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Michael van Dam", "links": { "alternate": { "href": "https://www.zotero.org/mvandam", "type": "text/html" } } }, "lastModifiedByUser": { "id": 2959198, "username": "noelha", "name": "", "links": { "alternate": { "href": "https://www.zotero.org/noelha", "type": "text/html" } } }, "creatorSummary": "Van Dam", "parsedDate": "1998", "numChildren": 2 }, "data": { "key": "2R6F7ITV", "version": 36765, "itemType": "thesis", "title": "Integration of a free-space optical interconnect into the NUMAchine multiprocessor", "creators": [ { "creatorType": "author", "firstName": "Michael", "lastName": "Van Dam" } ], "abstractNote": "Integration of a free-space optical interconnect\ninto the NUMAchine multiprocessor, Van Dam, Michael, 1998, University of Toronto. Copyright by the author unless stated otherwise.", "thesisType": "", "university": "University of Toronto", "place": "", "date": "1998", "series": "", "seriesNumber": "", "numPages": "", "DOI": "", "ISBN": "", "citationKey": "", "url": "http://oatd.org/oatd/record?record=oai%5C%3Acollectionscanada.gc.ca%5C%3AOOAMICUS.27866555", "accessDate": "2016-03-27T06:59:07Z", "ISSN": "", "archive": "", "archiveLocation": "", "shortTitle": "", "language": "", "libraryCatalog": "oatd.org", "callNumber": "", "rights": "", "extra": "00000", "tags": [], "collections": [ "NHI4JG3Z", "XJ9Y3QQP" ], "relations": { "dc:replaces": "http://zotero.org/groups/6185/items/6ALGQLYM" }, "dateAdded": "2016-03-27T06:59:07Z", "dateModified": "2026-04-15T07:08:43Z" } }, { "key": "DK5XDVCS", "version": 36763, "library": { "type": "group", "id": 6185, "name": "van Dam Research Group", "links": { "alternate": { "href": "https://www.zotero.org/groups/van_dam_research_group", "type": "text/html" } } }, "links": { "self": { "href": "https://api.zotero.org/groups/6185/items/DK5XDVCS", "type": "application/json" }, "alternate": { "href": "https://www.zotero.org/groups/van_dam_research_group/items/DK5XDVCS", "type": "text/html" } }, "meta": { "createdByUser": { "id": 15552, "username": "mvandam", "name": "R. Michael van Dam", "links": { "alternate": { "href": "https://www.zotero.org/mvandam", "type": "text/html" } } }, "lastModifiedByUser": { "id": 2959198, "username": "noelha", "name": "", "links": { "alternate": { "href": "https://www.zotero.org/noelha", "type": "text/html" } } }, "creatorSummary": "van Dam", "parsedDate": "2006", "numChildren": 4 }, "data": { "key": "DK5XDVCS", "version": 36763, "itemType": "thesis", "title": "Solvent-resistant elastomeric microfluidic devices and applications", "creators": [ { "creatorType": "author", "firstName": "R. Michael", "lastName": "van Dam" } ], "abstractNote": "Microfluidics is increasingly being used in many areas of biotechnology and chemistry to achieve reduced reagent volumes, improved performance, integration, and parallelism, among other advantages. Though early devices were based on rigid materials such as glass and silicon, elastomeric materials such as polydimethylsiloxane (PDMS) are rapidly emerging as a ubiquitous platform for applications in biotechnology. This is due, in part, to simpler fabrication procedures and to the ability to integrate mechanical microvalves at vastly greater densities. For many applications in the areas of chemical synthesis and analysis, however, PDMS cannot replace glass and silicon due to its incompatibility with many solvents and reagents.\n\nSuch areas could benefit tremendously from the development of an elastomeric microfluidic device technology that combines the advantages of PDMS with the property of solvent resistance. Simplified fabrication could increase the accessibility of microfluidics, and the possibility of dense valve integration could lead to significant advances in device sophistication. Applications could be more rapidly developed by design re-use due to the independence of mechanical valves on fluid properties (unlike electrokinetic pumping), and the property of permeability could enable novel fluidic functions for accessing a broader range of reactions than is possible in glass and silicon.\n\nThe first half of this thesis describes our strategies and efforts to develop this new enabling technology. Several approaches are presented in Chapter 3, and two particularly successful ones, based on new elastomers (FNB and PFPE), are described in Chapters 4 and 5. Chapter 6 describes a novel method of fabricating devices from 3D molds that could expand the range of useful elastomers.\n\nThe second half of this thesis discusses microfluidic combinatorial synthesis and high throughput screening—applications that take particular advantage of the ability to integrate thousands of individual valves and reaction chambers. Chapter 7 introduces several scalable device architectures and presents results of preliminary steps toward the synthesis of combinatorial DNA and peptide arrays. A novel method of performing universal gene expression analysis with combinatorial DNA arrays is described in Chapter 8 and an algorithm for predicting relationships among genes from gene expression array data is presented in Chapter 9.", "thesisType": "phd", "university": "California Institute of Technology", "place": "", "date": "2006", "series": "", "seriesNumber": "", "numPages": "", "DOI": "", "ISBN": "", "citationKey": "", "url": "http://resolver.caltech.edu/CaltechETD:etd-12052005-234258", "accessDate": "2016-03-27T06:55:21Z", "ISSN": "", "archive": "", "archiveLocation": "", "shortTitle": "", "language": "", "libraryCatalog": "thesis.library.caltech.edu", "callNumber": "", "rights": "", "extra": "00022", "tags": [], "collections": [ "NHI4JG3Z", "XJ9Y3QQP" ], "relations": { "dc:replaces": "http://zotero.org/groups/6185/items/B6R9EP2P" }, "dateAdded": "2016-03-27T06:55:21Z", "dateModified": "2026-04-15T07:08:26Z" } }, { "key": "2J39V6D4", "version": 36760, "library": { "type": "group", "id": 6185, "name": "van Dam Research Group", "links": { "alternate": { "href": "https://www.zotero.org/groups/van_dam_research_group", "type": "text/html" } } }, "links": { "self": { "href": "https://api.zotero.org/groups/6185/items/2J39V6D4", "type": "application/json" }, "alternate": { "href": "https://www.zotero.org/groups/van_dam_research_group/items/2J39V6D4", "type": "text/html" } }, "meta": { "createdByUser": { "id": 15552, "username": "mvandam", "name": "R. Michael van Dam", "links": { "alternate": { "href": "https://www.zotero.org/mvandam", "type": "text/html" } } }, "creatorSummary": "Nelson", "parsedDate": "2011", "numChildren": 2 }, "data": { "key": "2J39V6D4", "version": 36760, "itemType": "thesis", "title": "EWOD microfluidic chips for applications: Fundamentals of actuation, extensional rheometry, on-chip heating, and monolithic fabrication", "creators": [ { "creatorType": "author", "firstName": "Wyatt Ceder", "lastName": "Nelson" } ], "abstractNote": "The fundamentals of electrowetting-on-dielectric (EWOD) actuation are summarized in order to facilitate the design of microfluidic chips. Drawing from the work of others as well as our investigations, we discuss key parameters and useful modeling techniques. An experiment is devised to track dynamic drag on sliding droplets under EWOD; the data provide empirical evidence that electrowetting fields have a negligible effect on contact line friction at low speed and voltage. To meet the demands of applications beyond basic micro- and nanoliter droplet handling, multi-functional electrodes and a surface machining process are developed for effective implementations of EWOD actuation. We demonstrate EWOD-based devices for extensional rheometry, localized droplet heating for biochemical samples, and picoliter droplet handling.", "thesisType": "Ph.D.", "university": "University of California, Los Angeles", "place": "United States -- California", "date": "2011", "series": "", "seriesNumber": "", "numPages": "175", "DOI": "", "ISBN": "", "citationKey": "", "url": "https://search.proquest.com/docview/923292191/abstract/22E5376F56194DAFPQ/1", "accessDate": "2018-12-27T19:44:46Z", "ISSN": "", "archive": "", "archiveLocation": "", "shortTitle": "EWOD microfluidic chips for applications", "language": "English", "libraryCatalog": "ProQuest", "callNumber": "", "rights": "Database copyright ProQuest LLC; ProQuest does not claim copyright in the individual underlying works.", "extra": "", "tags": [ { "tag": "Applied sciences", "type": 1 }, { "tag": "Digital microfluidics", "type": 1 }, { "tag": "Droplet actuation", "type": 1 }, { "tag": "Electrowetting", "type": 1 }, { "tag": "Monolithic fabrication", "type": 1 } ], "collections": [ "NHI4JG3Z", "XJ9Y3QQP" ], "relations": { "dc:replaces": "http://zotero.org/groups/6185/items/A5V9ZU4B" }, "dateAdded": "2018-12-27T19:44:46Z", "dateModified": "2026-04-15T07:08:13Z" } }, { "key": "4BEUAWFM", "version": 36755, "library": { "type": "group", "id": 6185, "name": "van Dam Research Group", "links": { "alternate": { "href": "https://www.zotero.org/groups/van_dam_research_group", "type": "text/html" } } }, "links": { "self": { "href": "https://api.zotero.org/groups/6185/items/4BEUAWFM", "type": "application/json" }, "alternate": { "href": "https://www.zotero.org/groups/van_dam_research_group/items/4BEUAWFM", "type": "text/html" } }, "meta": { "createdByUser": { "id": 15552, "username": "mvandam", "name": "R. Michael van Dam", "links": { "alternate": { "href": "https://www.zotero.org/mvandam", "type": "text/html" } } }, "creatorSummary": "Berry-Pusey", "parsedDate": "2012", "numChildren": 4 }, "data": { "key": "4BEUAWFM", "version": 36755, "itemType": "thesis", "title": "A