1. Advanced Molecular Imaging Team at Shenzhen Bay Laboratory (AMIL-SZBL)

1.1 Brief History

    As of April 2022, the laboratory spaces designed for the Institute of Biomedical Engineering at Shenzhen Bay Laboratory were finalized, marking the commencement of the establishment of the AMIL team. By late July 2022, we welcomed the inaugural group of graduate students and engineers. The majority of our team members began their journey into the field of PET post their inclusion in the group. The burgeoning AMIL team , fueled by relentless dedication and resilience, achieving rapid growth amidst considerable pressure. In a span slightly over a year, noteworthy advancements have been achieved across all pivotal PET technologies, encompassing system simulation, image reconstruction, mechanical and detector design, electronic and software design, animal experiments, and the development of radioactive tracers.

    To date, our team has achieved significant milestones, especially in the advanced PET detector design. Our detectors achieved a decoding resolution of 0.25mm and a time resolution of 150ps. The new generation of our electronic systems has surpassed our initial expectations, facilitating the seamless design of a diverse array of advanced PET systems. The successful realization of system simulation design, high-performance image reconstruction algorithms, and physical calibration algorithms has paved the way for substantial advancements in the development of the next-generation super-resolution and dynamic imaging algorithms.

    Throughout this journey, five of our state-of-the-art PET systems have consecutively reached the imaging testing phase. These include Shenzhen's premier high-performance small animal PET/CT, the first wearable PET designed for mouse brain imaging, Shenzhen's inaugural high-performance small animal PET/MRI, the world's pioneering wearable mobile TOF-PET for human brain, and a high-resolution, high-sensitivity human brain DOI-TOF-PET. Our groundbreaking initiatives are reinforcing our belief in AMIL-SZBL's potential to evolve into a competitive PET technology R&D team in the future.

• 1.2 Our Aims
  

    Our primary aim is to achieve significant advancements in the core technologies and methodologies of next-generation high-performance PET, PET/CT and PET/MRI. These advancements are intended to enhance clinical diagnostic and therapeutic solutions for cancers, neurological disorders, and cardiovascular diseases. Another ambition is to develop wearable and mobile brain TOF-PET, addressing the limitations inherent in traditional static brain imaging techniques. This goal aspires to enable dynamic whole-brain functional imaging in awake, active, task-engaged, and natural environments, thereby offering novel tools for neuroscience research and the clinical diagnosis of major brain diseases such as Alzheimer's Disease (AD) and Parkinson's Disease (PD). 

1.3 Our Experiences

    At the Lawrence Berkeley National Laboratory (the birthplace of modern nuclear medicine) , Dr. Peng worked in collaboration with esteemed professionals, including Dr. Budinger, Dr. Derenzo, and Dr. Moses. We engaged in the development of high-performance TOF-PET for years. Dr. Peng paticipated in two international cooperative projects: the OpenPET Nuclear Imaging Electronic System Standard Project and the Whole-Body EXPLORER PET Project. He led the development of advanced PET detectors and imaging systems, such as the 314ps Tachyon I TOF-PET detector and system (holding the world record for PMT TOF-PET time resolution), and the 127ps high temporal resolution Tachyon II TOF-PET detector. 

    At Shenzhen Bay Laboratory, we have established an integrated team of“PET Instrument Development - PET Probe Development - Clinical Applications of PET”, created the first clinical cooperation center and supported the incubation of the first company by SZBL. We developed the PET detectors with the decoding resolution of 0.25mm, a wearable mouse brain PET and a wearable mobile human brain TOF-PET. Current projects under development include a high-performance whole-brain PET, the first small animal PET/MRI in Shenzhen, and a total-body TOF-PET/CT with DOI capability.

• 1.4 Open to Collaborations
  

    AMIL-SZBL team’s contemplation spans beyond PET technology itself. We are also pondering the future development trends of molecular imaging technology and contemplating a world-class molecular imaging research team that adapts to these trends. With this in mind, we proposed to construct an integrated PET molecular imaging collaborative innovation team at SZBL, encompassing "instrument R&D–PET tracer development–clinical application".

    Meanwhile, we look forward to establishing close cooperative relationships with more excellent scientific research teams, hospitals, universities, and companies globally, working together to solve scientific issues in the field of molecular imaging, enabling advanced PET molecular imaging technology to better serve science and clinical needs, and contributing more effectively to the cause of human health.

