Cell Manufacturing Process Research Articles

A Condition Change Detection Method for Solar Conversion Efficiency in Solar Cell Manufacturing Processes

A solar cell manufacturing process typically has multiple, serial fabrication stages. In general, there are limited quality inspection and control points along the multiple fabrication stages, resulting in inconsistent product quality at the final stage. The existing studies on solar cell manufacturing focus on offline quality monitoring after completion of all manufacturing stages. Thus, an effective in-process method of detecting changes in key stages in terms of product quality is necessary to mitigate the effect of the quality fluctuation. This paper proposes an in-process method of detecting the process changes in terms of product quality by studying multichannel sensing signals collected in the epitaxy stage. This stage is an important stage of material layer formation and considerably influences the solar conversion efficiency of the final product. Interpretable geometric features are obtained by considering the process knowledge for each channel of sensing data. A decision-level data fusion method is further proposed to integrate the changes detected from each sensing signal. The proposed method is demonstrated via a real case from solar cell manufacturing processes.

Rapid Manufacture and Isolation of Highly Viable Interferon-γ Expressing Virus-Specific T Cells: Validation Results for the Virus-Specific Cytotoxic T-Lymphocyte Consortium for Refractory EBV, CMV, and Adenovirus Infections

Background Children and young adults who develop treatment-refractory infection with EBV, CMV, and/or adenovirus (AdV) after allogeneic hematopoietic stem cell transplant (allo-HSCT) have a dismal prognosis (≥90% mortality). Adoptive transfer of ex-vivo expanded virus-specific cytotoxic T lymphocytes (CTLs) is a treatment option for these patients, but the cell manufacturing process is labor-intensive and typically takes several weeks of culturing to complete. More recently, a culture-free method has been developed to directly isolate virus-specific T cells from peripheral blood for adoptive transfer. The process is fully automated using the CliniMACS Prodigy device (Miltenyi Biotec), a cGMP-compliant, temperature-controlled, closed system. Importantly, virus-specific T cells ready for infusion can be isolated with Methods Peripheral blood mononuclear cells from volunteer donors were stimulated with PepTivators (CMV, EBV, and/or AdV), followed by isolation of the virus-specific T cells using the interferon-γ (IFNγ) cytokine capture system (CCS) on the CliniMACS Prodigy device (n=11). Expression of lineage and T-cell subset markers, IFNγ, and cell viability were determined by flow cytometry. Results The viability of recovered T cells was remarkably and consistently high (92.9% ± 7.4%, Table 1). The number of recovered viable T cells was 5.03 × 106 ± 5.09 × 106. The purity of IFNγ+ cells was 69.0% ± 23.8% for CD4 T cells and 82.9% ± 15.3% for CD8 T cells. At a dose of 2.5 × 104 T cells/kg, the mean T cell collection for a 70 kg recipient would suffice for 3 separate infusions. Conclusion The results presented here show that manufacture of virus-specific CTLs by the CCS method reproducibly produced sufficient quantities of viable T cells for patient treatment. These results thus support the feasibility of the multicenter VIRCTLC trial. The trial is currently enrolling patients.

Toward the development of true "off-the-shelf" synthetic T-cell immunotherapy.

Recent outstanding clinical results produced by engineered T cells, including chimeric antigen receptors, have already facilitated further research that broadens their applicability. One such direction is to explore new T cell sources for allogeneic “off‐the‐shelf” adoptive immunotherapy. Human pluripotent stem cells could serve as an alternative cell source for this purpose due to their unique features of infinite propagation ability and pluripotency. Here, we describe the current state of engineered T cell transfer with the focus on cell manufacturing processes and the potentials and challenges of induced pluripotent stem cell‐derived T cells as a starting material to construct off‐the‐shelf T‐cell banks.

Keeping the Engine Running: The Relevance and Predictive Value of Preclinical Models for CAR-T Cell Development.

The cellular immunotherapy field has achieved important milestones in the last 30 years towards the treatment of a variety of cancers due to improvements in ex-vivo T cell manufacturing processes, the invention of synthetic T cell receptors, and advances in cellular engineering. Here, we discuss major preclinical models that have been useful for the validation of chimeric antigen receptor (CAR)-T cell therapies and also promising new models that will fuel future investigations towards success. However, multiple unanswered questions in the CAR-T cell field remain to be addressed that will require innovative preclinical models. Key challenges facing the field include premature immune rejection of universal CAR-T cells and the immune suppressive tumor microenvironment. Immune competent models that accurately recapitulate tumor heterogeneity, the hostile tumor microenvironment, and barriers to CAR-T cell homing, toxicity, and persistence are needed for further advancement of the field.