vascular access system (VAS) for preclinical models", "creators": [ { "creatorType": "author", "firstName": "Brittany Nan", "lastName": "Berry-Pusey" } ], "abstractNote": "Preclinical Molecular Imaging technologies have an increasingly broader application base while they at the same time are becoming more user-friendly. Tail vein injections are a routine but critical step in most imaging applications, with poor injections greatly affectingthe experimental results. The high skills and experience required to perform successful tail vein injections leave many preclinical imaging scientists ill-suited to perform this task. In a recent study, we found that trained routine injectors left on average 14% of the injected probe in the tail tissue. Improvements in injection accuracy, injection consistency, safety, and a reduction in time required to perform the task are needed in preclinical molecular imaging. To achieve these goals, we have devised a semi-automated vascular access system (VAS) to facilitate injections and eventually blood sampling from the mouse tail. We have eliminated much of the human error involved in the manual approach by using a computer-controlled mechanically moving micro-needle.To make use of the VAS, one places an anesthetized mouse onto the temperature controlled mouse bed and secures the tail on a heated tail holder. The VAS uses NIR light, cross-polarizers, and a basic CCD camera to image the tail. The reflection image is processed and the vein is located using edge detection methods. The vein location is plotted and over-laid onto the live video feed of the mouse tail. Using a custom designed user interface, the user properly aligns the needle to the tail vein by employing computer-controlled motors. Once the needle is properly aligned, it begins to penetrate the tail tissue and enter the vein. A pressure transducer attached to the needle detects when the needle has entered the vein, and automatically stops further progression of the needle. With the needle inside the vein, probes can be injected manually, with a liquid handling system, or via a syringe pump. The VAS was first validated using a mouse tail phantom. The phantom was a PDMS chip with channels equivalent to the dimensions of a mouse tail vein (300um). The channels were filled with water and pressurized to variable pressures. With the phantom, the ability for the VAS to align a needle according to an image, insert a needle into a desired location, and stop the progression of the needle based on a pressure signal were tested and verified. Mouse studies were also performed with the VAS. These studies showed that the accuracy of the device, as measured by the percentage of injected probe left in the tail, is 3.4% (+/- 4.5). The VAS reduces the operator skill requirements and training, has the potential to improve injection accuracy, reduces the time required to perform a tail vein injection, and is potentially safer for users and mice in comparison to current manual methods.", "thesisType": "", "university": "UCLA", "place": "", "date": "2012", "series": "", "seriesNumber": "", "numPages": "", "DOI": "", "ISBN": "", "citationKey": "", "url": "https://escholarship.org/uc/item/8r8915f9", "accessDate": "2018-12-27T19:40:52Z", "ISSN": "", "archive": "", "archiveLocation": "", "shortTitle": "", "language": "en", "libraryCatalog": "escholarship.org", "callNumber": "", "rights": "", "extra": "", "tags": [], "collections": [ "NHI4JG3Z", "XJ9Y3QQP" ], "relations": { "dc:replaces": "http://zotero.org/groups/6185/items/6XASGZQB" }, "dateAdded": "2018-12-27T19:40:52Z", "dateModified": "2026-04-15T07:08:00Z" } }, { "key": "S6DKW7XC", "version": 36751, "library": { "type": "group", "id": 6185, "name": "van Dam Research Group", "links": { "alternate": { "href": "https://www.zotero.org/groups/van_dam_research_group", "type": "text/html" } } }, "links": { "self": { "href": "https://api.zotero.org/groups/6185/items/S6DKW7XC", "type": "application/json" }, "alternate": { "href": "https://www.zotero.org/groups/van_dam_research_group/items/S6DKW7XC", "type": "text/html" } }, "meta": { "createdByUser": { "id": 15552, "username": "mvandam", "name": "R. Michael van Dam", "links": { "alternate": { "href": "https://www.zotero.org/mvandam", "type": "text/html" } } }, "creatorSummary": "Chen", "parsedDate": "2014", "numChildren": 4 }, "data": { "key": "S6DKW7XC", "version": 36751, "itemType": "thesis", "title": "Production of positron emission tomography (PET) radiotracers with electrowetting-on-dielectric (EWOD) digital microfluidics", "creators": [ { "creatorType": "author", "firstName": "Supin", "lastName": "Chen" } ], "abstractNote": "There is currently a need to improve production of radiotracers for positron emission tomography (PET) imaging because although thousands of radiotracers have been developed in research settings, only a few are readily available, severely limiting the biological problems that can be studied in vivo via PET. An electrowetting-on-dielectric (EWOD) digital microfluidic chip was designed with multifunctional electrodes (for heating, temperature sensing, and EWOD driving) to synthesize a variety of 18F-labeled tracers targeting a range of biological processes. A single EWOD radiosynthesizer device design was used for complete synthesis of four radiotracers (a sugar, a DNA nucleoside, a protein-labelling compound, and a neurotransmitter). All of the key synthesis steps for radiochemistry have been demonstrated on chip: concentration of fluoride ion, solvent exchange, chemical reaction, and purification. A mirrored configuration of valve metal oxide was also investigated for use as a cost effective and high electrical performance dielectric in EWOD.", "thesisType": "", "university": "UCLA", "place": "", "date": "2014", "series": "", "seriesNumber": "", "numPages": "", "DOI": "", "ISBN": "", "citationKey": "", "url": "https://escholarship.org/uc/item/1zz6h16w", "accessDate": "2018-12-27T19:39:42Z", "ISSN": "", "archive": "", "archiveLocation": "", "shortTitle": "", "language": "en", "libraryCatalog": "escholarship.org", "callNumber": "", "rights": "", "extra": "", "tags": [], "collections": [ "NHI4JG3Z", "XJ9Y3QQP" ], "relations": { "dc:replaces": "http://zotero.org/groups/6185/items/ILJLKIQI" }, "dateAdded": "2018-12-27T19:39:42Z", "dateModified": "2026-04-15T07:07:39Z" } }, { "key": "URFKJ3C9", "version": 36746, "library": { "type": "group", "id": 6185, "name": "van Dam Research Group", "links": { "alternate": { "href": "https://www.zotero.org/groups/van_dam_research_group", "type": "text/html" } } }, "links": { "self": { "href": "https://api.zotero.org/groups/6185/items/URFKJ3C9", "type": "application/json" }, "alternate": { "href": "https://www.zotero.org/groups/van_dam_research_group/items/URFKJ3C9", "type": "text/html" } }, "meta": { "createdByUser": { "id": 15552, "username": "mvandam", "name": "R. Michael van Dam", "links": { "alternate": { "href": "https://www.zotero.org/mvandam", "type": "text/html" } } }, "creatorSummary": "Dooraghi", "parsedDate": "2014", "numChildren": 2 }, "data": { "key": "URFKJ3C9", "version": 36746, "itemType": "thesis", "title": "Applications of Beta Particle Detection for Synthesis and Usage of Radiotracers Developed for Positron Emission Tomography", "creators": [ { "creatorType": "author", "firstName": "Alex Abreu", "lastName": "Dooraghi" } ], "abstractNote": "Positron Emission Tomography (PET) is a noninvasive molecular imaging tool that requires the use of a radioactive compound or radiotracer which targets a molecular pathway of interest. We have developed and employed three beta particle radiation detection systems to advance PET. Specifically, the goals of these systems are to:\n1. Automate dispensing of solutions containing a positron emitting isotope.\n2. Monitor radioactivity on-chip during synthesis of a positron emitting radiotracer.\n3. Assay cellular uptake on-chip of a positron emitting radiotracer.\nAutomated protocols for measuring and dispensing solutions containing radioisotopes are essential not only for providing an optimum environment for radiation workers, but also to ensure a quantitatively accurate workflow. For the first project, we describe the development and performance of a system for automated radioactivity distribution of beta particle emitting radioisotopes such as fluorine-18 (F-18). Key to the system is a radiation detector in-line with a peristaltic pump. The system demonstrates volume accuracy within 5 % for volumes of 20 μL or greater. When considering volumes of 20 μL or greater, delivered radioactivity is in agreement with the requested radioactivity as measured with the dose calibrator. The integration of the detector and pump leads to a flexible system that can accurately dispense solutions containing F-18 in radioactivity concentrations directly produced from a cyclotron (~ 0.1-1 mCi/μL), to low activity concentrations intended for preclinical mouse scans (~ 1-10 μCi/μL), and anywhere in between.\nElectrowetting on dielectric (EWOD) is an attractive microfluidic platform for batch synthesis of PET radiotracers. Visualization of radioisotopes on-chip is critical for synthesis optimization and technological development. For the second project, we describe the development and performance of a Cerenkov/real-time imaging system for PET radiotracer synthesis on EWOD. We also investigate fundamental physical characteristics of Cerenkov photon yield at different stages of [F-18]FDG synthesis on the EWOD platform. We are able to use this imaging system to optimize the mixing protocol as well as identify and correct for loss of radioactivity due to the migration of radioactive vapor outside of the EWOD heater, enabling an overall increase in the crude radiochemical yield from 50 ± 3% (n = 3) to 72 ± 13% (n = 5).