| 1. |
Smart Data Analytics in Biomanufacturing (*Prize-Eligible) |
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Weike Sun |
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Braatz Group, Chemical Engineering,Massachusetts Institute of Technology |
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Although process data analytics is a valuable tool for improving the manufacturing of biologic drugs, selection of the best method requires a substantial level of expertise. This talk describes a robust and automated approach for process data analytics tool selection that allows the user to focus on goals rather than methods. The approach first applies tools to automatically interrogate the data to ascertain its characteristics, e.g., nonlinearity, correlation, dynamics. This information is then used to select a best-in-class process data analytics tool. The approach is demonstrated for industrial data for the manufacturing of a monoclonal antibody. |
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| 2. |
A Scalable Adenovirus Production Process, from Cell Culture to Purified Bulk |
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Yasser Kehail |
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GE Healthcare Life Sciences |
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Adenovirus (AdV) based vectors have been widely evaluated as vaccine delivery system in preclinical and clinical studies for various infectious diseases. Manufacturing of safe and efficacious clinical-grade virus relies on a scalable and cost-effective production process. Early-stage studies are often performed using anchorage-dependent cells cultured in roller bottles or cell factories. We have established an efficient and scalable process for AdV production using suspension HEK 293 cells cultivated in serum-free cell culture medium in a single use stirred-tank bioreactor. HEK 293 cells adapted to different cell culture media were evaluated for cell growth and virus productivity and a chemically defined serum-free medium was selected for further process development at bioreactor scale. Our process generated AdV titers at 10^9 infectious virus/mL in batch mode and demonstrated an efficient and robust process for adenovirus production in a single-use stirred-tank bioreactor. |
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| 3. |
A Toolbox for Bioprocess and Early Health Economics Modeling of Stem Cell therapies (*Prize-Eligible) |
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Catia Bandeiras |
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IDSS, MIT and DCI, BIDMC |
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In recent years, challenges in manufacturing and reimbursement of cell therapies have been highlighted by approvals of CAR-T based therapies for cancer and clinical trials involving stem cells for unmet medical needs. The manufacturing and supply chain of these therapies is very different than the typical drug manufacturing pipelines, due to the fact that cells are the product and are sensitive to external stress, as well as requiring expensive culture media and growth, labor-intensive tasks and extensive quality controls. Learning from CAR-T approvals, these therapies are approved at high prices to secure profit. In the development of these therapies, value can be assessed by combining early health economics modeling and manufacturing modeling. An open-source toolbox developed to combine these two approaches will be presented with clinical case studies, showcasing the need for manufacturing innovation together with clinical outcomes to make cell therapies more widely available. |
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| 4. |
Engineering In Vitro Tools for Cell Manufacturing and Drug Development in the Context of Myelin Disorders (*Prize-Eligible) |
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Daniela Espinosa Hoyos |
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Department of Chemical Engineering, MIT |
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Human oligodendrocytes (hOLs) hold great potential for cell therapies and in vitro studies of neurodegenerative disorders. Poor remyelination, due to hindered hOL migration, axon engagement, or maturation, is associated with poor nervous system function in diseases such as multiple sclerosis. Despite significant progress in hOL derivation technology, the length of protocols, heterogeneity of derived populations, low yields, and inefficiency of maturation remain significant limitations for application and scale-up of the technology in research and the clinic. Moreover, there is a lack of predictive pre-clinical models to assess the cells’ myelination potential and response to pro-myelinating treatments. Here we discuss the development of pre-clinical tools to study human myelination in vitro under near-physiological or pathological physicochemical conditions. Furthermore, we explore the existence of mechanosensitive pathways in the human oligodendrocyte lineage, which may shed light on new approaches to facilitate the path of hOLs and pro-myelination therapies to the clinic. |
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| 5. |
Container Closure Integrity Testing to Support the Storage of Cell and Gene Therapy Products at Ultra-Low-Storage Temperature (Cryogenic Temperature) |
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Liji Joseph |
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Pfizer |
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Sterile drug products require the establishment of a final container with sufficient integrity to prevent contamination. Many new biological products, such as cell and gene therapy products, require container closure systems to maintain integrity at ultra-low temperature (cryogenic temperature) storage conditions. No container closure integrity testing method or system is readily available “off-the-shelf” for the evaluation of container closure integrity (CCI) under the intended storage conditions, and there is a need to evaluate alternate CCI methods to establish an appropriate process for verifying integrity when the container closure systems are stored at cryogenic temperatures. We have developed a container closure integrity method using head space oxygen analysis. The results demonstrated that the method is capable of detecting an integrity failure (in comparison with positive controls included in the study) when stored at ultra-low storage temperatures. |
