(6ai) Living Biodevices for Precision Medicine:from Morphing Electronics to Medical Nanorobots

Biology and medicine have heavily relied on engineering advances to understand how the human body works and to revolutionize traditional medical practices. The rising interest in personalized and precision medicine requires innovative materials and devices which can seamlessly interface and precisely interact within the human body. Our human body is an active and dynamic system with inherent transport, motion, and growth across different time scales. However, synthetic materials and devices are normally made with limited adaptability and mobility, which limit their versatility for precise diagnosis and personalized treatment. This mismatch imposes both challenges and opportunities to develop active bioelectronic system which mimic the dynamic living organisms towards personalized and precision healthcare. My research addresses this problem by developing active bioelectronic system, which can transform, grow, or actuate within body towards both new discovery in both basic science as well as customized medical treatment. By developing such active bioelectronic system with high adaptability, mobility, and intelligence across nano to macroscales, we will enable a new interface that redefine the interactive relationship between human, environment, other living organisms, environment, tools and intangible data.

Keywords: Bioelectronics, Active Matter, Nanorobotics, Neuroengineering, Soft Robotics, Biomaterials, Wearable Devices, Biosensors, Nanomedicine, Mental Health.

Research Experience:

1. Morphing and elastic bioelectronics for neurological implants and neurochemical sensors, Department of Chemical Engineering, Stanford University (advised by Zhenan Bao)

a) Morphing electronics as chronic and adaptable neurological implantable devices

Bioelectronics for modulating nervous system, such as the vagus nerve stimulator, demonstrate great promise in treating various neurological diseases. However, their fixed sizes and shapes cannot accommodate the rapid tissue growth and negatively influence normal developmental functions. For infants, children and adolescents, once the implanted devices are ‘outgrown’, additional surgeries are usually needed for device removal, followed by replacement. These tedious processes inevitably lead to repeated intervention and elevated complication rates. Although stretchable electronics with high elasticity is ideal for repeated motion and volumetric expansion of organs, they still cannot adapt to developmental tissue growth, which should not be restricted by any strain. We address this limitation with Morphing Electronics (termed MorphE) which are designed and fabricated to suitably adapt to in vivo nerve tissue growth with zero strain. This is achieved by viscoplastic electronic materials (VEMs) that eliminate the stress and tissue constraint on growing tissue. In addition, water-insensitive self-healing property of the multilayered MorphE consisting of viscoplastic electrodes and a strain sensor allows fora reconfigurable platform for individualized implantation procedures. Animal study demonstrated that the soft and self-adapting MorphE showed no damage to the rat nerve after grown 2.4 times its initial diameter. This stable neural interface allowed chronic electrical stimulation and monitoring without disruption of functional behavior in developing rats. Our MorphE creates a new avenue for adaptive pediatric electronics medicine.

b) Elastic neurochemical interface for in vivo interrogation of the gut-brain axis

The bidirectional communication between the gastrointestinal (GI) tract and the brain, commonly dubbed the gut–brain axis, involves various afferent and efferent pathways to regulate aspects of homeostasis such as satiety, hunger, and inflammation. Disruption of the gut–brain axis has been shown to be involved in the pathogenesis of a diverse range of diseases, including depression, Parkinson’s disease, and irritable bowel syndrome. Meanwhile, the GI tract has substantial neural interactions with the central nervous system, and this provides opportunities for bioelectric neuromodulation therapy. However, understanding of the gut motility, gut-brain sensory transduction and their roles in pathogenesis remain unknown due to the absense of proper neuroengineering tools that can be used in vivo. The GI tract consists of a series of soft organs with inherent peristaltic movement, joined in a long and twisting tube from the mouth to the anus. Unlike the rigid and fragile neuroengineering tools used to study the brain, a bioelectrical device used to study the GI tract in awake, freely moving animals, would need to be soft and elastic in order to be compatible with the GI environment. As a result, conventional electrophysiological and neurochemical recording in the GI tract of awake animals has been impossible because no such device exists. I developed a bioelectronic toolkit, based on tissue-like elastic materials, for in vivo interrogation of the gut-brain axis. The toolkit includes: (1) neurochemical sensors to monitor gut serotonin, which is a critical link of gut–brain communication; (2) strain sensor to monitor the gut motility; (3) microelectrodes for monitoring gut myoelectric activity and delivering electric stimulation. This multifunctional device is then used to monitor serotonin dynamics, gut myoelectric activity, and peristalsis movement along the GI tract of freely moving wild-type mice, mice with depression-like or disease-like phenotypes. The new elastic bioelectronic tool will provide novel insights about the dynamics of gut serotonin and lay the foundation for the development of transformative diagnosis and treatment for patients with psychiatric disorders or GI dysmotility disorders through local intervention in the GI tract.