\nClinical use of PET has proven to be a critical tool for monitoring cancer treatment response. For the third project, we describe the redesign and performance of Betabox, a specialized device that incorporates PET radiotracers in an assay that gives clinicians and researchers the ability to assess the effectiveness of a drug therapy in-vitro by isolating small samples of patient tumor cells incubated in a polydimethylsiloxane (PDMS) microfluidic chip. We find that Betabox is a high sensitivity and low noise charged particle imaging system that can operate without significant impairment of its performance at both room and at elevated temperatures, such as those suitable for cell culture. The dark count rate is within range of the expected signal from cosmic rays, dictating a low detection limit that allows quantitative imaging of very small amounts of radioactivity. This system demonstrates the potential of direct cellular radioassay of small samples of cells (~100 cells per measurement).", "thesisType": "Ph.D.", "university": "University of California, Los Angeles", "place": "United States -- California", "date": "2014", "series": "", "seriesNumber": "", "numPages": "162", "DOI": "", "ISBN": "978-1-303-95315-6", "citationKey": "", "url": "https://www.proquest.com/docview/1548319004/abstract/3AB238B923B445E1PQ/1", "accessDate": "2025-08-22T20:30:39Z", "ISSN": "", "archive": "", "archiveLocation": "", "shortTitle": "", "language": "English", "libraryCatalog": "ProQuest", "callNumber": "", "rights": "Database copyright ProQuest LLC; ProQuest does not claim copyright in the individual underlying works.", "extra": "", "tags": [ { "tag": "Electrowetting on dielectric", "type": 1 }, { "tag": "Health and environmental sciences", "type": 1 }, { "tag": "Medical imaging", "type": 1 }, { "tag": "Nuclear physics", "type": 1 }, { "tag": "Positron emission tomography", "type": 1 }, { "tag": "Pure sciences", "type": 1 }, { "tag": "Radiation detection", "type": 1 }, { "tag": "Radiotracers", "type": 1 } ], "collections": [ "NHI4JG3Z", "XJ9Y3QQP" ], "relations": { "dc:replaces": "http://zotero.org/groups/6185/items/4DVA5532" }, "dateAdded": "2025-08-22T20:30:39Z", "dateModified": "2026-04-15T07:07:23Z" } }, { "key": "ASBRPP3U", "version": 36743, "library": { "type": "group", "id": 6185, "name": "van Dam Research Group", "links": { "alternate": { "href": "https://www.zotero.org/groups/van_dam_research_group", "type": "text/html" } } }, "links": { "self": { "href": "https://api.zotero.org/groups/6185/items/ASBRPP3U", "type": "application/json" }, "alternate": { "href": "https://www.zotero.org/groups/van_dam_research_group/items/ASBRPP3U", "type": "text/html" }, "up": { "href": "https://api.zotero.org/groups/6185/items/BPJTA6KF", "type": "application/json" } }, "meta": { "createdByUser": { "id": 15552, "username": "mvandam", "name": "R. 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Michael van Dam", "links": { "alternate": { "href": "https://www.zotero.org/mvandam", "type": "text/html" } } }, "creatorSummary": "Ma", "parsedDate": "2014", "numChildren": 1 }, "data": { "key": "BPJTA6KF", "version": 36742, "itemType": "thesis", "title": "Expanding the Capabilities of Microfluidic Systems for Positron Emission Tomography (PET) Tracer Synthesis and Analysis", "creators": [ { "creatorType": "author", "firstName": "Xiaoxiao", "lastName": "Ma" } ], "abstractNote": "", "thesisType": "Ph.D.", "university": "University of California, Los Angeles", "place": "Los Angeles, CA", "date": "2014", "series": "", "seriesNumber": "", "numPages": "", "DOI": "", "ISBN": "", "citationKey": "", "url": "", "accessDate": "", "ISSN": "", "archive": "", "archiveLocation": "", "shortTitle": "", "language": "", "libraryCatalog": "", "callNumber": "", "rights": "", "extra": "", "tags": [], "collections": [ "NHI4JG3Z", "XJ9Y3QQP" ], "relations": { "dc:replaces": "http://zotero.org/groups/6185/items/UPNG7I8T" }, "dateAdded": "2015-06-09T16:02:11Z", "dateModified": "2026-04-15T07:07:06Z" } }, { "key": "Y3KHWYW2", "version": 36739, "library": { "type": "group", "id": 6185, "name": "van Dam Research Group", "links": { "alternate": { "href": "https://www.zotero.org/groups/van_dam_research_group", "type": "text/html" } } }, "links": { "self": { "href": "https://api.zotero.org/groups/6185/items/Y3KHWYW2", "type": "application/json" }, "alternate": { "href": "https://www.zotero.org/groups/van_dam_research_group/items/Y3KHWYW2", "type": "text/html" }, "up": { "href": "https://api.zotero.org/groups/6185/items/45WSABBK", "type": "application/json" } }, "meta": { "createdByUser": { "id": 15552, "username": "mvandam", "name": "R. Michael van Dam", "links": { "alternate": { "href": "https://www.zotero.org/mvandam", "type": "text/html" } } } }, "data": { "key": "Y3KHWYW2", "version": 36739, "parentItem": "45WSABBK", "itemType": "attachment", "linkMode": "imported_url", "title": "Snapshot", "accessDate": "2021-11-14T05:56:31Z", "url": "https://escholarship.org/uc/item/8s34806v", "note": "", "contentType": "text/html", "charset": "utf-8", "filename": "8s34806v.html", "md5": "98e2da3063768844e3df68d4f06cc92b", "mtime": 1636869390827, "tags": [], "relations": { "dc:replaces": [ "http://zotero.org/groups/6185/items/RNIEUPX9", "http://zotero.org/groups/6185/items/XZU6FU9C" ] }, "dateAdded": "2021-11-14T05:56:31Z", "dateModified": "2026-04-15T07:06:48Z" } }, { "key": "45WSABBK", "version": 36737, "library": { "type": "group", "id": 6185, "name": "van Dam Research Group", "links": { "alternate": { "href": "https://www.zotero.org/groups/van_dam_research_group", "type": "text/html" } } }, "links": { "self": { "href": "https://api.zotero.org/groups/6185/items/45WSABBK", "type": "application/json" }, "alternate": { "href": "https://www.zotero.org/groups/van_dam_research_group/items/45WSABBK", "type": "text/html" } }, "meta": { "createdByUser": { "id": 15552, "username": "mvandam", "name": "R. Michael van Dam", "links": { "alternate": { "href": "https://www.zotero.org/mvandam", "type": "text/html" } } }, "creatorSummary": "Ly", "parsedDate": "2016", "numChildren": 3 }, "data": { "key": "45WSABBK", "version": 36737, "itemType": "thesis", "title": "Chemical Purity Analysis of PET Radiotracers via Microchip Capillary Electrophoresis", "creators": [ { "creatorType": "author", "firstName": "Jimmy", "lastName": "Ly" } ], "abstractNote": "Production of a positron emission tomography (PET) tracer involves three stages: production of the radioisotope, radio-labeling and purification of the tracer, and quality control (QC) testing of the final product (if the tracer is used in humans). Though the production of the positron-emitting radioisotope requires expensive and complex instrumentation (e.g. cyclotron or generator), in many cases, the radioisotope can simply be obtained from a commercial source. The radio-labeling and purification step is performed by machines called radiosynthesizers, which perform chemical synthesis and purification processes in a remote-controlled or automated manner within radiation-shielded “hot cells”. Quality control testing is performed to ensure each batch of radiopharmaceutical is safe prior to use in human subjects, and requires several analytical chemistry instruments. Though a couple of PET tracers are routinely available in final form from commercial sources, most other tracers need to be specially manufactured and quality tested at the researcher’s facility.Advances in radiosynthesizer technology such as automation, programmability, and reagent kits simplify the production of diverse tracers. Furthermore, recent efforts in miniaturized synthesizers based on microfluidics aim to reduce equipment cost, shielding and lab space needs, and quantities of expensive reagents, to make it more affordable to produce custom batches of PET tracers on demand.In the context of these emerging technologies, quality control testing still remains a bottleneck due to the high cost of the many expensive instruments, specially-trained staff, and documentation needed to determine the purity and ensure the levels of all potential contaminants are below acceptable limits. Several companies are developing automated systems for quality control testing to alleviate some of these issues. However, high cost and large size remain obstacles. We have therefore explored the use of microfluidic analytical chemistry techniques to address these remaining critical issues. In this dissertation, the feasibility of using capillary electrophoresis (CE) to analyze the chemical purity of PET tracers is investigated as a compact and inexpensive replacement for high performance liquid chromatography (HPLC) and other techniques that are normally used for this purpose. After establishing that CE has sufficient performance (comparable to HPLC) using several example chemical systems, the design, development, and characterization of a microscale chemical purity testing system are presented, along with a discussion of its capabilities and limitations. Overall, it appears that microchip CE could be used instead of HPLC for performing many of the required QC tests of PET tracers.", "thesisType": "Ph.D.", "university": "University of California, Los