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| 6. |
CAR-T Cell Therapy Manufacturing: Modeling the Effect of Offshore Production on Aggregate Cost of Goods |
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Ezequiel Zylberberg and Bruce Levine |
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Akron Biotech |
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Cell and gene therapies have demonstrated excellent clinical results across a range of indications with Chimeric Antigen Receptor (CAR) T cell therapies among the first to reach market. Though these therapies are currently manufactured using patient-derived cells, therapies utilizing healthy donor cells are in development, which may offer avenues towards process simplification. The introduction of an allogeneic model could significantly reduce aggregate cost of goods (COG), potentially improving market penetration of these life-saving treatments. Furthermore, the shift towards offshore production may help reduce manufacturing costs. In this paper, we examine production costs of an allogeneic CAR-T cell process and the potential differential manufacturing costs between regions. Two offshore locations are compared to regions within the United States. The critical findings of this paper identify the COG challenges facing manufacturing of allogeneic CAR-T immunotherapies, how these may evolve if production is offshored, and the wider implication this trend could have. |
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| 7. |
A Novel Technology Platform for Fast Access to High-Quality iPS cells |
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Klaus Graumann |
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Phoenestra |
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Cell-based therapies are currently revolutionizing the way how medicines are being developed or currently incurable diseases are treated. Induced Pluripotent Stem Cells (iPSCs) are increasingly being used to fuel these approaches, however access to cells with reproducibly correct quality and in the needed quantities is often limited. Phoenestra is currently setting up a technology platform to generate genetically stable iPSC from selected donors (HLA profile or disease type) with a targeted quality profile and in the needed amounts. With its proprietary cell source (renal cells from human urine), proven technical capabilities and experienced founding team, Phoenestra is more than well-positioned to make a difference in supplying high-quality iPSCs according to the needs of partners and customers. The poster presentation will provide some background on Phoenestra´s technology platform and the opportunities we see beyond iPS cell clones and cell banks. |
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| 8. |
High-Throughput 5'-UTR Engineering for Enhanced Protein Expression in Gene Therapy (*Prize-Eligible) |
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Jicong Cao |
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Tim Lu Lab, Synthetic Biology Center, MIT |
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Gene therapy holds the promise of treating diseases that cannot be treated using traditional small molecule or protein drugs. The in vivo drug expression levels depend highly on the genetic elements near the coding region. In this work, we developed a comprehensive strategy to identify novel 5’-untranslated region (5’UTR) sequences that can enhance protein expression from the human cytomegalovirus (CMV) promoter in human muscle cells. We designed a library of 12,000 5’UTR sequences based on genomic searches and in silico computation, and a novel recombinase-based library screening strategy. Compared with the traditional lentiviral infection-based library screening method, the recombinase-based library screening strategy can truly eliminate the copy number and position effects. We identified three candidates that can improve protein expression by greater than 2-fold in human muscle cells. We envision these synthetic UTRs can be used to enhance in vivo drug productivity for DNA vaccines, AAVs and mRNA therapeutics. |
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| 9. |
Mechanistic Modeling and Parameter-Adaptive Nonlinear Model Predictive Control of a Microbioreactor (*Prize-Eligible) |
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Moo Sun |
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Braatz Group, Department of Chemical Engineering,, MIT |
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Microbioreactors are a promising innovative technology to accelerate biologic drug development. In aerobic cellular respiration, one potential limit to the productivity of such systems is the transport of oxygen from an external gas to the most oxygen-deficient cells, whereas another limit is the potential for excessive spatially localized dissolved oxygen, which can result in cellular damage. In this work, a mechanistic model is constructed for the spatiotemporal transport of oxygen through a gas-permeable membrane to the cells within a microbioreactor. An analytical solution to the partial differential equations for oxygen transport is derived using the Finite Fourier Transform method. A parameter-adaptive extended Kalman filter is shown to produce highly accurate estimates of the oxygen uptake rate of the cells. The estimates are fed to a model predictive control formulation that improves the spatial control of dissolved oxygen during cell growth by more than 30% compared to a traditional controller. |
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| 10. |
Application of Deterministic Lateral Displacement in a Closed System to Streamline Therapeutic Cell Manufacturing |
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Jason Walsh and Tony Ward |
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GPB Scientific |
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Autologous cell therapies are increasingly viewed as providing exceptional potential for personalized treatments. However, broad deployment is limited by the lack of stable and specific automated unit operations solutions.