2. Medical micro/nanorobots for drug delivery. Department of NanoEngineering, University of California San Diego (advised by Joseph Wang and Liangfang Zhang)

My PhD research has been focusing on creating a new class of robots for an adventurous journey: micro/nanoscale robots, which mimic the intelligence of microorganism and work as autonomous medicine to fight diseases. I pioneered the first use of nanorobot to effectively treat disease in a live animal’s body, a milestone to realize the dream of “Fantastic Voyage”.

Designing miniaturized and versatile robots of a few micrometers and less would allow access throughout the whole human body, leading to new procedures down to the cellular level and offering localized diagnosis and treatment with greater precision and efficiency. A significant challenge of micro/nanorobots is the exploration energy sources for biocompatible in vivo operation, and then the translation of these inventions into clinical use. I developed a set of microscale machines, with dimensions similar to that of cancer cell or bacteria, which could smartly propel and target disease sites under their own power via reacting with body fluid such as stomach acid and intestinal fluid. Upon arrival inside of the body, these self-powered machines act in many ways—from directly mediating the physiological factor of local medical conditions, to releasing a medical payload at the target site, or penetrating the tissue so that the loaded medicine last longer in the body. After the mission, the microrobots would degrade themselves, leaving nothing toxic behind.

Specifically, my recent work has proven that microrobot-enabled delivery approach is a promising new method for easy and effective treatment of stomach and gastrointestinal tract diseases (published on Nature Communications 2017, 8, 272; Angewandte Chemie International Edition 2017, 56, 2156; Science Robotics 2017, 2, eaam6431). Drugs used to treat stomach diseases are normally taken with additional substances, called proton pump inhibitors, to suppress gastric acid production. But proton pump inhibitors can cause adverse side effects including headaches, diarrhea, or depression. The micromotors developed have a built-in mechanism to neutralize gastric acid and effectively deliver their drug payloads in the stomach, without the use of proton pump inhibitors, and further enhance the drug retention in the body through the tissue penetration. In the disease model of helicobacter pylori infection, my results show that treatment with microrobots kill the bacteria 6 times more efficiently than with conventional treatment, and obviates the use of proton pump inhibitor, the most widely sold drugs in the world. This research on the in vivo operation of micromotors represents the first example of using microrobots to treat disease in live animals. In this emerging research direction, a plethora of continuously successful tests will need to be run before the micro/nanorobots can be used in human trial. These initiative steps of translating new micro/nanorobot from test tubes to practical treatments in live animals, are vital in what could be a commonplace, precise, targeted, and safe alternative to traditional high-dose medications.