2. Introduction to Positron Emission Tomography (PET)

2.1 What is PET?

    Positron Emission Tomography (PET) is an advanced molecular imaging technique, used to observe the molecular processes and metabolic activities of biological activity within the human body. It provides information about the function of body tissues and organs by detecting the distribution and concentration of radiolabeled biomolecules, such as glucose, proteins, or drugs, within the body. It has broad clinical applications in diagnosing tumors, brain diseases, and cardiovascular diseases and extensive research applications in animal imaging and drug development.

2.2 Scientifc and Clinical Value of PET

    Among known molecular imaging methods, PET has the highest molecular sensitivity, capable of precisely detecting metabolic processes below 100 picoMolar in living organisms. This sensitivity is about four orders of magnitude greater than MRI. As metabolic or functional anomalies in human cells, tissues, and organs precede clinical symptoms, PET images often reveal pathological features earlier than anatomical images from CT or MRI. Consequently, PET scans have become indispensable in neuroscience research and diagnosis of major brain disorders like Alzheimer’s disease (AD), Parkinson’s disease (PD), and epilepsy. For instance, PET molecular imaging is the "gold standard" for clinical diagnosis of AD and is the only imaging technique that can quantitatively analyze abnormal aggregations of Aβ plaques and tau tangles in a living brain. PET imaging can precisely detect AD pathology approximately 10~15 years before clinical diagnosis, playing an irreplaceable role in preclinical evaluations and prognosis assessments.

2.3 Technical Challenges in PET

    Two major challenges in modern PET imaging are resolution and sensitivity. The performance of PET imaging largely depends on the performance of the PET detectors. (1) Resolution issue: Due to limitations in micro-cross-section crystal manufacturing and processing, photoelectric measurement systems, and decoding algorithms, designing and implementing a PET detector with a crystal cross-section size less than 0.5 mm is challenging. This serves as a significant hurdle for PET molecular imaging's evolution towards microscopic imaging. (2) Sensitivity issue: PET imaging is constrained by isotope dosage, causing its signal-to-noise ratio to be significantly lower than anatomical images from CT or MRI. The key to resolving this is the TOF (Time-of-Flight) technology. TOF improves the system's effective sensitivity and image signal-to-noise ratio by accurately measuring the annihilation position of positrons. Due to factors like photon loss during scintillation light transmission within the crystal, commercial PET systems' TOF currently reaches only about 200ps. AMIL-SZBL's ongoing research into ultra-high resolution below 250μm and super high temporal resolution of 100ps for PET detectors have the potential to propel the advancement of PET molecular imaging.

2.4 New Trends in PET Technology Development: Mobile Imaging

    Functional imaging of the brain with PET in active, task-specific, and natural settings holds tremendous value in cognitive studies, brain functional zone research, and understanding and treating brain diseases. However, current brain functional imaging, including PET and MRI, can only be conducted in a stationary position, not fully meeting the demands of neuroscience and clinical research. Catering to neuroscience research needs and the significant trend in brain functional imaging, AMIL-SZBL is developing the first wearable, mobile TOF-PET for the brain. This innovative approach disrupts traditional stationary imaging, pioneering functional imaging of the brains of animals and humans in active, task-specific, and more natural settings.

3. Ongoing Research Projects at AMIL-SZBL 

3.1 Major Research Interests of AMIL-SZBL

    (1) Research and development in core PET technologies. This includes gamma detectors with high spatial and time resolutions, advanced nuclear electronics, and image reconstruction and processing based on deep learning techniques. For instance, my current research on PET detectors with an ultra-high time resolution of 100ps and super-high resolution below 250μm is expected to drive the evolution of PET molecular imaging towards microscopic imaging. 

     (2) Development of the next-generation high-performance PET, PET/CT and PET/MRI systems, and radiotherapy systems under PET guidance, to meet scientific and clinical needs. For instance, an ongoing project is the development of a wearable, mobile brain TOF-PET system. This innovation aims to revolutionize traditional stationary imaging by facilitating dynamic brain functional imaging of animals and humans in awake, active, task-engaged, and natural environments. This offers new tools for neuroscience research and clinical treatments of major brain disorders, such as AD and PD.

