—akin to how a bandpass filter selectively permits certain frequencies while excluding others.<blockquote>Sailan Shui took inspiration from the functioning of a bandpass filter and engineered its biological equivalent.<footer>Professor Bruno Correia, head of LPDI</footer></blockquote>A current limitation in synthetic biology is that no design, up until now, offers this type of functionality—it’s all or nothing, only ‘on’ or only ‘off’. Think of penicillin delivery. As there is no regulatory system based on biological sensors for drug dosing, a diabetic needs to continuously monitor the insulin level. Sailan Shui’s work at LPDI focused on these types of biological sensors and switches that could drastically improve drug delivery and other biological systems. “Shui was unsatisfied by the on/off paradigm and decided to engineer a switch that could respond to changes in a cell’s internal and external environment. So she took inspiration from the functioning of a bandpass filter and engineered its biological equivalent,” explains Correia.To create this novel function in biological systems, the team designed proteins and inserted them into living cells. In biology, function flows from form. Correia and Shui observed the structure of folded proteins and their effect on self-regulating functions inside the cell. They then created computational models that could potentially act as a bandpass filter from these observations. Once the digital design was validated using computer simulations, they started working on building the protein structure by manipulating its DNA and amino acid configuration. Finally, they tested the design in cell cultures. The results are conclusive. Their design, which they share with the research community in the spirit of open research, will most likely be used by researchers around the world in ways yet foreseen.As a hypothetical application in synthetic biology, researchers could create a system that operates similarly to an electronic bandpass filter to regulate insulin delivery based on blood glucose levels. Engineered proteins would serve as sensors, detecting high glucose and triggering insulin release until levels normalize. This would automate insulin dosing, potentially improving diabetes management and reducing the need for frequent monitoring. Such a system would represent a significant advancement in the use of synthetic biology for therapeutic applications.This fundamental research is essential for developing the tools, building blocks and hardware of the future of synthetic biology. “We have a clear methodology but also embrace the serendipity of science. It was the scientist Leo Scheller in my lab who had the vision to understand the importance of this work. It was a team effort,” says Correia. A team effort that brings the field one important step closer to engineering better drug delivery technology, more efficient bioreactors, and even entirely new forms of biological entities.<hr>ReferencesShui, S., Scheller, L. &amp; Correia, B.E. Protein-based bandpass filters for controlling cellular signaling with chemical inputs. Nat Chem Biol (2023).&nbsp;<a href="https://doi.org/10.1038/s41589-023-01463-7" target="_blank" rel="noopener">https://doi.org/10.1038/s41589-023-01463-7</a>

EPFL scientists have crafted a biological system that mimics an electronic bandpass filter, a novel sensor that could revolutionize self-regulated biological mechanisms in synthetic biology.