Selected Awards:

2019/06 MIT Technology Review 35 Innovators Under 35 (TR35, Global List)

2018/08 Young Investigator Award, Division of Inorganic Chemistry, American Chemical Society

2018/07 EUDRAGIT Award, North American Region, Evonik Corporation

2017/08 Young Investigator Innovation Award, 1st International Conference on Micro/Nanomachines

2016/09 Siebel Scholar, bioengineering category, Thomas and Stacey Siebel Foundation

2016/05 Dan David Prize Scholarship in Nanoscience, The Dan David Foundation, Israel

2016/03 UCSD Interdisciplinary Research Award

2015/11 A.T. Kearney Scholarship, Falling Wall Foundation, Germany

2015/10 Brain Prize for Breakthrough Ideas in Neurotechnology, San Diego Brain Consortium

2015/04 Rudee Best Poster Award and NanoEngineering Best Poster Award, UCSD Research Expo

2015/04 Materials Research Society Graduate Student Award

Successful Proposals:

1. Stanford Bio-X Interdisciplinary Initiatives Program Seed Grant: “Closed-loop neurochemical sensing and modulation system for treating psychiatric disorders”. 2018/07.
2. Stanford Merck Initiative: "A Soft Haptic Interface Based on Liquid Crystal Elastomer". 2018/04.
3. Kavli Institute for Brain and Mind Innovative Research Grant Award (Student PI): “Development of a nanorobotic toolkit for ultrahigh precision neuron targeting and manipulation. 2015/06.

Selected Publications (* denotes equal contribution) :

1. J. Li *, Y. Liu *, B. Chen, E. Spear, L. Yuan, L. Beker, J. B.-H. Tok, Y. Cui, A. Habtezion, X. Chen, Z. Bao. “NeuString: an Elastic Neurochemical Interface for Brain and Gut”. In preparation.
2. Y. Liu *, J. Li *, S. Song *, J. Kang, Y. Tsao, S. Chen, W. Xu, Y.-Q. Zheng, J. B.-H. Tok, P. M. George, Z. Bao. “Morphing Electronics for Growing Tissue”. Nature 2019, under review.
3. C. Fang *, J. Li *, Y. Zhang, J.Z. Lee, Y. Yang, F. Yang, J. Alvarado, M.A. Schroeder, L. Yang, M. Cai, J. Gu, K. Xu, X. Wang, Y.S. Meng. “Quantifying Inactive Lithium in Lithium Metal Batteries”. Nature 2019. In press.
4. J. Li *, P. Angsantikul *, W. Liu, B. Esteban, X. Chang, E. Sandraz, Y. Liang, S. Zhu, Y. Zhang, C. Chen, W. Gao, L. Zhang, J. Wang. “Biomimetic Platelet‐Camouflaged Nanorobots for Binding and Isolation of Biological Threats”. Adv. Mater. 2018, 1704800.
5. J. Li, B. Esteban, W. Gao, L. Zhang, J. Wang. “Micro/Nanorobots for Biomedicine: Delivery, Surgery, Sensing, and Detoxification”. Science Robotics 2017, 2, eaam6431. Highlighted in IEEE Spectrum.

6. J. Li *, P. Angsantikul *, W. Liu *, B. Esteban *, S. Thamphiwatana, M. Xu, E. Sandraz, X. Wang, J. Delezuk, W. Gao, L. Zhang, J. Wang. “Micromotors Spontaneously Neutralize Gastric Acid for pH-Responsive Payload Release”. Angew. Chem. Int. Ed. 2017, 56, 2156–2161. Highlighted in New Scientist, Science Daily.

7. Esteban *, P. Angsantikul *, J. Li *, M. Lopez, D.E. Ramírez, S. Thamphiwatana, C. Chen, J. Delezuk, R. Samakapiruk, V. Ramez, L. Zhang, J. Wang. “Micromotor-Enabled Active Drug Delivery for In Vivo Treatment of Stomach Infection”. Nat. Commun. 2017, 8, 272. Highlighted in NPR, The Walt Street Journal.