Development and validation of broad-spectrum magnetic particle labelling processes for cell therapy manufacturing

BackgroundStem cells are increasingly seen as a solution for many health challenges for an ageing population. However, their potential benefits in the clinic are currently curtailed by technical challenges such as high cell dose requirements and point of care delivery, which pose sourcing and logistics challenges. Cell manufacturing solutions are currently in development to address the supply issue, and ancillary technologies such as nanoparticle-based labelling are being developed to improve stem cell delivery and enable post-treatment follow-up.MethodsThe application of magnetic particle (MP) labelling to potentially scalable cell manufacturing processes was investigated in a range of therapeutically relevant cells, including mesenchymal stromal cells (MSC), cardiomyocytes (CMC) and neural progenitor cells (ReN). The efficiency and the biological effect of particle labelling were analysed using fluorescent imaging and cellular assays.ResultsFlow cytometry and fluorescent microscopy confirmed efficient labelling of monolayer cultures. Viability was shown to be retained post labelling for all three cell types. MSC and CMC demonstrated higher tolerance to MP doses up to 100× the standard concentration. This approach was also successful for MP labelling of suspension cultures, demonstrating efficient MP uptake within 3 h, while cell viability was unaffected by this suspension labelling process. Furthermore, a procedure to enable the storing of MP-labelled cell populations to facilitate cold chain transport to the site of clinical use was investigated. When MP-labelled cells were stored in hypothermic conditions using HypoThermosol solution for 24 h, cell viability and differentiation potential were retained post storage for ReN, MSC and beating CMC.ConclusionsOur results show that a generic MP labelling strategy was successfully developed for a range of clinically relevant cell populations, in both monolayer and suspension cultures. MP-labelled cell populations were able to undergo transient low-temperature storage whilst maintaining functional capacity in vitro. These results suggest that this MP labelling approach can be integrated into cell manufacturing and cold chain transport processes required for future cell therapy approaches.

Commercial Scale Manufacturing of Allogeneic Cell Therapy.

Allogeneic cell therapy products are generating encouraging clinical and pre-clinical results. Pluripotent stem cell (PSC) derived therapies, in particular, have substantial momentum and the potential to serve as treatments for a wide range of indications. Many of these therapies are also expected to have large market sizes and require cell doses of ≥109 cells. As therapeutic technologies mature, it is essential for the cell manufacturing industry to correspondingly develop to adequately support commercial scale production. To that end, there is much that can be learned and adapted from traditional manufacturing fields. In this review, we highlight key areas of allogeneic cell therapy manufacturing, identify current gaps, and discuss strategies for integrating new solutions. It is anticipated that cell therapy scale-up manufacturing solutions will need to generate batches of up to 2,000 L in single-use disposable formats, which constrains selection of currently available upstream hardware. Suitable downstream hardware is even more limited as processing solutions from the biopharmaceutical field are often not compatible with the unique requirements of cell therapy products. The advancement of therapeutic cell manufacturing processes to date has largely been developed with a cell biology driven approach, which is essential in early development. However, for truly robust and standardized production in a maturing field, a highly controlled manufacturing engineering strategy must be employed, with the implementation of automation, process monitoring and control to increase batch consistency and efficiency.

In-process evaluation of culture errors using morphology-based image analysis.