Angeles", "place": "", "date": "2016", "series": "", "seriesNumber": "", "numPages": "", "DOI": "", "ISBN": "", "citationKey": "", "url": "https://escholarship.org/uc/item/8s34806v", "accessDate": "2021-11-14T05:56:16Z", "ISSN": "", "archive": "", "archiveLocation": "", "shortTitle": "", "language": "en", "libraryCatalog": "escholarship.org", "callNumber": "", "rights": "", "extra": "", "tags": [], "collections": [ "NHI4JG3Z", "W79MVFAJ", "XJ9Y3QQP" ], "relations": { "dc:replaces": [ "http://zotero.org/groups/6185/items/CD43BRHP", "http://zotero.org/groups/6185/items/YFRMN4AZ" ] }, "dateAdded": "2016-11-12T01:54:38Z", "dateModified": "2026-04-15T07:06:48Z" } }, { "key": "NTRRS3B9", "version": 36734, "library": { "type": "group", "id": 6185, "name": "van Dam Research Group", "links": { "alternate": { "href": "https://www.zotero.org/groups/van_dam_research_group", "type": "text/html" } } }, "links": { "self": { "href": "https://api.zotero.org/groups/6185/items/NTRRS3B9", "type": "application/json" }, "alternate": { "href": "https://www.zotero.org/groups/van_dam_research_group/items/NTRRS3B9", "type": "text/html" } }, "meta": { "createdByUser": { "id": 1981188, "username": "auska945", "name": "", "links": { "alternate": { "href": "https://www.zotero.org/auska945", "type": "text/html" } } }, "creatorSummary": "Ha", "parsedDate": "2018", "numChildren": 3 }, "data": { "key": "NTRRS3B9", "version": 36734, "itemType": "thesis", "title": "Microfluidics for the analysis and synthesis of radiopharmaceuticals", "creators": [ { "creatorType": "author", "firstName": "Noel", "lastName": "Ha" } ], "abstractNote": "Radiopharmaceuticals labeled with short-lived positron-emitting or gamma-emitting isotopes are injected into patients just prior to performing a positron emission tomography (PET) or single photon emission computed tomography (SPECT) scan. These imaging modalities are widely used in clinical care, as well as in the development and evaluation of new therapies via clinical trials. Unlike ordinary pharmaceuticals, the short lifetime of radiopharmaceuticals requires that they be produced in relatively small batches close to the geographical location where the patient is scanned. Since PET tracers are classified as drugs by regulatory agencies, they must pass stringent quality control (QC) tests after their production to ensure patient safety prior to injection. Performing and documenting these tests is cumbersome and time-consuming, and requires an array of expensive analytical chemistry equipment and significant dedicated lab space, and there is considerable interest in the development of automated and lower-cost approaches. By replacing conventional techniques with lab-on-a-chip technologies, it may be possible to achieve further reductions in the size, cost, and complexity of automated QC testing platforms. While some advances have been made for some of the many QC tests, high-resolution miniaturized methods suitable for assessment of chemical or radiochemical identity and purity are notably missing. We have been exploring microchip capillary electrophoresis (MCE) as a potential means to fill this gap. We have shown the potential to perform chemical identity and purity analysis by successful separation of the PET tracer [18F]FLT from all of its side products, with comparable limit of detection as HPLC. More recently, we demonstrated first-in-field work to add radiation detection to the MCE system, using a high-resolution positron detector to perform the radiochemical identity analysis of PET tracers. Microfluidic systems are also useful for the synthesis of radiopharmaceuticals such as radiolabeled peptides and antibody fragments, which provide a means to image disease-specific targets with extremely high specificity. To substantially reduce the high cost of radiolabeling, we have explored the feasibility of using a microdroplet reactor approach. As an example, a thiol-containing RGD peptide was labeled with fluorine-18 in a site-specific manner via the maleimide-based prosthetic group, [18F]FBEM on a microfluidic chip. We have also explored the site-specific radiofluorination of engineered antibody fragments (diabody) for ImmunoPET imaging via this microfluidic approach.These studies, and other work on small-molecule synthesis, have shown that there are advantages in performing radiochemistry in microdroplets. Active means of manipulating microdroplets, such as electrowetting-on-dielectric (EWOD) provides more flexibility of reaction implementation than passive methods, but EWOD devices are well known to suffer from a charging effect and the dielectric and hydrophobic layers have been found to suffer defects during harsh chemical reactions. Therefore, a novel droplet actuation mechanism, electro-dewetting, has been developed to address these challenges. Electro-dewetting uses an electric field formed inside a droplet to manipulate the adsorption of ionic surfactant molecules on the solid surface to change the contact angle. The underlying mechanism of this pheromone has been elucidated. We believe that all the work described here shows the potential for dramatic miniaturization of the complete PET tracer production process, and ultimately increasing the availability of diverse PET tracers for research use, further development, and clinical translation via lowering the cost and complexity of tracer production.", "thesisType": "", "university": "UCLA", "place": "", "date": "2018", "series": "", "seriesNumber": "", "numPages": "", "DOI": "", "ISBN": "", "citationKey": "", "url": "https://escholarship.org/uc/item/1b96c44k", "accessDate": "2020-04-28T04:10:10Z", "ISSN": "", "archive": "", "archiveLocation": "", "shortTitle": "", "language": "en", "libraryCatalog": "escholarship.org", "callNumber": "", "rights": "", "extra": "", "tags": [], "collections": [ "NHI4JG3Z", "XJ9Y3QQP" ], "relations": { "dc:replaces": "http://zotero.org/groups/6185/items/6KVYHKRS" }, "dateAdded": "2020-04-28T04:10:10Z", "dateModified": "2026-04-15T07:06:25Z" } }, { "key": "G5Y3KBEE", "version": 36731, "library": { "type": "group", "id": 6185, "name": "van Dam Research Group", "links": { "alternate": { "href": "https://www.zotero.org/groups/van_dam_research_group", "type": "text/html" } } }, "links": { "self": { "href": "https://api.zotero.org/groups/6185/items/G5Y3KBEE", "type": "application/json" }, "alternate": { "href": "https://www.zotero.org/groups/van_dam_research_group/items/G5Y3KBEE", "type": "text/html" } }, "meta": { "createdByUser": { "id": 15552, "username": "mvandam", "name": "R. Michael van Dam", "links": { "alternate": { "href": "https://www.zotero.org/mvandam", "type": "text/html" } } }, "creatorSummary": "Chao", "parsedDate": "2019", "numChildren": 3 }, "data": { "key": "G5Y3KBEE", "version": 36731, "itemType": "thesis", "title": "Novel microfluidic technologies for the concentration of radionuclides and radiotracers for positron emission tomography", "creators": [ { "creatorType": "author", "firstName": "Philip Hong-Sean", "lastName": "Chao" } ], "abstractNote": "Positon emission tomography (PET) is an imaging modality capable of visualizing biomolecules in vivo and can be used to aid in disease diagnosis, staging of disease severity, and monitoring of disease response to treatment. PET relies on the use of tracers (i.e. biomolecules labeled with radionuclides) for imaging. Due to the short half-life of the radionuclides used, PET tracer production is typically performed right before an imaging event. Production of a PET tracer can be broken down into three major parts: production of the radionuclide, radiochemical synthesis of the tracer, and, lastly, purification, formulation and quality control testing of the tracer.Several groups, including our own, have looked into leveraging the benefits of microfluidics (reduced system size, finer control of reaction parameters, reduced reagent consumption) towards the production of PET tracers. These microfluidic versions of commonly-used PET tracer production equipment enable users to scale up or down the amount of tracer that is produced at a given time. Compared to current commercial systems which are designed to synthesize large batches of PET tracers for clinical applications, these microfluidic systems can offer substantial cost savings by enabling production of smaller batches based on user needs.Microfluidic approaches have already been applied successfully towards radiochemical synthesis, purification, and quality control testing of tracers. There, however, still exists several steps in tracer production that could benefit from microfluidic technologies. Evaporation of solvent during the concentration and formulation steps following tracer purification is currently performed on slow and bulky rotary evaporators. Microfluidic technology could aid in size reduction while also leveraging microfluidic advantages such as faster heat transfer to increase evaporation rates. Part of this dissertation is focused on applying microfluidic technologies towards the concentration and formulation of PET tracers following purification.Despite successful design and operation of microfluidic radiosynthesizers, one main limitation that microfluidic radiosynthesizers face is differences between radionuclide volumes (mL) and microfluidic reactor volumes (μL). This disconnect limits the amount of starting radioactivity that can loaded into microscale reactors for radiosyntheses. To address this need, work presented in this dissertation also focuses on the design, fabrication, and testing of an automated microfluidic radionuclide concentrator based on miniaturized anion and cation exchange cartridges enabling the concentration of various types of radionuclides (e.g. fluorine-18 and gallium-68). Concentrated radionuclides in microliter volumes enables