A bandpass filter for synthetic biology

<h2 id="isPasted">Comparing Inkjet and Extrusion Printing Methods</h2>Biomedical electrodes play a crucial role in evaluating the internal processes of the human body by converting biological stimuli into electrical signals. This process is commonly used for electrocardiograms (ECG/EKG), electromyography (EMG), and electroencephalogram (EEG) procedures, and almost always uses silver/silver chloride (Ag/AgCl) electrodes with male connector snap closures.&nbsp;While there are benefits to using these electrodes, they “are susceptible to motion artifacts, can be uncomfortable for the user, and are unsuitable for long term use,” according to <a href="https://www.researchgate.net/publication/361717600_Inkjet_and_Extrusion_Printed_Silver_Biomedical_Tattoo_Electrodes" target="_blank">research</a> by York University’s Yoland El-hajj et al.&nbsp;In contrast, electrodes printed on tattoo paper offer a promising alternative for monitoring biological activities. In an interview with Voltera, El-hajj noted the best way to acquire signals from the body is to use a sensor that fits seamlessly with the body, rather than a sensor that sits rigidly on the skin.&nbsp;<iframe width="640" height="360" src="https://www.youtube.com/embed/MEW3q7GKYQA?&amp;wmode=opaque&amp;rel=0&amp;enablejsapi=1&amp;origin=https://www.wevolver.com" frameborder="0" allowfullscreen="" class="fr-draggable" data-lf-form-tracking-inspected-kn9eq4roawkarlvp="true" data-lf-yt-playback-inspected-kn9eq4roawkarlvp="true" data-lf-vimeo-playback-inspected-kn9eq4roawkarlvp="true" data-gtm-yt-inspected-12="true" id="575592054" title="NOVA at York University: Biomedical Tattoos">&nbsp;&nbsp;</iframe><h2 id="isPasted">Extrusion Printing with NOVA</h2>In <a href="https://www.researchgate.net/publication/361717600_Inkjet_and_Extrusion_Printed_Silver_Biomedical_Tattoo_Electrodes" target="_blank">Inkjet and Extrusion Printed Silver Biomedical Tattoo Electrodes</a>, El-hajj et al compared two common methods — <a href="https://www.voltera.io/blog/introduction-inkjet-technology" target="_blank">inkjet printing</a> and extrusion printing — to print the electrodes using silver ink.According to the study, “Silver-based inks were selected as the printing medium due to their high conductivity, mechanical robustness, biocompatibility, and moderate cost compared to other inks (e.g. gold, graphene).”Using <a href="http://www.voltera.io/nova" target="_blank">Voltera NOVA</a>, the group studied various shapes to test the performance and signal quality of the printed electrodes. El-hajj noted that, because the tattoo paper is quite thin, it can be used for many functional purposes, such as integration with prosthetic devices.&nbsp;“This is a starting point. Once the printing parameters for printing the specific ink on the specific substrate are optimized, you can go further. You can work on different sensors that can be integrated with the body, such as strain sensors, or even potentially explore areas of energy harvesting.”&nbsp;When it came to summarizing how NOVA helped her in this study, El-hajj observed that NOVA makes the printing process more efficient, and calibrating materials and aligning patterns is easier than ever. NOVA is more cost effective and reduces the time it takes to print patterns on a substrate compared to other printing methods, including inkjet.<h2>Results: Inkjet vs. Extrusion Printing</h2>The research findings indicated that inkjet printed electrodes are ideal for acquiring signals in areas of the body engaged in higher movement (e.g. EMG) due to their ability to better withstand bending strain. However, the extrusion printed electrodes exhibit a lower sheet resistance and impedance, and the ink does not absorb into the paper — a common issue encountered with inkjet printed tattoo electrodes.<h3>Inkjet vs. Extrusion Sheet Resistance</h3><ul><li>Extrusion printed electrodes: 9.4 mΩ/sq</li><li>Inkjet printed electrodes: 25.1 kΩ/sq</li></ul><h3>Inkjet vs. Extrusion Impedance</h3><img src="https://s3-us-west-1.amazonaws.com/wevolver-project-images/froala%2F1699263958757-IMAGE+02-01.jpg" style="width: 300px;" class="fr-fic fr-dib"><h2 id="isPasted">Conclusion</h2>Printed silver biomedical tattoo electrodes represent a promising advancement in biomedical monitoring technology. Their potential to offer greater comfort, flexibility, and efficiency, as well as their personalized, non-invasive nature compared to traditional electrode options, is paving the way for innovative advancements in healthcare. In fact, El-hajj has gone on to continue her research in biomedical printed electronics, founding her own company called Epictrode Health.<a href="https://www.voltera.io/blog/printed-tattoo-electrodes" target="_blank" rel="noopener noreferrer"></a>

Electrodes printed on tattoo paper offer a promising alternative for monitoring biological activities.