IntroductionAdvancing industrial-scale manufacture of cells as therapeutic products is an example of the wide applications of regenerative medicine. However, one bottleneck in establishing stable and efficient cell manufacture is quality control. Owing to the lack of effective in-process measurement technology, analyzing the time-consuming and complex cell culture process that essentially determines cellular quality is difficult and only performed by manual microscopic observation. Our group has been applying advanced image-processing and machine-learning modeling techniques to construct prediction models that support quality evaluations during cell culture. In this study, as a model of errors during the cell culture process, intentional errors were compared to the standard culture and analyzed based only on the time-course morphological information of the cells.MethodsTwenty-one lots of human mesenchymal stem cells (MSCs), including both bone-marrow-derived MSCs and adipose-derived MSCs, were cultured under 5 conditions (one standard and 4 types of intentional errors, such as clear failure of handlings and machinery malfunctions). Using time-course microscopic images, cell morphological profiles were quantitatively measured and utilized for visualization and prediction modeling. For visualization, modified principal component analysis (PCA) was used. For prediction modeling, linear regression analysis and the MT method were applied.ResultsBy modified PCA visualization, the differences in cellular lots and culture conditions were illustrated as traits on a morphological transition line plot and found to be effective descriptors for discriminating the deviated samples in a real-time manner. In prediction modeling, both the cell growth rate and error condition discrimination showed high accuracy (>80%), which required only 2 days of culture. Moreover, we demonstrated the applicability of different concepts of machine learning using the MT method, which is effective for manufacture processes that mostly collect standard data but not a large amount of failure data.ConclusionsMorphological information that can be quantitatively acquired during cell culture has great potential as an in-process measurement tool for quality control in cell manufacturing processes.

Abstract 3577: Application of deep IL-15 backpacks to human T cells demonstrates tunable loading with enhanced cell proliferation and antitumor activity

Abstract Cell therapies have demonstrated clinical benefit for some patients; however, in more resistant tumors, efficacy, persistence, and cell expansion may be improved with co-administration of an inflammatory cytokine such as interleukin 15 (IL-15). Clinical use of IL-15 has been limited due to systemic toxicity resulting in a narrow therapeutic index. Torque has advanced a “backpack” technique to attach IL-15 to the surface of T cells for adoptive transfer. IL-15 backpacks are ~120 nanometer particles consisting of multiple chemically crosslinked human IL-15/IL-15Rα/Fc heterodimers. Following crosslinker cleavage the IL-15 fusion proteins are released and drive T cell division in an autocrine fashion, providing a targeted, controllable and time-dependent immune stimulus which we term Deep Priming. Torque's lead program, TRQ15-01, consists of antigen-directed, autologous T cells carrying IL-15 backpacks. To explore the effects of IL-15 backpacks on T cells, we characterized backpack-carrying capacity of T cells, IL-15 heterodimer release kinetics, and T cell expansion by incubating IL-15 backpacks with human T cells activated by CD3/CD28 beads. Across 4 donors, T-cells were loaded in a reproducible manner proportional to the backpack labeling solution concentration. Backpacks promote the exponential expansion of activated T-cells for over one week through sustained release of IL-15 into the extracellular space. To explore the effect of IL-15 backpacks on CAR-T cell activity, IL-15 backpacks were loaded onto anti-EGFR CAR-expressing human CD3 cells. NSG mice bearing human H1299 tumor xenografts received CAR-T therapy with and without backpacks 7 days after tumor implantation. IL-15 backpacks significantly improved in vivo expansion of CAR-T cells (p < 0.008, at Day 10) and improved tumor growth inhibition (p < 0.003, 2-way ANOVA). To enable exploration of the clinical utility of backpacking using antigen-directed T-cells, we developed a novel, fully-closed, semi-automated cell manufacturing process with a yield of up to several billion antigen-directed cells. This process utilizes monocyte-derived dendritic cells pulsed with peptides from multiple tumor-associated antigens to expand cytotoxic T lymphocytes (CTLs). In a final step the antigen-directed CTLs are loaded with IL-15 backpacks to generate the TRQ15-01 cell product. Characterization of TRQ15-01 reveals controllable, dose-dependent loading of IL-15 backpacks on the antigen-directed T cells. Compared to non-backpacked antigen-directed cells, TRQ15-01 products displayed significantly higher expansion levels both in vitro (10-fold increase) and in NSG mice (20-fold increase). IL-15 backpack loading on human T cells is tunable and produces slow IL-15 release with sustained cell expansion and enhanced anti-tumor activity. Clinical trials with TRQ15-01 will be initiated in 2018. Citation Format: Pengpeng Cao, De-Kuan Chang, Andy Rakestraw, Amy Shaw, Ferdinando Pucci, Fabio Fachin, Christine McInnis, Shawn Carey, Austin Boesch, David Chirgwin, Carlos Tassa, Aaron Handler, Khristianna Jones, Philip D. Bardwell, Elena Geretti, Jon Nardozzi, Doug Jones, Jesse Lyons, Jonathan B. Fitzgerald, Becker Hewes, Ulrik B. Nielsen, Thomas Andresen. Application of deep IL-15 backpacks to human T cells demonstrates tunable loading with enhanced cell proliferation and antitumor activity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3577.