microfluidic synthesis of a diverse range of PET tracers in large quantities.We have also pursued further development of microreactors leading to new advancements to improve the radiosynthesis step during tracer production. Previously our group has demonstrated synthesis of a diverse range of PET tracers using a microfluidic radiosynthesizer based on electrowetting on dielectric (EWOD). Despite advantages of compact size and reduced reagent consumption, a limitation was the cost and complexity of the single-use EWOD chips used during production. In this dissertation, we combat these limitations through the design and fabrication of an automated microfluidic radiosynthesizer based on patterned wettability. This new platform uses reaction chips that are easier to fabricate (compared to EWOD), are a fraction of the cost, and are significantly easier to operate.Lastly, in this dissertation we demonstrate successful integration of our radionuclide concentrator with our newly design radiosynthesizer. We perform synthesis of [18F]fallypride using high starting activities and demonstrate the ability to produce tracers in high quantities. This integrated platform thus enables both production of low and high quantities of tracer depending on user needs.The developments presented in this dissertation represent tools for performing portions of the whole PET tracer production process in a more cost effective and efficient manner. Future work will be focused on the successful integration of all components (both microfluidic and conventional) necessary for PET tracer production to enable automated, reliable, high yielding radiosyntheses of clinical grade PET tracers.", "thesisType": "", "university": "UCLA", "place": "", "date": "2019", "series": "", "seriesNumber": "", "numPages": "", "DOI": "", "ISBN": "", "citationKey": "", "url": "https://escholarship.org/uc/item/7qb3p6x1", "accessDate": "2019-05-07T01:36:21Z", "ISSN": "", "archive": "", "archiveLocation": "", "shortTitle": "", "language": "en", "libraryCatalog": "escholarship.org", "callNumber": "", "rights": "", "extra": "", "tags": [], "collections": [ "NHI4JG3Z", "XJ9Y3QQP" ], "relations": { "dc:replaces": "http://zotero.org/groups/6185/items/P8BEMMHL" }, "dateAdded": "2019-05-07T01:36:21Z", "dateModified": "2026-04-15T07:06:12Z" } }, { "key": "7QHZG7BP", "version": 36728, "library": { "type": "group", "id": 6185, "name": "van Dam Research Group", "links": { "alternate": { "href": "https://www.zotero.org/groups/van_dam_research_group", "type": "text/html" } } }, "links": { "self": { "href": "https://api.zotero.org/groups/6185/items/7QHZG7BP", "type": "application/json" }, "alternate": { "href": "https://www.zotero.org/groups/van_dam_research_group/items/7QHZG7BP", "type": "text/html" } }, "meta": { "createdByUser": { "id": 1981188, "username": "auska945", "name": "", "links": { "alternate": { "href": "https://www.zotero.org/auska945", "type": "text/html" } } }, "creatorSummary": "Wang", "parsedDate": "2019", "numChildren": 3 }, "data": { "key": "7QHZG7BP", "version": 36728, "itemType": "thesis", "title": "Radiochemistry in microdroplets: technologies and applications", "creators": [ { "creatorType": "author", "firstName": "Jia", "lastName": "Wang" } ], "abstractNote": "Despite the increasing importance of positron emission tomography (PET) imaging in research and clinical management of disease, access to myriad new radioactive tracers is severely limited due to their short half-lives (which requires daily production) and the high cost and complexity of tracer production. Digital microfluidic radiosynthesizer technology can reduce the cost of equipment and facilities for tracer production, and could increase access to diverse tracers by reducing the cost of each batch (by reducing reagent consumption, reduced synthesis time, higher yield, etc.) and by enabling decentralized production closer to the point of use.Previously, our group has demonstrated that electrowetting on-dielectric (EWOD) microfluidic platform can be used to efficiently synthesize several tracers with minimal reagent usage and with high “specific activity”. However, widespread adoption of this new approach has not yet occurred in the field of radiochemistry, due in part to the operating complexity, suboptimal robustness (Teflon delamination, electrical breakdown of dielectric layer) and high cost of prototype chips. To address the robustness issue, one project I worked on was to optimize several aspects of the fabrication of EWOD chips (Teflon adhesion to dielectric layer, deposition of dielectric layer) to improve their reliability and then demonstrated the successful production of several tracers with the improved chips. However, even after optimization, the fabrication cost remained too high for use as a disposable components. To lower the cost, I developed a new, simpler microfluidic chip leveraging an alternative passive method of droplet manipulation method for tracer production. Cost was reduced through elimination of fabrication steps and reliability was increased due to elimination of electrodes and dielectric layers. After successful synthesis of several tracers, the chip was integrated with a fully-automated standalone [18F]fluoride concentrator to produce higher (clinically-relevant) amounts of clinical-grade tracer (i.e., that passes all quality control (QC) tests). Then, I developed an even further simplified microfluidic chip for microdroplet radiosynthesis and an ultra-compact system for operating the chips. A further advantage of this platform was that the reaction site was identical to that of the “model chips” we use for initial optimization when implementing syntheses in microdroplet format; this avoided the need for re-optimization when transitioning from optimization experiments to automated syntheses. To further reduce the time needed for reaction optimization, I also worked on developing some new methods and technologies (high-throughput radio-TLC analysis, high-throughput multi-reaction microfluidic chip) to enable radiochemistry to be performed in a high-throughput fashion. These techniques relieve operators from tedious and repetitive work and facilitate extensive synthesis optimization for new tracers in a short time-frame.Finally, I applied these new technologies (high-throughput optimization platform and the compact microdroplet reactor) for optimization and then automation of the synthesis of [18F]FDOPA.", "thesisType": "", "university": "UCLA", "place": "", "date": "2019", "series": "", "seriesNumber": "", "numPages": "", "DOI": "", "ISBN": "", "citationKey": "", "url": "https://escholarship.org/uc/item/70j622xm", "accessDate": "2020-04-28T04:14:27Z", "ISSN": "", "archive": "", "archiveLocation": "", "shortTitle": "Radiochemistry in microdroplets", "language": "en", "libraryCatalog": "escholarship.org", "callNumber": "", "rights": "", "extra": "", "tags": [], "collections": [ "NHI4JG3Z", "XJ9Y3QQP" ], "relations": { "dc:replaces": "http://zotero.org/groups/6185/items/APLGQ34Z" }, "dateAdded": "2020-04-28T04:14:27Z", "dateModified": "2026-04-15T07:05:59Z" } }, { "key": "D6TUZPI5", "version": 36726, "library": { "type": "group", "id": 6185, "name": "van Dam Research Group", "links": { "alternate": { "href": "https://www.zotero.org/groups/van_dam_research_group", "type": "text/html" } } }, "links": { "self": { "href": "https://api.zotero.org/groups/6185/items/D6TUZPI5", "type": "application/json" }, "alternate": { "href": "https://www.zotero.org/groups/van_dam_research_group/items/D6TUZPI5", "type": "text/html" }, "up": { "href": "https://api.zotero.org/groups/6185/items/DBBEAZAA", "type": "application/json" } }, "meta": { "createdByUser": { "id": 15552, "username": "mvandam", "name": "R. 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Michael van Dam", "links": { "alternate": { "href": "https://www.zotero.org/mvandam", "type": "text/html" } } }, "creatorSummary": "Jones", "parsedDate": "2021", "numChildren": 6 }, "data": { "key": "DBBEAZAA", "version": 36723, "itemType": "thesis", "title": "Microfluidic Tools for Radiochemical Analysis and High-throughput Radiopharmaceutical Development", "creators": [ { "creatorType": "author", "firstName": "Jason", "lastName": "Jones" } ], "abstractNote": "Positron emission tomography (PET) is a highly sensitive non-invasive imaging modality that uses small masses of radiolabeled “tracer” compounds to probe specific biochemical pathways within the whole body. PET is used extensively in clinical diagnostics, basic research, drug development, treatment monitoring, and in the new field of theranostics. To minimize radiation exposure to the radiochemist, the preparation (synthesis, purification and formulation) of PET tracers is performed using automated instruments known as radiosynthesizers. Because current systems are quite expensive, bulky (requiring operation in a specialized radiation-shielded hot cell) and consume tens to hundreds of times as much precursors and reagents compared to the amount of tracer needed for imaging, there has been intense interest in microfluidics in this field. A particular promising avenue has been the use of droplet-based radiochemistry platforms that can produce similar quantities as conventional systems, yet reduce volume and reagents by 100x, reduce synthesis times, and are small enough that they could be self-shielded and operated as a benchtop instrument in a normal laboratory. In addition to advantages for tracer production, this approach enables parallel syntheses by performing multiple reactions together on a single chip, paving the way to