Printed Tattoo Electrodes: Cutting-Edge Biomedical Monitoring

Under a new $26.3 million federal contract from the <a href="https://arpa-h.gov/" data-extlink="" target="_blank">Advanced Research Projects Agency for Health</a> (ARPA-H), a multidisciplinary team of researchers at Stanford University aims to bioprint a fully functioning human heart and implant it in a living pig within five years.“It’s truly a moonshot effort, but the raw ingredients for bioprinting a complete and complex human organ are now in place for this big push,” said <a href="https://profiles.stanford.edu/mark-skylar-scott" data-extlink="" target="_blank">Mark Skylar-Scott</a>, assistant professor of bioengineering, a member of the <a href="https://med.stanford.edu/cvi.html" data-extlink="" target="_blank">Stanford Cardiovascular Institute</a>, and principal investigator on the project.The vision of fabricating bespoke, patient-specific human organs – livers, lungs, kidneys, brain, and, yes, a human heart – has been a tantalizing dream of modern medicine for years, but only recently has stem cell science, the scale of cell production, and 3D bioprinting advanced to a point where the dream is within reach.Bioprinting is a 3D printing technology that, instead of using plastic or metal, prints living tissues cell by cell. The key development, Skylar-Scott said, is that we can now print cells and blood vessels into those tissues.“With vasculature comes the ability to make large and thick tissues that can be implanted and survive,” Skylar-Scott said. “Thus begins the era of organ biofabrication.”<h2>Leap in scale</h2>That bioprinting expertise is coupled with a dramatic leap in scale in cell production, from the petri dish of old to today’s reactors able to turn out heart-specific cells billions at a time. These will become the bioprinter’s “ink.”“We are going to use an automated bank of bioreactors to produce the different cell types of the heart,” Skylar-Scott said.This bank of bioreactors will turn out billions of ventricular and atrial cardiomyocytes, specialized conduction cells that form the Purkinje fibers, nodal cells that are the heart’s pace-making cells, as well as smooth muscle cells, macrophages that support tissue development, and, of course, the blood vessel endothelial cells needed to keep the tissue alive. Skylar-Scott estimates that the team will be able to generate sufficient cells for a heart every two weeks.<iframe width="640" height="360" src="https://www.youtube.com/embed/1DncnbEE3Ls?&amp;wmode=opaque&amp;enablejsapi=1&amp;origin=https://www.wevolver.com" frameborder="0" allowfullscreen="" class="fr-draggable" data-gtm-yt-inspected-8="true" data-lf-form-tracking-inspected-kn9eq4roawkarlvp="true" data-lf-yt-playback-inspected-kn9eq4roawkarlvp="true" data-lf-vimeo-playback-inspected-kn9eq4roawkarlvp="true"></iframe>“We will use these vast numbers of cells to practice, practice, practice and learn all the design rules of the heart and optimize viability and function at the whole-heart scale for eventual implantation into a pig,” he said. The bioprinted human heart will be transplanted into a pig with severe congenital immunodeficiency to prevent rejection. However, the team’s approach uses patient-specific stem cells that, when transplanted into that same patient, may not require immunosuppression. “Your own heart, made out of your own cells; that is the dream,” Skylar-Scott added.The dramatic scope of the project prompts vision of a day when similar biofabrication plants manufacture new hearts, lungs, livers, and other organs for implantation into ailing humans – each bioprinted organ a perfect genetic match for its patient. Such aspirations are to be expected, Skylar-Scott said, but he adds that he believes that day is still decades off, if not more. Still, this bioprinting initiative will serve as a necessary and powerful proof-of-concept to accelerate the commercialization and translation of organ engineering.