Advancing autologous CAR T-cell therapy through real-time patient health data integration: a simulation-based approach.

Autologous chimeric antigen receptor T-cell therapy presents promising treatment outcomes for various cancers. However, its potential is restrained by unique supply chain challenges, including dynamic patient health conditions and extended turnaround time. These challenges often lead to missed optimal treatment windows, impeding the effective delivery of life-saving treatments. This article presents SimPAC (simulation-based decision support for Patient-centric manufacturing of autologous cell therapies). SimPAC is designed to model and incorporate real-time patient health conditions into the supply chain decisions of autologous chimeric antigen receptor T-cell therapy. SimPAC integrates system dynamics and agent-based simulation techniques, facilitating the adaptation of manufacturing processes and production schedules based on real-time patient health conditions. SimPAC can model various patient disease progressions using parametric functions, nonparametric functions, or tabular data. Additionally, SimPAC offers easy configuration options to model various cell therapy supply chains. We provide two case studies to demonstrate the capabilities of SimPAC and highlight the benefits of patient-centric manufacturing, including improved survival rates and potential economic advantages. However, while the benefits are significant, our study also emphasizes the importance of balancing improved patient outcomes, economic viability and ethical considerations in the context of personalized medicine. SimPAC can be used to explore applications of this approach to diverse therapeutic contexts and supply chain configurations.

Bioprinting: an assessment based on manufacturing readiness levels.

Over the last decade, bioprinting has emerged as a promising technology in the fields of tissue engineering and regenerative medicine. With recent advances in additive manufacturing, bioprinting is poised to provide patient-specific therapies and new approaches for tissue and organ studies, drug discoveries and even food manufacturing. Manufacturing Readiness Level (MRL) is a method that has been applied to assess manufacturing maturity and to identify risks and gaps in technology-manufacturing transitions. Technology Readiness Level (TRL) is used to evaluate the maturity of a technology. This paper reviews recent advances in bioprinting following the MRL scheme and addresses corresponding MRL levels of engineering challenges and gaps associated with the translation of bioprinting from lab-bench experiments to ultimate full-scale manufacturing of tissues and organs. According to our step-by-step TRL and MRL assessment, after years of rigorous investigation by the biotechnology community, bioprinting is on the cusp of entering the translational phase where laboratory research practices can be scaled up into manufacturing products specifically designed for individual patients.

Nanoscale infiltration behaviour and through-thickness permeability of carbon nanotube buckypapers.

Carbon nanotube thin films or 'buckypapers' show potential for various applications including electrodes for energy devices, nanoscale filtration devices and composite materials. This paper reports on the study of through-thickness permeability of different buckypaper materials. The infiltration behaviours of different liquids into four types of buckypaper were investigated. Infiltration of the liquids into buckypaper was found to follow Darcy's law, except in the case of epoxy resin solution permeation into SWNT buckypaper. The results revealed that the permeability of SWNT buckypaper was of the order of 10(-19) m(2), which is about two orders of magnitude lower than the 10(-17) m(2) permeability for the MWNT buckypaper. The factors of wider pores, higher porosity and less surface area appear to contribute to a higher permeability, which is consistent with Darcy's law and the Kozeny-Carman model. The Kozeny constants of buckypapers correlated well with the tortuosity of their flow paths and nanoscale pore size. The polarity of working fluids did not show an impact on the permeability. Solutions with molecular size near the size of the nanopores in the buckypaper led to lower permeability due to the occurrence of pore blockage. In addition, a threshold pressure existed for liquid to infiltrate into nanoscale pores in buckypapers, which does not exist in fibre reinforcement preforms.

Vanadium oxide-carbon nanotube composite electrodes for energy storage by supercritical fluid deposition: experiment design and device performance.

Vanadium pentoxide (V2O5) deposited on porous multiwalled carbon nanotube (MWCNT) buckypaper using supercritical fluid CO2(scCO2) deposition shows excellent performance for electrochemical capacitors. However, the low weight loading of V2O5 is one of the main problems. In this paper, design of experiments and response surface methods were employed to explore strategies for improving the active material loading by increasing the organo-vanadium precursor adsorption. A second-order response surface model was fitted to the designed experiments to predict the loading of the vanadium precursors onto carbon nanotube buckypaper as a function of time, temperature and pressure of CO2, buckypaper functionalization, precursor type, initial precursor mass and stir speed. Operation conditions were identified by employing a model that led to a precursor loading of 19.33%, an increase of 72.28% over the initial screening design. CNTs-V2O5 composite electrodes fabricated from deposited samples using the optimized conditions demonstrated outstanding electrochemical performance (947.1 F g(-1) of V2O5 at a high scan rate 100 mV s(-1)). The model also predicted operation conditions under which light precursor aggregation took place. The V2O5 from aggregated precursor still possessed considerable specific capacitance (311 F g(-1) of V2O5 at a scan rate 100 mV s(-1)), and the significantly higher V2O5 loading (∼81%) contributed to an increase in overall electrode capacitance.