rapid, high-throughput radiochemistry for basic investigations, synthesis optimization, and tracer development. In one project, I designed a droplet chemistry heating platform involving a fast ceramic heater for accurate temperature control for a singular droplet synthesis. This initial platform was used in the development of the droplet synthesis of [18F]AMBF3-TATE, realizing an Isolated radiochemical yield (RCY) of 16�1% (n=5) with via isotopic exchange radiofluorination. I also developed a robotic system to perform fully-automated droplet reactions (up to 64 at a time). A Cartesian 3-axis gantry was built that could quickly move a fluidics head (for reagent dispensing and crude product collection) across a 20cm x 40cm workspace containing a set of four multi-reaction chips (each with 16 sites) each controlled by an independent heater, a pipette tip rack, microwell plates for reagents and reaction products, and a set of thin-layer chromatography (TLC) plates for reaction analysis. The system was extensively tested and characterized, and a scripting language was developed to allow high-throughput studies to be programmed as a series of intuitive operation sequences applied to sets of reaction sites. Consistency was assessed by performing a series of identical reactions (synthesis of [18F]Fallypride) which exhibited crude RCY of 79�5% (n=16). This was lower than the manual optimal conditions (90�1%, n=4), and with slightly higher variation. In a second project, I explored microfluidic technology related to the analysis of radiotracers. After the synthesis of a PET tracer, the resulting product must be purified, formulated in saline and finally must pass a number of quality control (QC) tests to ensure safety of the tracer and identity of the product. These tests are typically performed using equipment such as high-performance liquid chromatography (HPLC) which is an expensive instrument that requires significant table space for the device. We designed a “hybrid” capillary and PDMS microfluidic chip for the performance of these QC tests using capillary electrophoresis (CE). I helped develop a volumetric injection chip to inject a 4nL volume of analyte into the separation capillary in a highly repeatable manner. Using this device, injected sample peak relative standard deviation (RSD) was found from the UV absorbance detector electropherogram to be <1.5%, allowing for baseline separation (i.e. resolution > 1.5) of FLT from known synthesis impurities, and enabling impurity species to be quantified independently. The major limitation towards this device performing some of the required QC tests was the lack of a method for in situ radiation detection. Therefore, I added an avalanche photodiode (APD) to the previous device for the purpose of detecting radioactive species. This detector provides highly localized detection due to the short positron range and thus narrow peak widths in the radiation detector electropherogram. The radiation detector enabled confirmation of radiochemical identity, and radiochemical purity, and a limit of quantitation of 114 MBq/mL (3.1 mCi/mL), suitable for testing batches of tracers at higher levels of radioactivity concentration.", "thesisType": "", "university": "UCLA", "place": "", "date": "2021", "series": "", "seriesNumber": "", "numPages": "", "DOI": "", "ISBN": "", "citationKey": "", "url": "https://escholarship.org/uc/item/2gw749kt", "accessDate": "2024-12-11T07:15:08Z", "ISSN": "", "archive": "", "archiveLocation": "", "shortTitle": "", "language": "en", "libraryCatalog": "escholarship.org", "callNumber": "", "rights": "", "extra": "", "tags": [], "collections": [ "58V8I4WI", "NHI4JG3Z", "QN6WZ2SP", "XJ9Y3QQP" ], "relations": { "dc:replaces": [ "http://zotero.org/groups/6185/items/QYNNWVW5", "http://zotero.org/groups/6185/items/23Q7IKR7", "http://zotero.org/groups/6185/items/QJJYCJF8" ] }, "dateAdded": "2022-10-08T18:22:12Z", "dateModified": "2026-04-15T05:46:13Z" } }, { "key": "7H2ZBGBA", "version": 36718, "library": { "type": "group", "id": 6185, "name": "van Dam Research Group", "links": { "alternate": { "href": "https://www.zotero.org/groups/van_dam_research_group", "type": "text/html" } } }, "links": { "self": { "href": "https://api.zotero.org/groups/6185/items/7H2ZBGBA", "type": "application/json" }, "alternate": { "href": "https://www.zotero.org/groups/van_dam_research_group/items/7H2ZBGBA", "type": "text/html" }, "up": { "href": "https://api.zotero.org/groups/6185/items/DYL6FWSL", "type": "application/json" } }, "meta": { "createdByUser": { "id": 15552, "username": "mvandam", "name": "R. Michael van Dam", "links": { "alternate": { "href": "https://www.zotero.org/mvandam", "type": "text/html" } } } }, "data": { "key": "7H2ZBGBA", "version": 36718, "parentItem": "DYL6FWSL", "itemType": "attachment", "linkMode": "imported_url", "title": "Snapshot", "accessDate": "2021-11-14T05:55:30Z", "url": "https://escholarship.org/uc/item/2f26f3xg", "note": "", "contentType": "text/html", "charset": "utf-8", "filename": "2f26f3xg.html", "md5": "eaf12bd3b62922a3aeabf308e7281f9b", "mtime": 1636869330046, "tags": [], "relations": { "dc:replaces": "http://zotero.org/groups/6185/items/8PIYP9KL" }, "dateAdded": "2021-11-14T05:55:30Z", "dateModified": "2026-04-15T05:45:51Z" } }, { "key": "DYL6FWSL", "version": 36716, "library": { "type": "group", "id": 6185, "name": "van Dam Research Group", "links": { "alternate": { "href": "https://www.zotero.org/groups/van_dam_research_group", "type": "text/html" } } }, "links": { "self": { "href": "https://api.zotero.org/groups/6185/items/DYL6FWSL", "type": "application/json" }, "alternate": { "href": "https://www.zotero.org/groups/van_dam_research_group/items/DYL6FWSL", "type": "text/html" } }, "meta": { "createdByUser": { "id": 15552, "username": "mvandam", "name": "R. Michael van Dam", "links": { "alternate": { "href": "https://www.zotero.org/mvandam", "type": "text/html" } } }, "creatorSummary": "Lisova", "parsedDate": "2021", "numChildren": 3 }, "data": { "key": "DYL6FWSL", "version": 36716, "itemType": "thesis", "title": "Novel economical approaches for the fluorine-18 radiopharmaceuticals production via droplet radiochemistry", "creators": [ { "creatorType": "author", "firstName": "Ksenia", "lastName": "Lisova" } ], "abstractNote": "Positron emission tomography (PET) is a powerful medical diagnostics and research tool that uses radiolabeled molecules (tracers) to image biological processes in vivo. By administering only nanomolar quantities of the tracers, PET scans enable non-invasive assessment of normal biological processes in cells and their failure in disease to aid in medical diagnostics, staging of disease severity and monitoring treatment response. Short-lived radioisotopes used in the synthesis of diagnostic PET tracers necessitate that the tracer production is carried out shortly before imaging. Each production is a multistep process involving acquisition of the radioisotope, radiochemical synthesis and quality control. Radiochemical synthesis is further broken down into radiochemical reaction to link the radioisotope with a ligand, purification and formulation to obtain pure injection-ready product.Despite impressive sensitivity and accuracy of PET in medical diagnostics, access to the wide variety of short-lived radioactive tracers is hindered due to a high cost of their preparation. The overall preparation cost covers: (i) radiosynthesis units and various consumables, (ii) large shielded fume hoods (hot-cells), (iii) reagents and radioisotope, (iv) labor and safety. A typical centralized production of PET tracers in large radiochemistry facilities alleviates the high cost per production by splitting of the large batches and shipping those to multiple users, which is only possible for tracers in high demand such as [18F]fluorodeoxyglucose ([18F]FDG). Newly introduced dose-on-demand concept proposes convenient production of any tracer of interest directly at the imaging location, leading to a decentralized approach. While setting up dedicated conventional radiosynthesis modules for this purpose is unrealistic due to the high cost and large footprint, microfluidic approaches provide a path for a miniaturized, economical tracer production. Our lab among others has been extensively working on the radiosynthesis miniaturization using droplet microfluidic methods. Microfluidics offers potential of cost reduction in almost all aspects of radiosynthesis. (i) The synthesizer cost can be reduced as a result of reduced system size, complexity and consumables cost, (ii) the compact units can be self-shielded not requiring use of hot-cells, (iii) the reagent and radioisotope consumption per synthesis is orders of magnitude less, (iv) the faster synthesis times and small-scale production levels reduce labor burden and improve safety. Additionally, in fluorine-18 radiochemistry, the conventional synthesizers must use high starting radioactivity to ensure good molar activity (radioactivity per moles of the substance) of the final product. Previously, our group has developed automated droplet reactors based on electrowetting on dielectric (EWOD) technology. However, those devices had limitations due to high cost and complexity of fabrication. More recently, we introduced low-cost disposable silicon chips which serve as a reactor within an ultra-compact automated radiosynthesizer unit, comparable in size to a 12 oz. coffee cup. The major part of this dissertation was adapting various conventional fluorine-18-labeling synthesis methods to a droplet format to demonstrate the versatility of this radiosynthesis