GPB Scientific is employing a fully-closed microfluidic process, Deterministic Lateral Displacement (DLD), to achieve superior cell separation, debulking, washing, concentration, and media exchange on a single platform. A DLD system will automate cell handling processes from apheresis clean-up to final formulation, resulting in simplified and automatable workflows that are highly reproducible while maximizing shop-floor operations.
Anticipated benefits of the technology include:
- De-skilling and automating the post-apheresis isolation
- Reducing cell loss, improving point-of-collection cost and patient care
- Improving cell quality, enhancing cell manufacturing outcomes
- Reducing overall cost, accelerating deployment of therapies and patient access.
Examples showing key benefits of GPB’s approach, specifically addressing CAR-T cell manufacturing issues, will be presented. |
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| 11. |
Development of Bench Scale Bioreactor Process for Transient Lentivirus Production using Suspension Adapted HEK293T Clone |
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Sonal Patel, Onur Kas, and Ashish Saksule |
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MilliporeSigma |
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In recent years, the use of lentiviral vectors for gene therapy applications has become increasingly popular. As a result, there has been an increased demand for manufacturing of these viral vectors in large volumes for clinical trials. Current production processes are labor-intensive and make use of adherent flat stock cultures. Bioreactors enable production of large volumes of viral vectors with improved environmental control (pH, dissolved oxygen, mixing and temperature) and reduced production costs. Here, we describe the development of a bench scale bioreactor suspension-based transient lentivirus production process. The effects of pH, dissolved oxygen and mixing on growth of the cells and viral vector production were tested in 3L Mobius® CellReady single-use bioreactors. Optimal process parameters were defined for growth and lentivirus production phases, and the bench-scale bioreactor lentivirus production process has been shown to yield similar functional titers to the adherent, serum-containing lentivirus process. |
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| 12. |
Biomanufacturing Functionalized Green Gold Nanoparticles Using a Hydroxylated Tetraterpenoid for Anti-Cancer Applications (*Prize-Eligible) |
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Jiulong Li, Bing Tian, and Thomas J Webster |
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Department of Chemical Engineering, Webster Nanomedicine Laboratory, Northeastern University |
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Gold nanoparticles (AuNPs) are a type of especially promising candidate nanomaterials for biomanufacturing cell or gene therapeutic products due to their ease of synthesis, versatility in surface modification and relative cyto/biocompatibility. Functionalized AuNPs are especially useful for therapeutic strategies for cancer. Understanding the manufacturing mechanisms and cell–nanoparticle interactions is important for the use of AuNPs. Here, we detail the biotransformation mechanism of Au(III) into AuNPs using hydroxylated deinoxanthin (DX) from the extremophile Deinococcus radiodurans, which is attributed to the deprotonation of the hydroxyl groups of DX. The functionalized DX–AuNPs exhibited significant anticancer activity by altering gene expression levels and affecting cell membrane integrity and metabolism, inducing ROS generation, autophagy, and apoptosis in cancer cells. These novel findings provide significant insight into the biomanufacturing mechanism of green AuNPs functionalized with natural products, which possess enhanced anticancer activity. The biomanufactured AuNPs could have therapeutic potential in the treatment of cancer. |
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| 13. |
CAR-37 T Cells Manufacturing Process Development with CliniMACS Prodigy System (*Prize-Eligible) |
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Irene Scarfo and Alena Chekmasova |
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Cellular Immunotherapy Program, Massachusetts General Hospital Cancer Center |
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A CAR-37 T cells manufacturing process was developed at the Dana-Farber GMP Manufacturing Facility using the CliniMACS Prodigy system. As part of the CAR-37 process development, three training runs were conducted using the same process and equipment intended for GMP manufacture, but using cells obtained from healthy donors, in place of autologous cells from study subjects. For all runs, PBMCs were collected from healthy donors via leukapheresis. Development lots of anti-CD37 CAR lentiviral vector were used to transduce the cells for training runs. The final CAR T cell drug product was tested in vitro and in vivo in comparison to small- scale manufacturing. The current data, in combination with the in-process data, indicate the successful implementation of the CAR-37 manufacturing process using CliniMACS Prodigy system. The successful completion of the three training runs demonstrate reproducibility of the CAR-37 manufacturing process as well as capability to manufacture CAR-37 T cells for clinical use. |
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| 14. |
Projections from the Existing Pipeline of Gene and Cellular Therapies: Launches and Patient Numbers |
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Johnathan Thomas |
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Center for Biomedical Innovation, NEWDIGS, FoCUS Project, MIT |