<h2>Ecosystem of expertise</h2>Discussion of such possibilities brings Skylar-Scott full circle to the challenge ahead. Bioprinting and implanting a heart into a living creature will require a profound collection of expertise well beyond the skills of any one researcher. In that regard, Skylar-Scott returns to the Stanford research ecosystem that makes this project a possibility.While he is the principal investigator on the project, the full team of Stanford experts needed to make the dream a reality is remarkable in its depth and breadth (see sidebar). It includes experts in engineering, biochemistry, computer modeling, cardiology, cardiothoracic surgery, biology, materials science, and more. Only Stanford concentrates leadership in all these disparate but interrelated fields within walking distance of one another.Stanford is a real center of excellence for cardiovascular medicine, Skylar-Scott said – the Cardiovascular Institute, stem cell derivation expertise, and vascular experts to provide the raw materials combined with a great ecosystem of 3D bioprinting and materials faculty to think how to use and assemble the materials.“When you have all these resources in one place, it makes it easier to collaborate and to do some pretty amazing things,” Skylar-Scott said.<hr><h2 id="isPasted">Research team</h2><ul><li><a href="https://profiles.stanford.edu/mark-skylar-scott" data-extlink="" target="_blank">Mark Skylar-Scott</a>, Bioengineering, Principal Investigator</li><li><a href="https://profiles.stanford.edu/joseph-desimone" data-extlink="" target="_blank">Joseph DeSimone</a>, Chemical Engineering</li><li><a href="https://profiles.stanford.edu/daniel-ennis" data-extlink="" target="_blank">Daniel Ennis</a>, Radiology</li><li><a href="https://profiles.stanford.edu/sarah-heilshorn" data-extlink="" target="_blank">Sarah Heilshorn</a>, Materials Science and Engineering</li><li><a href="https://profiles.stanford.edu/ellen-kuhl" data-extlink="" target="_blank">Ellen Kuhl</a>, Mechanical Engineering</li><li><a href="https://profiles.stanford.edu/kyle-loh" data-extlink="" target="_blank">Kyle Loh</a>, Developmental Biology</li><li><a href="https://profiles.stanford.edu/michael-ma" data-extlink="" target="_blank">Michael Ma</a>, Cardiothoracic Surgery</li><li><a href="https://profiles.stanford.edu/alison-marsden" data-extlink="" target="_blank">Alison Marsden</a>, Cardiology</li><li><a href="https://profiles.stanford.edu/allison-okamura" data-extlink="" target="_blank">Allison Okamura</a>, Mechanical Engineering</li><li><a href="https://profiles.stanford.edu/marlene-rabinovitch" data-extlink="" target="_blank">Marlene Rabinovitch</a>, Cardiology</li><li><a href="https://profiles.stanford.edu/mac-schwager" data-extlink="" target="_blank">Mac Schwager</a>, Aeronautical Engineering</li><li><a href="https://profiles.stanford.edu/joseph-woo" data-extlink="" target="_blank">Joseph Woo</a>, Cardiothoracic Surgery</li><li><a href="https://profiles.stanford.edu/joseph-wu" data-extlink="" target="_blank">Joseph Wu</a>, Cardiology</li><li><a href="https://profiles.stanford.edu/ming-wu" data-extlink="" target="_blank">Sean Wu</a>, Cardiology</li></ul>