Optimizing the Organic Solar Cell Manufacturing Process by Means of AFM Measurements and Neural Networks

In this paper we devise a neural-network-based model to improve the production workflow of organic solar cells (OSCs). The investigated neural model is used to reckon the relation between the OSC’s generated power and several device’s properties such as the geometrical parameters and the active layers thicknesses. Such measurements were collected during an experimental campaign conducted on 80 devices. The collected data suggest that the maximum generated power depends on the active layer thickness. The mathematical model of such a relation has been determined by using a feedforward neural network (FFNN) architecture as a universal function approximator. The performed simulations show good agreement between simulated and experimental data with an overall error of about 9%. The obtained results demonstrate that the use of a neural model can be useful to improve the OSC manufacturing processes.

Development and Evaluation of in-Situ Instrumentation for Li-Ion Cells

This work demonstrates the development and evaluation of sensing technology for monitoring the distributed in-situ in-operando temperature of lithium-ion cells. The influence of the sensing element on the electrochemical system was evaluated using EIS, CT scanning and cell cycling characterisation and was proven to be negligible. Furthermore, the thermal sensors were proven to be resistant to the strain imposed during the cell instrumentation procedure and the harsh chemical environment inside the Li-ion cells. The sensing methodologies and modification techniques developed in this work can be applied to large scale battery modules and pack systems and integrated within the cell manufacturing process. This work identified a clear and significant difference between the cell’s can and core temperatures, as well as axial temperature gradient. The findings of this study are of significance to the performance and safety limits of energy storage systems. This research indicates the clear need for reliable sensing systems that enable accurate in-situ in-operando monitoring of lithium-ion energy storage systems.

Development and evaluation of in-situ instrumentation for cylindrical Li-ion cells using fibre optic sensors

Abstract This work demonstrates the development and evaluation of FBG optical fibre sensor technology for monitoring the distributed in-situ in-operando temperature of cylindrical 18650 lithium-ion cells. The influence of the sensing element on the electrochemical system was evaluated using EIS, CT scanning and cell cycling characterisation and was proven to be negligible. Furthermore, the FBG sensors were proven to be resistant to the strain imposed during the cell instrumentation procedure and the harsh chemical environment inside the Li-ion cells. The sensing methodologies and modification techniques developed in this work can be applied to large scale battery modules and pack systems and integrated within the cell manufacturing process. This work identified a clear and significant difference between the cells can and core temperatures of up to 6 °C at discharge and 3 °C at charge, as well as axial temperature gradient. The findings of this study are of significance to the performance and safety limits of energy storage systems. This article indicates the clear need for reliable sensing systems that enable accurate in-situ in-operando monitoring of lithium-ion energy storage systems.

Improving performance by Na doping of a buffer layer—chemical and electronic structure of the InxSy:Na/CuIn(S,Se)2 thin‐film solar cell interface

AbstractDoping an indium sulfide buffer layer with sodium is a promising route to replace the “state‐of‐the‐art” CdS buffer layer in chalcopyrite‐based thin‐film solar cells, as it achieves efficiencies as high as 17.9% for large‐area devices (30 cm × 30 cm). We report on the chemical and electronic structure of the InxSy:Na/CuIn(S,Se)2 (CISSe) interface for thin‐film solar cells by means of photoelectron, soft x‐ray emission, and inverse photoemission spectroscopy. For as‐deposited InxSy:Na buffer layers, we find a sulfur‐poor surface and, in comparison to undoped InxSy and the standard CdS buffer, derive a large electronic surface band gap of 2.60 ± 0.11 eV. The conduction band offset at the buffer/absorber interface is a spike of 0.32 ± 0.10 eV. After annealing at 200°C to simulate the thermal load of subsequent cell manufacturing processes, an additional diffusion of copper and selenium from the absorber towards the buffer layer surface is observed, leading to a distinct electronic surface band gap decrease of the InxSy:Na buffer layer (to 2.11 ± 0.11 eV). We speculate that the diffusion of absorber elements causes a band gap widening at the former absorber surface and that both effects lead to a reduction of the conduction band spike for the buried InxSy:Na/CISSe interface after annealing.