8. J. Li, P. Angsantikul, W. Liu, B. Esteban, X. Chang, E. Sandraz, Y. Liang, S. Zhu, Y. Zhang, C. Chen, W. Gao, L. Zhang, J. Wang. “Biomimetic Platelet‐Camouflaged Nanorobots for Binding and Isolation of Biological Threats”. Adv. Mater. 2017, 1704800.
9. J. Li *, X. Yu *, M. Xu, W. Liu, E. Sandraz, H. Lan, J. Wang, S. Cohen. “Metal-Organic Frameworks as Micromotors with Tunable Engines and Brakes”, J. Am. Chem. Soc. 2017, 139, 611–614. Highlighted in Nature Review Chemistry.

10. J. Li, W. Liu, T. Li, I. Rozen, J. Zhao, B. Bahari, B. Kante, J. Wang. “Swimming Micro-Robot Optical Nanoscopy”, Nano Lett. 2016, 16, 6604–6609. Highlighted in Chemistry World.

11. J. Li *, S. Thamphiwatana *, W. Liu *, B. Esteban, P. Angsantikul, E. Sandraz, J. Wang, T. Xu, F. Soto, V. Ramez, X. Wang, W. Gao, L. Zhang, J. Wang. “Enteric Micromotor Can Selectively Position and Spontaneously Propel in the Gastrointestinal Tract”, ACS Nano 2016, 10, 9536–9542. Highlighted in Chemical & Engineering News.

12. J. Li, I. Rozen, J. Wang. “Rocket Science on the Nanoscale”, ACS Nano 2016, 10, 5619–5634.
13. J. Li*, O. Shklyaev *, T. Li *, W. Liu, H. Shum, I. Rozen, A. C. Balazs, J. Wang. “Self-Propelled Nanomotors Autonomously Seek and Repair Cracks”, Nano Lett. 2015, 15, 7077–7085. Highlighted in PNAS, Chemical Engineering News.

14. J. Li*, T. Li *, T. Xu *, M. Kiristi, W. Liu, Z. Wu, J. Wang. “Magneto-Acoustic Hybrid Nanomotor”, Nano Lett. 2015, 15, 4814–4821.
15. Zhu *, J. Li*, Y. J. Leong, I. Rozen, X. Qu, R. Dong, Z. Wu, W. Gao, P. H. Chung, J. Wang, S. Chen. “3D-Printed Artificial Microfish”, Adv. Mater. 2015, 27, 4411–4417. Highlighted in Wired, Discovery News, Forbes, Guardian, The Washington Post, etc.

16. J. Li*, W. Gao *, R. Dong, A. Pei, S Sattayasamitsathit, J. Wang. “Nanomotor Lithography”, Nature Commun. 2014, 5, 5026.

Teaching and Service

2017/3-2017/6 Teaching assistant of CHEM 240 “Electrochemistry”, UCSD

2016/3-2016/6 Teaching assistant of NANO 244 “Nanomachines and Nanorobots”, UCSD

2011/9-2012/1 Teaching assistant of laboratory class “Nanofabrication”, FDU

2017/9-now Mentor of “Second-Year Mentoring” of Stanford chemical engineering PhD program

2012/9-now Mentored 16 undergrads and 2 high school students, co-authored 30 publications

2016/8-2017/6 Academic planning committee members of UCSD YKAVLI

2016/9 Panelist of UCSD STEM PhD student orientation

2016/8 Outreach demo for high school students of Johns Hopkins Centre for Talented Youth

2016/7 Guest speaker for 5th graders of Ocean Discovery Institute STEM Professional

2016/8 Volunteer of UCSD Moores Cancer Center Luau and Legends of Surfing Invitational

2016/8 NanoEngineering Session Host of 2016 UCSD Summer Research Conference

2012/5 Curator of Fudan NanoArt Exhibition

Teaching Interests:

I am interested in teaching most of the major courses for Chemical Engineering, especially Heat and Mass Transfer, Fluids Dynamics, and Thermodynamics, Separation Process. I am also interested in other courses including Electrochemistry, Soft Materials, Nanotechnology and Nanofabrication, Nanorobotics, Nanomedicine.