Active learning-based multistage sequential decision-making model with application on common bile duct stone evaluation.

Multistage sequential decision-making occurs in many real-world applications such as healthcare diagnosis and treatment. One concrete example is when the doctors need to decide to collect which kind of information from subjects so as to make the good medical decision cost-effectively. In this paper, an active learning-based method is developed to model the doctors' decision-making process that actively collects necessary information from each subject in a sequential manner. The effectiveness of the proposed model, especially its two-stage version, is validated on both simulation studies and a case study of common bile duct stone evaluation for pediatric patients.

A disposable impedance-based sensor for in-line cell growth monitoring in CAR-T cell manufacturing.

This paper presents the development of low-cost, disposable impedance-based sensors for real-time, in-line monitoring of suspension cell culture. The sensors consist of electrical discharge machining (EDM) cut aluminum electrodes and polydimethylsiloxane (PDMS) spacers, both of which are low-cost materials that can be safely disposed of. Our research demonstrates the capability of these low-cost sensors for in-line, non-invasive monitoring of suspension cell growth in cell manufacturing. We use a hybrid equivalent circuit model to extract key features/parameters from intertwined impedance signals, which are then fed to a novel physics-inspired (gray-box) model designed for α-relaxation. This model determines viable cell count (VCC), a critical quality attribute (CQA) in cell manufacturing. Predicted VCC trends are then compared with image-based cell count data to verify their accuracy.

Functional screening of amplification outlier oncogenes in organoid models of early tumorigenesis.

Somatic copy number gains are pervasive across cancer types, yet their roles in oncogenesis are insufficiently evaluated. This inadequacy is partly due to copy gains spanning large chromosomal regions, obscuring causal loci. Here, we employed organoid modeling to evaluate candidate oncogenic loci identified via integrative computational analysis of extreme copy gains overlapping with extreme expression dysregulation in The Cancer Genome Atlas. Subsets of "outlier" candidates were contextually screened as tissue-specific cDNA lentiviral libraries within cognate esophagus, oral cavity, colon, stomach, pancreas, and lung organoids bearing initial oncogenic mutations. Iterative analysis nominated the kinase DYRK2 at 12q15 as an amplified head and neck squamous carcinoma oncogene in p53-/- oral mucosal organoids. Similarly, FGF3, amplified at 11q13 in 41% of esophageal squamous carcinomas, promoted p53-/- esophageal organoid growth reversible by small molecule and soluble receptor antagonism of FGFRs. Our studies establish organoid-based contextual screening of candidate genomic drivers, enabling functional evaluation during early tumorigenesis.

Recycling of woven carbon-fibre-reinforced polymer composites using supercritical water.

Over the past few years, there has been great deal of interest in recycling carbon-fibre-reinforced polymer composites. One method that has shown promising results involves the use of supercritical fluids to achieve separation between matrix and fibres by effectively degrading the resin into lower molecular weight compounds. In addition, the solvents used are environmentally benign and can also be recovered and reused. In this study, supercritical water with 0.05 M KOH as the catalyst was used for the recycling of an aerospace-grade high-performance epoxy carbon fibre composite (Hexcel 8552/IM7). The morphology of the reclaimed fibres was observed by scanning electron microscopy, and the tensile properties of the fibres were measured by single filament testing. The effects of processing time on the resin elimination efficiency and fibre property retention were investigated. With the process developed in this research, as much as 99.2 wt% resin elimination was achieved, resulting in the recovery of clean, undamaged fibres. The reclaimed fibres retained the original tensile strength. The feasibility of recycling multiple layer composites was also explored.

Effects of solvent immersion and evaporation on the electrical conductance of pre-stressed carbon nanotube buckypapers.

Buckypapers (BPs) are free standing thin sheets made of carbon nanotubes, such as single-walled carbon nanotubes (SWCNTs) or multi-walled carbon nanotubes (MWCNTs) or their mixtures. In this research, through in situ electrical resistance measurements, we studied the electrical conductance changes of carbon nanotube networks (NTNs) in various BP samples from complete immersion to evaporation using different chemical solvents. BP samples demonstrated a 20-30% decrease in conductance upon the immersion and almost full recovery after the drying process. We found that by pre-stressing, BP samples demonstrated highly reproducible patterns of conductance changes corresponding to solvent quantity. This feature can be potentially used for sensor applications to simultaneously detect both the occurrence and the amount of organic solvent leakage.

Supercritical fluid deposition of vanadium oxide on multi-walled carbon nanotube buckypaper for supercapacitor electrode application.

Composite electrodes were fabricated for supercapacitor applications by depositing vanadium oxide onto multi-walled carbon nanotube (MWCNT) buckypaper using supercritical fluid deposition (SFD). The deposited thin vanadium oxide layer showed amorphous structure with excellent uniformity. In aqueous KCl electrolyte, the vanadium oxide exhibited a constant pseudo-capacitance of ∼ 1024 F g(-1), which was independent of the oxide material loading (up to 6.92 wt%) and voltage scan rate (up to 100 mV s(-1)). The highest specific electrode capacitance achieved was ∼ 85 F g(-1), which was almost four times that of the pristine buckypaper electrode.