Deterministic Lateral Displacement: The Next-Generation CAR T-Cell Processing?

Reliable cell recovery and expansion are fundamental to the successful scale-up of chimeric antigen receptor (CAR) T cells or any therapeutic cell-manufacturing process. Here, we extend our previous work in whole blood by manufacturing a highly parallel deterministic lateral displacement (DLD) device incorporating diamond microposts and moving into processing, for the first time, apheresis blood products. This study demonstrates key metrics of cell recovery (80%) and platelet depletion (87%), and it shows that DLD T-cell preparations have high conversion to the T-central memory phenotype and expand well in culture, resulting in twofold greater central memory cells compared to Ficoll-Hypaque (Ficoll) and direct magnetic approaches. In addition, all samples processed by DLD converted to a majority T-central memory phenotype and did so with less variation, in stark contrast to Ficoll and direct magnetic prepared samples, which had partial conversion among all donors (<50%). This initial comparison of T-cell function infers that cells prepared via DLD may have a desirable bias, generating significant potential benefits for downstream cell processing. DLD processing provides a path to develop a simple closed system that can be automated while simultaneously addressing multiple steps when there is potential for human error, microbial contamination, and other current technical challenges associated with the manufacture of therapeutic cells.

Blockade of CD7 expression in T cells for effective chimeric antigen receptor targeting of T-cell malignancies.

Effective immunotherapies for T-cell malignancies are lacking. We devised a novel approach based on chimeric antigen receptor (CAR)-redirected T lymphocytes. We selected CD7 as a target because of its consistent expression in T-cell acute lymphoblastic leukemia (T-ALL), including the most aggressive subtype, early T-cell precursor (ETP)-ALL. In 49 diagnostic T-ALL samples (including 14 ETP-ALL samples), median CD7 expression was >99%; CD7 expression remained high at relapse (n = 14), and during chemotherapy (n = 54). We targeted CD7 with a second-generation CAR (anti-CD7-41BB-CD3ζ), but CAR expression in T lymphocytes caused fratricide due to the presence of CD7 in the T cells themselves. To downregulate CD7 and control fratricide, we applied a new method (protein expression blocker [PEBL]), based on an anti-CD7 single-chain variable fragment coupled with an intracellular retention domain. Transduction of anti-CD7 PEBL resulted in virtually instantaneous abrogation of surface CD7 expression in all transduced T cells; 2.0% ± 1.7% were CD7+ vs 98.1% ± 1.5% of mock-transduced T cells (n = 5; P < .0001). PEBL expression did not impair T-cell proliferation, interferon-γ and tumor necrosis factor-α secretion, or cytotoxicity, and eliminated CAR-mediated fratricide. PEBL-CAR T cells were highly cytotoxic against CD7+ leukemic cells in vitro and were consistently more potent than CD7+ T cells spared by fratricide. They also showed strong anti-leukemic activity in cell line- and patient-derived T-ALL xenografts. The strategy described in this study fits well with existing clinical-grade cell manufacturing processes and can be rapidly implemented for the treatment of patients with high-risk T-cell malignancies.

Simple pretreatment processes for successful reclamation and remanufacturing of crystalline silicon solar cells

AbstractThis study presents an effective method for recovering unbroken solar cells from photovoltaic (PV) modules. The combustion process is effective at removing ethylene vinyl acetate (EVA) in PV modules. However, the solar cell tends to break during the combustion process. We verify that the breakage mechanisms of the solar cell in the module are related to the thermal changes of EVA during the heat treatment process, that is, generated gases form bubbles behind the glass, and the thermal deformation of the rear EVA applies stress to the solar cell. This study investigates the simple pretreatments of glass cracking and EVA patterning to prevent the breakage behavior. An unbroken solar cell was successfully recovered from the module after complete EVA removal using the combustion process. The recovered solar cell was immersed in a mixed acid solution of HNO3 and HF to reclaim the crystalline silicon wafer, which subsequently underwent the solar cell manufacturing process. The PV performances of the solar cells based on the reclaimed wafer and a commercial wafer were evaluated and compared. The PV performance of the solar cell manufactured from the reclaimed wafer was measured at 18.5%, whereas that from the commercial wafer‐based solar cell was measured at 18.7%. Consequently, the considered pretreatment processes yielded solar cells acceptable for use in the PV industry.