A 3D bioprinter in the Skylar-Scott lab prints a sample of heart tissue in 2022. | Photo by Andrew Broadhead

Advances in the 3D printing of living tissue – a field known as bioprinting – puts within reach the possibility of fabricating whole organs from scratch and implanting them in living beings. A multidisciplinary team from Stanford received a federal contract to do just that.

Moonshot effort aims to bioprint a human heart and implant it in pig

When Carnegie Mellon’s <a href="https://engineering.cmu.edu/mfi/index.html" rel="noopener" target="_blank">Manufacturing Futures Institute</a> (MFI) issues its annual call for proposals each fall, it makes clear its objectives for offering seed funding to groups of CMU faculty whose research is aligned with MFI’s mission to inspire, engineer, and lead technological and workforce advances for agile, intelligent, efficient, resilient, and sustainable manufacturing.They are interested in funding research that falls into one of MFIs strategic priority areas; plays to CMU’s strengths in fields, such as AI and machine learning, coupled with advanced manufacturing technologies, such as robotics and additive manufacturing; benefits from convergent research and expertise from different disciplines; and shows potential for seeding the future of advanced manufacturing with new ideas that fuel innovation and attract future investments.“We receive so many great proposals across a wide variety of advanced manufacturing topics that deciding which to fund is difficult. We focus on the ones that propose innovative interdisciplinary approaches that can truly advance the state of the art. Industrial relevance is important as well, given our interest in technology transition,” said <a href="https://engineering.cmu.edu/directory/bios/wolf-sandra-devincent.html" target="_blank">Sandra DeVincent Wolf</a>, executive director of the MFI.<blockquote>We focus on funding projects that propose innovative interdisciplinary approaches that can truly advance the state of the art. Industrial relevance is important as well, given our interest in technology transition.<cite>Sandra DeVincent Wolf,&nbsp;Executive Director, <cite id="isPasted">Manufacturing Futures Institute</cite></cite></blockquote>She and <a href="https://engineering.cmu.edu/directory/bios/fedder-gary.html" target="_blank">Gary Fedder</a>, faculty director of MFI, reserve the right to ask for modifications to a proposal when timelines are too aggressive, funding amounts are not fully justified, or the project is missing a partner with a vital set of skills and expertise.That was the case when faculty members <a href="https://engineering.cmu.edu/directory/bios/leduc-philip.html" target="_blank">Phil LeDuc</a>, <a href="https://engineering.cmu.edu/directory/bios/ozdoganlar-burak.html" target="_blank">Burak Ozdoganlar</a>, and <a href="https://engineering.cmu.edu/directory/bios/ren-xi.html" target="_blank">Charlie Ren</a> requested funding last year for the next phase of their ice printing research.The team developed a novel approach to 3D print ice structures that are small enough to create vasculature in artificial tissue and other open features inside a fabricated part by creating sacrificial templates that later form the conduits and voids. It has proven to be a promising method. Still, it relied upon a lot of trial and error, as many automated approaches do initially, in their development to achieve the specific intended geometry.Creating more precise and reproducible geometries necessitates developing a feedback control approach, which would intelligently adjust parameters during printing to achieve the desired intricate geometries.Since LeDuc and Ozdoganlar <a href="https://onlinelibrary.wiley.com/doi/10.1002/advs.202201566" rel="noopener" target="_blank">published their findings</a>, which was featured on the cover of the prestigious Advanced Science journal in July 2022, they have received positive feedback at numerous conference presentations, as well as support that has encouraged them to explore how their ice printing method can be further developed.The initial biomedical engineering applications were clear and showed direct potential for use in personalized medicine. Still, the method also has the potential to revolutionize manufacturing by enabling the automated production of tiny internal 3D microchannels for many applications in various fields ranging from medicine to soft robotics.Micromanufacturing technology and advanced approaches are fundamental to numerous critical applications across various sectors, including scientific research, healthcare, national security, and space exploration, as well as the digital transformation in industry that is at the heart of MFI’s manufacturing mission.According to LeDuc and Ozdoganlar, the experimental and computational methods needed to build models to control the ice printing process are challenging. The microscale size and the fast nature of the thermal-fluidic processes and phase-changes (solid, liquid, gas) processes further exacerbate the challenges. &nbsp;“We know that if we can build a sensor feedback system that can make adjustments in real-time, it will be very powerful for these approaches.” said LeDuc.Wolf knew just the person who could help them develop the sensor hardware and computer vision algorithms needed to create a feedback control approach to produce the degree of control needed for printing the microscale ice structures.Lu Li, a project scientist at Carnegie Mellon’s Robotics Institute, had already brought his artificial intelligence and robotics expertise to several other MFI-funded projects. And according to LeDuc, Li has already made some great contributions to this new project.With Li’s help, the team has reduced the time required for image segmentation from two to three seconds to 50 microseconds. Image segmentation is a computer vision task in machine learning that involves dividing an image into multiple segments or regions based on certain criteria so that the image can be changed into something that is more meaningful and easier to analyze.“This is so typical of how we work at CMU. First of all, the ability to collaborate with someone like Lu Li, who has the skills we needed to move this forward, has been fantastic. And even though the MFI funding is not a huge amount of money, it has allowed us to keep moving forward with an idea that has huge potential,” said LeDuc.Wolf is equally excited to be working with LeDuc, who she says was open to her suggestions, grateful for her recommendation, and brings enthusiasm and energy to our manufacturing community at CMU.

Manufacturing Futures Institute funds a biomanufacturing research project that could revolutionize microchip production for use in medical devices and engineered tissue.

3D micro-ice printing for medical applications

In this episode, we explore the groundbreaking potential of an implantable device that promises a future without injections for diabetes control and we delve into the science, the impact on patients, and the promises it holds for a brighter future in diabetes care. 