approach. For a number of tracers, we describe synthesis miniaturization process and demonstrate that the droplet syntheses exhibit higher yields and improved synthesis times in comparison to the conventional methods. All syntheses feature orders-of-magnitude reduction in reagent consumption and are able to achieve high molar activity even when lower starting amounts of the radioisotope are used. As a result, low cost per production can be achieved and such methods are readily useable for research in particular that involves small animal PET imaging. Importantly, we further demonstrate that these syntheses are scalable, and that production of a few human doses is feasible. For validation, we also perform full clinical quality control on these tracer batches. These results suggest that in the future it would be possible to introduce this technology in a clinical setting as well for an easy access to a wide variety of PET tracers. From the radiochemistry standpoint, microfluidic fluorine-18 radiolabeling has been shown to work for different type of ligands. Apart from small molecule radiolabeling, peptide labeling routes via droplet radiochemistry are also shown. In this work we feature isotopic exchange (IEX) fluorination that has a benefit of simplified purification but is challenging on conventional scale due to inherently lower molar activity in this type of reactions. We demonstrate that the droplet approach with its small volumes allows one to perform IEX synthesis of trifluoroborate-based peptides and prosthetic groups with high yields and molar activities. This dissertation presents reliable methods for fluorine-18-labeled radiopharmaceutical production on demand, in a time- and cost-efficient manner for diverse PET tracers. While with the current progress, these methods can be readily applied for research purposes including pre-clinical PET imaging, and future work will focus on improvements and optimization of the droplet microfluidic technologies to advance these methods to the clinical PET.", "thesisType": "", "university": "UCLA", "place": "", "date": "2021", "series": "", "seriesNumber": "", "numPages": "", "DOI": "", "ISBN": "", "citationKey": "", "url": "https://escholarship.org/uc/item/2f26f3xg", "accessDate": "2021-11-14T05:55:15Z", "ISSN": "", "archive": "", "archiveLocation": "", "shortTitle": "", "language": "en", "libraryCatalog": "escholarship.org", "callNumber": "", "rights": "", "extra": "", "tags": [], "collections": [ "NHI4JG3Z", "XJ9Y3QQP" ], "relations": { "dc:replaces": "http://zotero.org/groups/6185/items/GIET45PA" }, "dateAdded": "2021-11-14T05:55:15Z", "dateModified": "2026-04-15T05:45:51Z" } }, { "key": "P6YA7E6X", "version": 36713, "library": { "type": "group", "id": 6185, "name": "van Dam Research Group", "links": { "alternate": { "href": "https://www.zotero.org/groups/van_dam_research_group", "type": "text/html" } } }, "links": { "self": { "href": "https://api.zotero.org/groups/6185/items/P6YA7E6X", "type": "application/json" }, "alternate": { "href": "https://www.zotero.org/groups/van_dam_research_group/items/P6YA7E6X", "type": "text/html" }, "up": { "href": "https://api.zotero.org/groups/6185/items/P8KGBGDV", "type": "application/json" } }, "meta": { "createdByUser": { "id": 18231878, "username": "rsarker1", "name": "", "links": { "alternate": { "href": "https://www.zotero.org/rsarker1", "type": "text/html" } } }, "numChildren": 0 }, "data": { "key": "P6YA7E6X", "version": 36713, "parentItem": "P8KGBGDV", "itemType": "attachment", "linkMode": "imported_url", "title": "Full Text PDF", "accessDate": "2026-03-31T21:28:31Z", "url": "https://www.nature.com/articles/s41596-023-00890-z.pdf", "note": "", "contentType": "application/pdf", "charset": "", "filename": "Halder et al. - 2023 - Deoxyfluorination of phenols for chemoselective 18F-labeling of peptides.pdf", "md5": "0294cdd65e13c4dcc9c9492d5b62f450", "mtime": 1774992511480, "tags": [], "relations": { "dc:replaces": [ "http://zotero.org/groups/6185/items/7HXALTDG", "http://zotero.org/groups/6185/items/UA9HKKA6" ] }, "dateAdded": "2026-03-31T21:28:31Z", "dateModified": "2026-04-15T05:45:26Z" } }, { "key": "P8KGBGDV", "version": 36712, "library": { "type": "group", "id": 6185, "name": "van Dam Research Group", "links": { "alternate": { "href": "https://www.zotero.org/groups/van_dam_research_group", "type": "text/html" } } }, "links": { "self": { "href": "https://api.zotero.org/groups/6185/items/P8KGBGDV", "type": "application/json" }, "alternate": { "href": "https://www.zotero.org/groups/van_dam_research_group/items/P8KGBGDV", "type": "text/html" } }, "meta": { "createdByUser": { "id": 18231878, "username": "rsarker1", "name": "", "links": { "alternate": { "href": "https://www.zotero.org/rsarker1", "type": "text/html" } } }, "creatorSummary": "Halder et al.", "parsedDate": "2023-11", "numChildren": 1 }, "data": { "key": "P8KGBGDV", "version": 36712, "itemType": "journalArticle", "title": "Deoxyfluorination of phenols for chemoselective 18F-labeling of peptides", "creators": [ { "creatorType": "author", "firstName": "Riya", "lastName": "Halder" }, { "creatorType": "author", "firstName": "Gaoyuan", "lastName": "Ma" }, { "creatorType": "author", "firstName": "Jens", "lastName": "Rickmeier" }, { "creatorType": "author", "firstName": "James W.", "lastName": "McDaniel" }, { "creatorType": "author", "firstName": "Roland", "lastName": "Petzold" }, { "creatorType": "author", "firstName": "Constanze N.", "lastName": "Neumann" }, { "creatorType": "author", "firstName": "Jennifer M.", "lastName": "Murphy" }, { "creatorType": "author", "firstName": "Tobias", "lastName": "Ritter" } ], "abstractNote": "The challenge of forming C–18F bonds is often a bottleneck in the development of new 18F-labeled tracer molecules for noninvasive functional imaging studies using positron emission tomography (PET). Nucleophilic aromatic substitution is the most widely employed reaction to functionalize aromatic substrates with the radioactive fluorine-18 but its scope is restricted to arenes containing electron-withdrawing substituents. Furthermore, many protic functional groups are incompatible with basic fluoride anions. Peptide substrates, which are highly desirable targets for PET molecular imaging, are particularly challenging to label with fluorine-18 because they are densely functionalized and sensitive to high temperatures and basic conditions. To expand the utility of nucleophilic aromatic substitution with fluorine-18, we describe two complementary procedures for the radiodeoxyfluorination of bench-stable and easy-to-access phenols that ensure rapid access to densely functionalized electron-rich and electron-poor 18F–aryl fluorides. The first procedure details the synthesis of an 18F–synthon and its subsequent ligation to the cysteine residue of Arg–Gly–Asp–Cys in 10.5 h from commercially available starting materials (189-min radiosynthesis). The second procedure describes the incorporation of commercially available CpRu(Fmoc–tyrosine)OTf into a fully protected peptide Lys–Met–Glu–(CpRu–Tyr)–Leu via solid-phase peptide synthesis and subsequent ruthenium-mediated uronium deoxyfluorination with fluorine-18 followed by deprotection, accomplished within 7 d (116-min radiosynthesis). Both radiolabeling methods are highly chemoselective and have conveniently been automated using commercially available radiosynthesis equipment so that the procedures described can be employed for the synthesis of peptide-based PET probes for in vivo imaging studies according to as low as reasonably achievable (ALARA) principles.", "publicationTitle": "Nature Protocols", "publisher": "Nature Publishing Group", "place": "", "date": "2023-11", "volume": "18", "issue": "11", "section": "", "partNumber": "", "partTitle": "", "pages": "3614-3651", "series": "", "seriesTitle": "", "seriesText": "", "journalAbbreviation": "Nat Protoc", "DOI": "10.1038/s41596-023-00890-z", "citationKey": "", "url": "https://www.nature.com/articles/s41596-023-00890-z", "accessDate": "2026-03-31T21:28:28Z", "PMID": "", "PMCID": "", "ISSN": "1750-2799", "archive": "", "archiveLocation": "", "shortTitle": "", "language": "en", "libraryCatalog": "www.nature.com", "callNumber": "", "rights": "2023 Springer Nature Limited", "extra": "", "tags": [ { "tag": "Nuclear chemistry", "type": 1 }, { "tag": "Synthetic chemistry methodology", "type": 1 } ], "collections": [ "AFVTZQ2K", "QN6WZ2SP", "U7523I9Z" ], "relations": { "dc:replaces": [ "http://zotero.org/groups/6185/items/SYK3NX8D", "http://zotero.org/groups/6185/items/HTKTQQI2" ] }, "dateAdded": "2023-12-15T08:11:29Z", "dateModified": "2026-04-15T05:45:26Z" } }, { "key": "DMCRVJKE", "version": 36707, "library": { "type": "group", "id": 6185, "name": "van Dam Research Group", "links": { "alternate": { "href": "https://www.zotero.org/groups/van_dam_research_group", "type": "text/html" } } }, "links": { "self": { "href": "https://api.zotero.org/groups/6185/items/DMCRVJKE", "type": "application/json" }, "alternate": { "href": "https://www.zotero.org/groups/van_dam_research_group/items/DMCRVJKE", "type": "text/html" } }, "meta": { "createdByUser": { "id": 15552, "username": "mvandam", "name": "R. Michael van Dam", "links": { "alternate": { "href": "https://www.zotero.org/mvandam", "type": "text/html" } } }, "creatorSummary": "Lu", "parsedDate": "2023", "numChildren": 2 }, "data": { "key": "DMCRVJKE", "version": 36707, "itemType": "thesis", "title": "Preparation of positron emission tomography (PET) tracers on advanced microvolume platforms", "creators": [ { "creatorType": "author", "firstName": "Yingqing", "lastName": "Lu" } ], "abstractNote": "Positron