Preclinical Studies in CAR T Cell Development

T cells that express chimeric antigen receptors (CARs) have shown remarkable efficacy against CD19 expressing hematological tumors1-3. Patients receive autologous T cells that are typically virally transduced to express a CAR that can recognize a specific antigen expressed on the surface of tumor cells and generates large numbers of effective tumor-specific T cells. The value of preclinical models is to establish some evidence for efficacy, uncover potential toxicities, and to study the mechanism of action. Ideally, preclinical models will provide predictive data that will guide the decision making on the best approach for CAR design, selection of targets, in vitro cell manufacturing processes, and identification of biomarkers of activity. At a minimum, CAR T cells should be specific for the target antigen(s) and induce potent T cell cytotoxicity and cytokine production when engaging with antigen-expressing tumor cells, including activity against tumor samples from clinical patients, such as bone marrow aspirates or patient-derived tumor specimens. Beyond targeting, research has been done in how to enhance CAR T cell activity through design alterations using different costimulation domains to trigger specific activation programs within the CAR T cells, use of specific T cell populations to enhance CAR T cell activity or persistence, targeting strategies to avoid off-tumor activity or tumor antigen escape, and modulation of CAR expression/activity to enhance efficacy and safety. In vivo preclinical tumor models have been valuable to test CAR designs because high activity in vitro has not been a strong of a predictor of in vivo efficacy. In general, the less activated and differentiated a CAR T cell population, the better the in vivo anti-tumor activity.

Recent Advances in Tissue Engineering Strategies for the Treatment of Joint Damage

While the clinical potential of tissue engineering for treating joint damage has yet to be realized, research and commercialization efforts in the field are geared towards overcoming major obstacles to clinical translation, as well as towards achieving engineered grafts that recapitulate the unique structures, function, and physiology of the joint. In this review, we describe recent advances in technologies aimed at obtaining biomaterials, stem cells, and bioreactors that will enable the development of effective tissue-engineered treatments for repairing joint damage. 3D printing of scaffolds is aimed at improving the mechanical structure and microenvironment necessary for bone regeneration within a damaged joint. Advances in our understanding of stem cell biology and cell manufacturing processes are informing translational strategies for the therapeutic use of allogeneic and autologous cells. Finally, bioreactors used in combination with cells and biomaterials are promising strategies for generating large tissue grafts for repairing damaged tissues in pre-clinical models. Together, these advances along with ongoing research directions are making tissue engineering increasingly viable for the treatment of joint damage.

Measurement and Analysis of Effect of Ionic Conductivity on Nonlinear Behavior of All-Solid-State Battery