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Our objective in this analysis was to estimate from the existing trials pipeline, at the indication level, durable gene and cellular therapy new product launches in the US through 2030, and the number of potentially treatable patients. We conclude that the next 12 years will likely see significant changes in the US healthcare system with major improvements in the treatment paradigms for numerous diseases that previously had high morbidity and mortality. These will require the overall system to adapt, particularly in terms of how treatments are reimbursed and financed, as we move from chronic palliative therapies to acute curative ones. Tools for precision financing need to be developed and in place so as to address these challenges when they arise. |
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| 15. |
Economic Evaluation of Manufacturing Options for Biologic Therapies |
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Donovan Guttieres |
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Center for Biomedical Innovation, BioACCESS, MIT |
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Sustained access to high-quality, affordable medicines continues to be a global unmet need. Barriers are found across the supply-side and demand-side of the value-chain, leading to increased costs and preventable deaths. More specifically, biologics have unique molecular and manufacturing features that jeopardize widespread access. Innovations have the potential to address these barriers, but tools are needed to determine the best use of resources, design of policies, and scale of technologies that will have the most cost-effective impact. While the biologics market and manufacturing industry have historically been concentrated to several geographic locations (i.e. US, Europe and Japan), various factors have led to an increased interest in decentralized systems. This research investigates the optimal location and allocation of manufacturing capacity that maximizes supply security by presenting models for 1) location selection, 2) cost-of-goods analysis, 3) risk forecasting, and 4) testing innovations. A case study using Trastuzumab evaluates tradeoffs across different manufacturing options, while a discussion highlights potential application of these tools for cell-and-gene therapies. |
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| 16. |
Semi-Rational Design of Steroid Biosensors Using Compositionally Controlled Corona Phase Molecular Recognition (*Prize-Eligible) |
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Michael Lee |
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Strano Lab, Department of Chemical Engineering, MIT |
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By controlling gene expression, steroid hormones alter cellular protein production and thus may be critical ingredients in certain bioprocesses. Real-time, continuous measurements of these steroids may provide critical control data for bioprocesses. In this study, we applied Corona Phase Molecular Recognition (CoPhMoRe) using near-infrared, fluorescent single walled carbon nanotubes (SWNT) non-covalently functionalized with polymers for steroid detection. A templating strategy was employed in the semi-rational design of the polymers. Twenty polymers varying in monomer composition were synthesized and interfaced with SWNT to create a sensor library, which was screened against 9 steroid hormones selected for their biological significance. Design principles were established by tracking sensor response against polymer composition. Two constructs selective for cortisol and progesterone were discovered. The progesterone sensor was encapsulated in a biocompatible hydrogel and shown to function in a biological environment. Upon implantation, the hydrogels were shown to be responsive to local progesterone levels. |
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| 17. |
Development of Carbon Nanotube Sensors Towards In Vivo Analyte Detection (*Prize-Eligible) |
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Naveed Bakh |
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Strano Lab, Department of Chemical Engineering, MIT |
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The development of carbon nanotube based sensors, where amphiphilic polymers on the nanotube surface screen the interaction between analytes and the nanotube in an effect known Corona Phase Molecular Recognition (CoPhMoRe), provides an opportunity for long term in vivo biomonitoring of analytes due to their near infrared fluorescence. In this work, we develop a platform to track an intensity- modulated sensor response to the administration of riboflavin in mice. Hydrogel encapsulation of the nanotubes allows for the diffusion of small molecules, such as riboflavin, to reach the corona of the nanotube sensors, while maintaining the sensors in a localized patch for repeated imaging. A wide-field-of-view imaging setup allows for spatiotemporal imaging of the hydrogel patches. |
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| 18. |
Amplification-Free Adventitious Agent Detection by Cascade Nanofluidic Concentrator (*Prize-Eligible) |
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Wei Ouyang |
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Department of Electrical Engineering and Computer Science, Research Lab of Electronics, MIT |
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We will present a cascade nanofluidic concentrator for the rapid and reliable detection of ultra-low-abundance adventitious agents during biomanufacturing. By concentrating target nucleic acids from ~10 mL to ~10 pL (with background protein simultaneously removed), we are able to achieve near billion-fold concentration of nucleic acids and subsequent in situ detection. This method matches the amplification capacity of PCR, but is fast (30 min), reagent-free, multiplex-able, and not prone to non-target amplification. It can potentially be implemented at-line for near real-time monitoring of biomanufacturing. |