emission tomography (PET) is a widely-used nuclear medicine imaging technique for assessing biodistribution of drugs, diagnosing diseases, and monitoring therapy response. The rapid development of new PET tracers in both research and clinical applications (to image new targets) demands new advances in radiolabeling techniques to facilitate the frequent production of diverse tracers. Recent developments in droplet-based radiochemistry have shrunk reaction volumes 100x (i.e. to <10 µL), offering advantages like minimal reagent use, rapid synthesis, high yields, and increased molar activity; they also enable high-throughput optimization and scalable production, with great potential to revolutionize radiopharmaceutical production. While our group has successfully utilized microdroplet reactors (a small Teflon-coated silicon chip containing hydrophilic reaction sites) for multiple different radiopharmaceuticals, exploration into metal-mediated radiosynthesis remains limited, primarily due to concerns about the sensitivity of metal reagents to environmental moisture in droplet-based reactors. As a proof-of-concept, I conducted the first microscale copper (Cu)-mediated synthesis of [18F]FDOPA (a clinical PET probe used for imaging dopaminergic function). Substantial enhancement in yield and time was achieved while utilizing only nanomole quantities of precursors and other reagents. Later, I explored the versatility of this method in optimizing additional tracers employing similar Cu-mediated 18F-radiolabeling routes on a high-throughput microdroplet reactor. For example, across 5 days, I conducted 117 reactions, exploring 36 conditions with <15 mg of precursor, and achieved 12x yield improvement for a novel monoacylglycerol lipase (MAGL) probe ([18F]YH149). Leveraging an automated robotic platform for high-throughput studies, we optimized the production of [18F]FBnTP, a potentiometric radiopharmaceutical, with 64 simultaneous droplet reactions in one morning. In addition, on the technology side, many researchers have wondered whether the droplet-based optimized conditions can guide reaction conditions in conventional vial-based reactors, and I demonstrated for the first time that this indeed can be done. This suggests a rapid and economical approach for novel tracer development, i.e., optimizing radiochemistry on a high-throughput microdroplet platform (rapidly, with minimal reagents) and then performing straightforward translation to vial-based systems to enable wider applicability to the existing install base of radiosynthesizer technology. Furthermore, to assess the adaptability of droplet-based radiochemistry in handling exceptionally complex syntheses, I undertook the investigation of a highly intricate three-step radiosynthesis of [18F]FMAU (imaging cell proliferation), encompassing radiofluorination, coupling, and deprotection reactions all within a microdroplet reactor. Compared the lengthy (~150 min) and low-yielding conventional production, the microdroplet-based radiosynthesis of [18F]FMAU provided significant improvement, completing the production in <60 min and achieving >2x higher radiochemical yield and >3x activity yield, while consuming 34-200x less reagents. Moreover, to establish the clinical relevance of droplet-based radiochemistry, we developed various droplet-based scale-up approaches including (i) iteratively loading and evaporating [18F]fluoride aliquots in a single droplet reaction, (ii) pre-concentrating [18F]fluoride in a miniature cartridge compatible with a single reaction site, and (iii) pooling multiple droplet reactions for on-demand dose. These methods, validated for reliability and versatility, successfully delivered clinically-relevant doses of [18F]FET (an amino acid tracer), [18F]Florbetaben (an amyloid imaging agent), [18F]FBnTP, isotopic exchange fluorinated compounds, and aluminum-[18F]fluoride probes. Apart from droplet-based radiosynthesis techniques, I also pursued other novel radiochemistry systems. I helped to develop a platform for microvolume reactions, featuring a pipettor on an XYZ motion gantry and a disposable cassette with integrated micro-vial. The versatile setup performs operations like trapping/releasing [18F]fluoride, liquid transfers, and lid installation/removal for reactor. Comprehensive experiments have been conducted to characterize the system and demonstrate the radiosynthesis feasibility, using [18F]Fallypride as an example. I also helped develop a novel electrochemical radiofluorination (ECRF) technique using a spilt bipolar electrode (s-BPE) for electron-rich compounds such as thioether derivatives. Unlike traditional ECRF which requires high salt concentration, this s-BPE system, with its dual conductive materials, facilitates anodic and cathodic reactions at lower salt concentrations. We achieved a 5x increase in molar activity for [18F]fluoromethyl (methylthio)acetate compared to conventional ECRF approaches, mainly attributed to reduced [19F]F- contamination from less salt. Radiochemistry in droplets and electrochemistry for [18F]fluoride labeling showcased an innovative optimization approach and scalable method for clinically-relevant production, surpassing conventional methods. The methodologies outlined in this dissertation provide a comprehensive pathway to speed up the transition of both established and novel PET tracers from the laboratory to clinical application swiftly and cost-effectively.", "thesisType": "", "university": "UCLA", "place": "", "date": "2023", "series": "", "seriesNumber": "", "numPages": "", "DOI": "", "ISBN": "", "citationKey": "", "url": "https://escholarship.org/uc/item/1fp031cf", "accessDate": "2025-06-15T01:26:18Z", "ISSN": "", "archive": "", "archiveLocation": "", "shortTitle": "", "language": "en", "libraryCatalog": "escholarship.org", "callNumber": "", "rights": "", "extra": "", "tags": [], "collections": [ "NHI4JG3Z", "XJ9Y3QQP" ], "relations": { "dc:replaces": "http://zotero.org/groups/6185/items/T2Y24HSF" }, "dateAdded": "2025-06-15T01:26:18Z", "dateModified": "2026-04-15T05:44:58Z" } }, { "key": "THDXDIEI", "version": 36704, "library": { "type": "group", "id": 6185, "name": "van Dam Research Group", "links": { "alternate": { "href": "https://www.zotero.org/groups/van_dam_research_group", "type": "text/html" } } }, "links": { "self": { "href": "https://api.zotero.org/groups/6185/items/THDXDIEI", "type": "application/json" }, "alternate": { "href": "https://www.zotero.org/groups/van_dam_research_group/items/THDXDIEI", "type": "text/html" }, "up": { "href": "https://api.zotero.org/groups/6185/items/F4I3PMDX", "type": "application/json" } }, "meta": { "createdByUser": { "id": 15552, "username": "mvandam", "name": "R. 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Michael van Dam", "links": { "alternate": { "href": "https://www.zotero.org/mvandam", "type": "text/html" } } }, "creatorSummary": "Śmiłowicz et al.", "parsedDate": "2023-04-17", "numChildren": 4 }, "data": { "key": "F4I3PMDX", "version": 36703, "itemType": "journalArticle", "title": "Radiometallation and photo-triggered release of ready-to-inject radiopharmaceuticals from the solid phase", "creators": [ { "creatorType": "author", "firstName": "Dariusz", "lastName": "Śmiłowicz" }, { "creatorType": "author", "firstName": "Shawn", "lastName": "Eisenberg" }, { "creatorType": "author", "firstName": "Shin Hye", "lastName": "Ahn" }, { "creatorType": "author", "firstName": "Angus J.", "lastName": "Koller" }, { "creatorType": "author", "firstName": "Philip P.", "lastName": "Lampkin" }, { "creatorType": "author", "firstName": "Eszter", "lastName": "Boros" } ], "abstractNote": "The efficient, large-scale synthesis of radiometallated radiopharmaceuticals represents an emerging clinical need which, to date, is inherently limited by time consuming, sequential procedures to conduct isotope separation, radiochemical labeling and purification prior to formulation for injection into the patient. In this work, we demonstrate that a solid-phase based, concerted separation and radiosynthesis strategy followed by photochemical release of radiotracer in biocompatible solvents can be employed to prepare ready-to-inject, clinical grade radiopharmaceuticals. Optimization of resin base, resin loading, and radiochemical labeling capacity are demonstrated with 67Ga and 64Cu radioisotopes using a short model peptide sequence and further validated using two peptide-based radiopharmaceuticals with clinical relevance, targeting the gastrin-releasing peptide and the prostate specific membrane antigen. We also demonstrate that the solid-phase approach enables separation of non-radioactive carrier ions Zn2+ and Ni2+ present at 105-fold excess over 67Ga and 64Cu by taking advantage of the superior Ga3+ and Cu2+ binding affinity of the solid-phase appended, chelator-functionalized peptide. Finally, a proof of concept radiolabeling and subsequent preclinical PET-CT study with the clinically employed positron emitter 68Ga successfully exemplifies that Solid Phase Radiometallation Photorelease (SPRP) allows the streamlined preparation of radiometallated radiopharmaceuticals by concerted, selective radiometal ion capture, radiolabeling and photorelease.", "publicationTitle": "Chemical Science", "publisher": "The Royal Society of Chemistry", "place": "", "date": "2023-04-17", "volume": "", "issue": "", "section": "", "partNumber": "", "partTitle": "", "pages": "", "series": "", "seriesTitle": "", "seriesText": "", "journalAbbreviation": "Chem. 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