Podcast: Implantable Chip To Cure Diabetes

This article was discussed in our <a href="https://www.wevolver.com/profile/the.next.byte" rel="noopener noreferrer" target="_blank">Next Byte podcast</a>.&nbsp;<iframe height="200px" width="100%" frameborder="no" scrolling="no" seamless="" src="https://player.simplecast.com/0a80bd29-e245-4c39-8375-0c544a26f6f8?dark=false" class="fr-draggable" data-lf-form-tracking-inspected-kn9eq4roawkarlvp="true" data-lf-yt-playback-inspected-kn9eq4roawkarlvp="true" data-lf-vimeo-playback-inspected-kn9eq4roawkarlvp="true"></iframe> The full article will continue below.<hr>This article originally appeared in <a href="https://news.mit.edu/2023/implantable-device-enable-injection-free-control-diabetes-0918" target="_blank" rel="noopener noreferrer">MIT News</a> and has been republished with permission.<hr>One promising approach to treating Type 1 diabetes is implanting pancreatic islet cells that can produce insulin when needed, which can free patients from giving themselves frequent insulin injections. However, one major obstacle to this approach is that once the cells are implanted, they eventually run out of oxygen and stop producing insulin.To overcome that hurdle, MIT engineers have designed a new implantable device that not only carries hundreds of thousands of insulin-producing islet cells, but also has its own on-board oxygen factory, which generates oxygen by splitting water vapor found in the body.The researchers showed that when implanted into diabetic mice, this device could keep the mice’s blood glucose levels stable for at least a month. The researchers now hope to create a larger version of the device, about the size of a stick of chewing gum, that could eventually be tested in people with Type 1 diabetes.“You can think of this as a living medical device that is made from human cells that secrete insulin, along with an electronic life support-system. We’re excited by the progress so far, and we really are optimistic that this technology could end up helping patients,” says Daniel Anderson, a professor in MIT’s Department of Chemical Engineering, a member of MIT’s Koch Institute for Integrative Cancer Research and Institute for Medical Engineering and Science (IMES), and the senior author of the study.While the researchers’ main focus is on diabetes treatment, they say that this kind of device could also be adapted to treat other diseases that require repeated delivery of therapeutic proteins.MIT Research Scientist Siddharth Krishnan is the lead author of the <a href="https://www.pnas.org/doi/10.1073/pnas.2311707120" target="_blank">paper</a>, which appears today in the Proceedings of the National Academy of Sciences. The research team also includes several other researchers from MIT, including Robert Langer, the David H. Koch Institute Professor at MIT and a member of the Koch Institute, as well as researchers from Boston Children’s Hospital.<h2><img src="https://images.wevolver.com/eyJidWNrZXQiOiJ3ZXZvbHZlci1wcm9qZWN0LWltYWdlcyIsImtleSI6ImZyb2FsYS8xNjk1NjM1MTI1ODM3LU1JVC1Jc2xldHMtT3h5Z2VuLTAyLXByZXNzLmpwZyIsImVkaXRzIjp7InJlc2l6ZSI6eyJ3aWR0aCI6OTUwLCJmaXQiOiJjb3ZlciJ9fX0=" style="width: 766px;" class="fr-fic fr-dib">Pictured is the device submerged in water, generating oxygen (bottom) and hydrogen (top) bubbles without the need for any batteries or wires. Image: Courtesy of Claudia Liu and Dr. Siddharth Krishnan, MIT/Boston Children’s HospitalReplacing injections</h2>Most patients with Type 1 diabetes have to monitor their blood glucose levels carefully and inject themselves with insulin at least once a day. However, this process doesn’t replicate the body’s natural ability to control blood glucose levels.“The vast majority of diabetics that are insulin-dependent are injecting themselves with insulin, and doing their very best, but they do not have healthy blood sugar levels,” Anderson says. “If you look at their blood sugar levels, even for people that are very dedicated to being careful, they just can’t match what a living pancreas can do.”A better alternative would be to transplant cells that produce insulin whenever they detect surges in the patient’s blood glucose levels. Some diabetes patients have received transplanted islet cells from human cadavers, which can achieve long-term control of diabetes; however, these patients have to take immunosuppressive drugs to prevent their body from rejecting the implanted cells.More recently, researchers have shown similar success with islet cells derived from stem cells, but patients who receive those cells also need to take immunosuppressive drugs.Another possibility, which could prevent the need for immunosuppressive drugs, is to encapsulate the transplanted cells within a flexible device that protects the cells from the immune system. However, finding a reliable oxygen supply for these encapsulated cells has proven challenging.Some experimental devices, including one that has been tested in clinical trials, feature an oxygen chamber that can supply the cells, but