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| 19. |
Bionanosensors for Real-Time Assessment & Treatment Monitoring in Cancer (*Prize-Eligible) |
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Freddy Nguyen |
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Department of Electrical Engineering and Computer Science, Research Lab of Electronics, MIT |
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Brain tumors are the most common form of pediatric solid tumors affecting ~20% of all pediatric cancers. Current management follows a multipronged approach that include surgery, radiation, and chemotherapy. There is a pressing need for a platform to provide precision chemotherapy screening to increase survival rates, reduce adverse effects, and lower overall costs. Endogenous H2O2 and NO are involved in numerous signaling pathways that contribute to the initiation, progression, metastasis, and regression of cancer. Being able to measure in real-time and in vivo, the concentrations of NO and H2O2 during tumor initiation, progression, and regression will be crucial to better understand their roles in cancer metabolism. We recently developed a series of nIR fluorescent probes for NO and H2O2 using single-walled carbon nanotubes. We also present novel bionanosensors for some of the major chemotherapeutic drugs in brain cancers (AIC, an inactive byproduct of degradation of temozolomide; irinotecan; cisplatin; and lomustine). |
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| 20. |
VHU Perfusion for Scalable Lentiviral Production |
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Maurizio Cattaneo |
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Artemis Biosystems |
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Artemis Biosystems has developed a scaleable perfusion process based on its VHU technology for lentiviral vector production. The VHU Perfusion system was tested at NRC using a stable inducible HEK293 cell line for LV production. The VHU Perfusion system allowed unprecedented LV yield compared to the BioSep system. A 30-fold improvement in functional vector yield compared to batch mode was observed. |
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| 21. |
Real-Time Microbial Detection for Biomanufacturing |
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Nicholas Brancazio |
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Fluid-Screen |
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Throughout the production of next generation pharmaceuticals, prevention of microbial contamination is crucial. Standard growth-based detection methods require a minimum 14-day incubation, a period which often exceeds the shelf-life and delays release of cell therapies, gene therapies, and CAR-T treatments (1). To improve patient safety and increase efficiency of drug production, new real-time microbial detection methods are required.
Fluid-Screen aims to enable real-time sterility testing by capturing and identifying microbial contaminants in 30 minutes. This method utilizes dielectrophoresis (DEP) and electroosmosis (EO), electromagnetic phenomena which influence particle motion in fluids. Fluid-Screen has designed a novel electrode configured with a high-volume throughput microfluidic chip which induces electric field gradients to utilize DEP and EO for high efficiency microbial capture. Pilot studies have demonstrated separation of Escherichia coli and Mycoplasma species from mammalian cell culture, label-free microbial viability, and >99% bacterial capture efficiency.
Fluid-Screen presents a microbial capture technology that for the first time is suitable for high precision sterility testing. Culture-free microbial detection will allow for real-time results, allowing previously un-testable bioproducts for cell and gene therapies to be tested before expiration, thus increasing product yield and patient safety. With faster detection capabilities than current methods, Fluid-Screen demonstrates the potential to establish a 30 minute maximum for microbial detection in biomanufacturing.
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| 22. |
Move over Matrigel: Assessing Intestinal Organoid Drug Response in a Well-Defined 3D Microenvironment (*Prize-Eligible) |
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Victor Hernandez-Gordillo |
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Center for Gynepathology Research, Biological Engineering Department, MIT |
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Intestinal organoids have similar microarchitecture and function to native tissue. They have gained relevance as a tool in preclinical drug discovery. For instance, forskolin-induced swelling is currently used to asses drug response in organoids derived from Cystic Fibrosis patients. Similarly, organoids have been used to investigate intestinal wound repair upon prostaglandin E2 (PGE2) stimulation. Matrigel, an ill-defined commercial hydrogel that contains numerous residual growth factors and cytokines, is the preferred substrate for drug discovery applications. Exactly how these soluble factors could impact drug discovery (either synergist or antagonist with the test drug) is unknown. To solve this limitation, we designed a synthetic matrix that can support human and mouse intestinal organoids. Here, we show that that human-derived intestinal organoids in the synthetic matrix have similar response to forskolin PGE2 as organoids emerging in Matrigel. Upon forskolin or PGE2 stimulation, organoids increased in size on average 1.2 to 1.6 times in the synthetic matrix or Matrigel. Further, the synthetic matrices will be used to investigate autocrine and paracrine signaling loops from within the hydrogel that might occur during intestinal organoid drug response that is not currently possible when using Matrigel. |
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