     (3) Applications and translations of the high-performance PET molecular imaging technologies, devices, and methods in the mechanism research and clinical diagnosis and treatment of cancers, brain diseases, and cardiovascular diseases. For example, a cardiac-specific TOF-PET system is under development, promising a cost-effective diagnostic tool for major cardiovascular diseases like ischemic heart disease, heart failure, cardiac inflammation, and valve disorders.

• 3.2 High-resolution Small Animal PET/CT and PET/MRI

•     AMIL has successfully developed Shenzhen's first high-resolution small animal PET/CT system with a 1 mm cross-sectional crystal. It provides an advanced imaging tool for scientific research in the Greater Bay Area. Various research groups from institutions such as Peking University, Southern Medical University, Southern University of Science and Technology, Sun Yat-sen University, Shenzhen Bay Laboratory, and the Shenzhen Institutes of Advanced Technology of the Chinese Academy of Sciences have utilized this system in over 260 mouse imaging experiments. These scientific studies encompass the development of radiomolecular probes, as well as diagnostic and therapeutic research on tumors and neurological diseases. Based on this, AMIL initiated a company dedicated to the translation of small animal PET systems.  It stands as the first company successfully incubated by the SZBL.

 3.3 Super-resolution PET Detector and System

•     Considering that the organ sizes of commonly used biological models, such as mice and rats, are much smaller than those of humans, achieving high spatial resolution is crucial for small animal PET imaging. The technology of constructing PET detectors using micro-cross-sectional crystals is the key to achieving ultra-high-resolution micro PET molecular and functional imaging. However, due to limitations in micro-cross-sectional crystal manufacturing and processing, photodetection systems, and decoding algorithms, designing PET detectors with a crystal cross-sectional size less than 0.5 mm poses significant challenges. AMIL-SZBL team successfully developed a high-resolution PET detector with a crystal cross-section of 0.5 mm, achieving a breakthrough in the spatial resolution of small animal PET systems (0.5mm). AMIL-SZBL's latest development, a PET detector based on a 16x16 crystal array with micro-sized LYSO: Ce crystals measuring 0.25×0.25×6.25 mm3, is the known PET detector with the smallest crystal cross-sectional area. This innovation holds promise for propelling PET molecular imaging technology towards micro-imaging.

• 

• 3.4 Wearable Brain PET for Mouse

•     During traditional small animal PET imaging, anesthesia is required. Anesthetics severely interfere with the metabolism and function of the brain and nervous system, significantly diminishing the application of PET—one of the most molecularly sensitive functional imaging techniques—in neuroscience research. Addressing the needs of neuroscience researches, our team has pioneered the world's most compact wearable imaging system designed for mice. This groundbreaking development aims to shift away from imaging under deep anesthesia, allowing for the capture of brain activity in awake and potentially freely-moving mouses, thus offering a powerful tool for advanced neuroscience studies. 

• 3.5 Wearable Brain PET for Human

•     Functional brain imaging with PET and MRI can only be conducted while the patient is in a resting state. Current technology cannot achieve brain functional imaging in humans during activities, tasks, social interactions, and other natural situations. AMIL-SZBL is developing the first wearable, mobile brain TOF-PET for human. This innovative approach disrupts traditional stationary imaging, pioneering functional imaging of the brains of humans in active, task-specific, and more natural settings.

• 

• 3.6 Total-body TOF-PET/CT with DOI Capabilities

•     Traditional PET/CT systems typically have an axial field of view (FOV) ranging from 16~24cm. This limitation results in low system sensitivity and a confined imaging area. To achieve whole-body imaging, multiple bed positions are required for image stitching, making simultaneous multi-organ imaging impossible. The ultra-wide FOV TOF PET/CT system, with an axial FOV exceeding 1.4 meters, substantially boosts system sensitivity. It allows for dynamic imaging of the entire human body simultaneously, offering significant potential value for both scientific research and clinical applications. AMIL-SZBL team is responsible for the development of the next-generation ultra-wide FOV TOF-PET/CT system with DOI capabilities. This endeavor aims to introduce DOI functionality in ultra-wide FOV PET systems for the first time, driving the advancement of high-resolution Total-body PET technology and its applications.