Now a days all solid state batteries draw attentions of researchers, battery and vehicle developers due to its high energy density characteristic and safety issues. The numerous benefits make solid-state batteries more convenient for automotive industries to invest. However some issues of solid state batteries such as low ionic conductivity and interface between electrodes and solid electrolyte remain which need more in depth research and investigations during coming years. This paper tries to introduce a method to analyze and evaluate the effects of solid electrolyte conductivity on the battery linear and nonlinear behaviors. In the proposed method the measured current and voltage of the battery in frequency domain are analyzed and linear part as well as the nonlinear distortions is extracted. In order to evaluate the ionic conductivity, two all-solid-stat coin cells are prepared. Both cells have same cathode and anode materials, LiNbO3-coated LiCoO2 and graphite respectively. Surface area is 1cm2 and the thickness of each part is also similar. Capacity of each cell is 0.67 mAh. However the only difference is ionic conductivity inside of the cathode layer. The ionic conductivity of cathode layer has been controlled by changing solid electrolyte (SE) materials; in cell number 1, LiI-Li2S-P2S5 glass exhibiting ionic conductivity (σ 25ºC) of 10-3 S/cm was equipped, while for second cell, the solid electrolyte of γ-Li3PS4 (σ25ºC ≈ 10-5S/cm) was used. In the proposed method several sinusoidal waves with same amplitude and different frequencies and also different phase realizations are added together in one signal, which is called multisine excitation. The zero signal means and overall SoC remains constant during the experiment. Furthermore charge and discharge signals can be distinguished and analyzed, separately. Thanks to frequency domain analysis, every excited waves and its response can be analyzed and also corresponding impedance can be calculated. A nonlinear system can be approximated by a linear dynamic system, which is called the best liner approximation. This linear part (linear part of battery impedance) is approximated from the voltage response to multisine excitation current in frequency domain. Besides the noise and transient, the main source of signal distortion in a measurement is nonlinear behavior of the battery which this paper tries to find the link between distortions and ionic conductivity of cathode layer. In this paper 2 different multisine realizations with different current amplitudes at 2mA and 15mA are designed and applied to both cells at 60°C ambient temperature. Figure 1 shows the input cell current for15mA case. The signal shape suggests that it is random but if we look at it in frequency domain, it is made of specified frequencies with exact same amplitudes. The purpose of choosing these two cases is to evaluate how battery voltage and impedance are affected by ionic conductivity of cathode layer in low and high currents. The measured voltages for both cases are shown in figure 2a and 2b. As expected, the voltage amplitude is much bigger for cell 2 due to the higher impedance. However the interesting point is the voltage variation during charge and discharge, which is different for cell 2 at low and high currents. According to figure 2.a when the input current is 2mA, the voltage drop during discharge is higher than charge if the blue curve is considered as a reference. However when current has been increased to 15mA, the voltage during charge has been increased more compared with the voltage during the discharge phase. In the way that voltage variation seems more balanced than the 2mA case, which is due to the ionic conductivity reduction. For calculating the approximated linear impedance and nonlinear distortions in each case, the measured current and voltage have been transformed to frequency domain. Based on the mathematical and statistical methods the best linear approximation of impedance and nonlinear distortion on the excited sine waves has been calculated, which has been indicated in figure 3. According to the figure 3a when the current is 2mA, the linear part of the impedance is increased to 15 times in case of cell2 while nonlinear distortion has been increased to 200 times. But when the current increases to 15mA (figure 3.b) the linear part of the impedance increases to around 14 times and nonlinear distortion changes only 40 times more due to the symmetrical pattern, which has been discussed at figure 2b. Such analysis will formulate the nonlinear effects of ionic conductivity on SSB behaviors. This method will be used for developing nonlinear models which is useful for optimized cell manufacturing process. Figure 1

Graceful Space Degradation: An Uneven Space Management for Flash Storage Devices

The high cell density, multilevel-cell programming, and manufacturing process variance force the new coming flash memory to have large bit-error-rate variance among blocks and pages, where a flash chip consists of multiple blocks and each block consists of a fixed number of pages. In order to avoid storing the crucial user data in more fragile pages, conventional flash management software tends to aggressively discard the high bit-error-rate area in the unit of a block. However, together with the aggressive discarding strategies and the enlarging sizes of pages/blocks of next generation flash memory, the available space of flash devices might encounter a very sharp degradation and therefore result in rapidly-shortened device lifespan. Thus, we advocate the concept of “graceful space degradation” to mitigate this problem by discarding the high bit-error-rate (or worn-out) area in the unit of pages (instead of blocks). To furthermore realize this concept, we are the pioneer to put forward an “uneven space management” to manage flash blocks containing different number of bad pages. Our design especially focuses on placing data with different access behaviors to make the best uses of blocks with different available space so as to ultimately prolong the device lifespan with good access performance. The experiments were conducted based on representative realistic workloads, and the results reveal that the proposed design can extend the device lifetime by at least 2.38 times of that of existent approaches, with very limited performance overheads.

Experience of contamination during autologous cell manufacturing in cell processing facility under the Japanese Medical Practitioners Act and the Medical Care Act.

Cell therapy and regenerative medicine technologies require strict cell manufacturing procedures to be defined and addressed. Maintenance of the aseptic environment is critical to preclude extrinsic contamination risks, similar to conventional pharmaceutical manufacturing. However, intrinsic contamination risks exist in all cell manufacturing processes owing to the use of cells as the raw materials that cannot be sterilized, thus giving rise to the primary and secondary risks of cell contamination and cross-contamination, respectively. Analysis of contamination risks was conducted on experienced batches (29,858 batches) for the production of immune cells derived from autologous blood mononuclear cells under the Medical Practitioners Act and the Medical Care Act in Japan. From these batches, 0.06% (18 cases) of contamination occurred, representing low probability of contamination incidence during cell processing. Almost all the causes of these contaminations were regarded to be from the collected blood (intrinsic contamination), and subsequent cross-contaminations were prevented, considering that the secondary contamination risk can be reduced by adequate managements of operational procedures for changeover in aseptic environment.