this chamber needs to be reloaded periodically. Other researchers have developed implants that include chemical reagents that can generate oxygen, but these also run out eventually.The MIT team took a different approach that could potentially generate oxygen indefinitely, by splitting water. This is done using a proton-exchange membrane — a technology originally deployed to generate hydrogen in fuel cells — located within the device. This membrane can split water vapor (found abundantly in the body) into hydrogen, which diffuses harmlessly away, and oxygen, which goes into a storage chamber that feeds the islet cells through a thin, oxygen-permeable membrane.A significant advantage of this approach is that it does not require any wires or batteries. Splitting this water vapor requires a small voltage (about 2 volts), which is generated using a phenomenon known as resonant inductive coupling. A tuned magnetic coil located outside the body transmits power to a small, flexible antenna within the device, allowing for wireless power transfer. It does require an external coil, which the researchers anticipate could be worn as a patch on the patient’s skin.<img src="https://images.wevolver.com/eyJidWNrZXQiOiJ3ZXZvbHZlci1wcm9qZWN0LWltYWdlcyIsImtleSI6ImZyb2FsYS8xNjk1NjM1MjM0Njc0LU1JVC1Jc2xldHMtT3h5Z2VuLTAzLXByZXNzLmpwZyIsImVkaXRzIjp7InJlc2l6ZSI6eyJ3aWR0aCI6OTUwLCJmaXQiOiJjb3ZlciJ9fX0=" style="width: 768px;" class="fr-fic fr-dib">This photo shows the cathode side of fully assembled device, with a United States quarter-dollar coin for scale.&nbsp; Image: Courtesy of Claudia Liu and Dr. Siddharth Krishnan, MIT/Boston Children’s Hospital<h2>Drugs on demand</h2>After building their device, which is about the size of a U.S. quarter, the researchers tested it in diabetic mice. One group of mice received the device with the oxygen-generating, water-splitting membrane, while the other received a device that contained islet cells without any supplemental oxygen. The devices were implanted just under the skin, in mice with fully functional immune systems.The researchers found that mice implanted with the oxygen-generating device were able to maintain normal blood glucose levels, comparable to healthy animals. However, mice that received the nonoxygenated device became hyperglycemic (with elevated blood sugar) within about two weeks.Typically when any kind of medical device is implanted in the body, attack by the immune system leads to a buildup of scar tissue called fibrosis, which can reduce the devices’ effectiveness. This kind of scar tissue did form around the implants used in this study, but the device’s success in controlling blood glucose levels suggests that insulin was still able to diffuse out of the device, and glucose into it.This approach could also be used to deliver cells that produce other types of therapeutic proteins that need to be given over long periods of time. In this study, the researchers showed that the device could also keep alive cells that produce erythropoietin, a protein that stimulates red blood cell production.“We’re optimistic that it will be possible to make living medical devices that can reside in the body and produce drugs as needed,” Anderson says. “There are a variety of diseases where patients need to take proteins exogenously, sometimes very frequently. If we can replace the need for infusions every other week with a single implant that can act for a long time, I think that could really help a lot of patients.”The researchers now plan to adapt the device for testing in larger animals and eventually humans. For human use, they hope to develop an implant that would be about the size of a stick of chewing gum. They also plan to test whether the device can remain in the body for longer periods of time.“The materials we’ve used are inherently stable and long-lived, so I think that kind of long-term operation is within the realm of possibility, and that’s what we’re working on,” Krishnan says.“We are very excited about these findings, which we believe could provide a whole new way of someday treating diabetes and possibly other diseases,” Langer adds.<hr>"Reprinted with permission of <a href="https://news.mit.edu/2023/implantable-device-enable-injection-free-control-diabetes-0918" target="_blank" rel="noopener noreferrer" id="isPasted">MIT News</a>" &nbsp;

MIT engineers designed an implantable device that carries hundreds of thousands of islet cells along with its own on-board oxygen factory to keep the cells healthy. Image: Felice Frankel

The device contains encapsulated cells that produce insulin, plus a tiny oxygen-producing factory that keeps the cells healthy.

An implantable device could enable injection-free control of diabetes

Scanning Electron Microscope (SEM) Machine in Laboratory

This article delves into the fundamental principles of SEM, various imaging modes and techniques, sample preparation methods, and the applications of SEM in different fields.

Biomedical Devices

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