Highly conductive carbon nanotube buckypapers with improved doping stability via conjugational cross-linking.

Carbon nanotube (CNT) sheets or buckypapers have demonstrated promising electrical conductivity and mechanical performance. However, their electrical conductivity is still far below the requirements for engineering applications, such as using as a substitute for copper mesh, which is currently used in composite aircraft structures for lightning strike protection. In this study, different CNT buckypapers were stretched to increase their alignment, and then subjected to conjugational cross-linking via chemical functionalization. The conjugationally cross-linked buckypapers (CCL-BPs) demonstrated higher electrical conductivity of up to 6200 S cm( - 1), which is more than one order increase compared to the pristine buckypapers. The CCL-BPs also showed excellent doping stability in over 300 h in atmosphere and were resistant to degradation at elevated temperatures. The tensile strength of the stretched CCL-BPs reached 220 MPa, which is about three times that of pristine buckypapers. We attribute these property improvements to the effective and stable conjugational cross-links of CNTs, which can simultaneously improve the electrical conductivity, doping stability and mechanical properties. Specifically, the electrical conductivity increase resulted from improving the CNT alignment and inter-tube electron transport capability. The conjugational cross-links provide effective 3D conductive paths to increase the mobility of electrons among individual nanotubes. The stable covalent bonding also enhances the thermal stability and load transfer. The significant electrical and mechanical property improvement renders buckypaper a multifunctional material for various applications, such as conducting composites, battery electrodes, capacitors, etc.

Elastic property prediction of single-walled carbon nanotube buckypaper/polymer nanocomposites: stochastic bulk response modeling.

In this study, we investigated the statistical relationship between nanostructure variations of carbon nanotube buckypaper-polymer (BPP) composites and their resulting elastic properties. A statistical simulation was developed to predict the elastic properties of a single-layer BPP lamina and extrapolated to the resultant bulk composite part. The stochastic characteristics of BPP composite nanostructure were quantified from experimental observations and used to generate the input for each simulation set performed. The Mori-Tanaka method was used to calculate the stiffness tensor within the buckypaper-polymer region, and a Monte-Carlo simulation was applied to generate the probability distribution for the effective stiffness tensor within each BPP lamina. Classical laminate theory was then employed to predict the effective elastic response for a multi-layered BPP composite laminate. The theoretical predictions were compared with experimental data, and the resulting trends for the effective tensile modulus between experimental and theoretical corresponded well with each other.

Textile-based sandwich scaffold using wet electrospun yarns for skin tissue engineering.

One of the key elements in tissue engineering is to design and fabricate scaffolds with tissue-like properties. However, mimicking the strain-stiffening property of human tissues by using synthetic materials is still a challenge in scaffold fabrication since most synthetic materials exhibit strain-softening behavior. To address this challenge, we propose a textile-based sandwich scaffold to mimic strain-stiffening behavior observed in human tissues. For this purpose, we first fabricate polycaprolactone (PCL) yarns by wet electrospinning. Then, we crochet PCL yarns into a textile fabric. Finally, we fabricate the sandwich scaffold by embedding the textile fabric inside two electrospun mats. The wet electrospun PCL yarns induce cellular alignment and elongation. The textile-based sandwich scaffold exhibits strain-stiffening behavior. By changing process parameters during the yarn fabrication and textile process, we can adjust the maximum stress of the scaffold from 3.74 to 11.82 MPa, the maximum strain from 0.16 to 2.37, and the elastic modulus from 2.10 to 18.05 MPa, all within the ranges of that of human skin. The scaffold is also able to support cell proliferation and infiltration after optimizing the thickness of the outer layers of the sandwich scaffold. This study validates the potential of the textile-based sandwich scaffold to mimic the physical, mechanical, and biological properties of human skin and other tissues.

Using Wet Electrospun PCL/Gelatin/CNT Yarns to Fabricate Textile-Based Scaffolds for Vascular Tissue Engineering.

Incorporating conductive materials in scaffolds has shown advantages in regulating adhesion, mitigation, and proliferation of electroactive cells for tissue engineering applications. Among various conductive materials, carbon nanotubes (CNTs) have shown great promises in tissue engineering because of their good mechanical properties. However, the broad application of CNTs in tissue engineering is limited by current methods to incorporate CNTs in polymers that require miscible solvents to dissolve CNTs and polymers or CNT surface modification. These methods either limit polymer selections or adversely affect the properties of polymer/CNT composites. Here, we report a novel method to fabricate polymer/CNT composite yarns by electrospinning polycaprolactone/gelatin into a bath of CNT dispersion and extracting electrospun fibers out of the bath. The concentration of CNTs in the bath affects the thermal and mechanical properties and the yarns' degradation behavior. In vitro biological test results show that within a limited range of CNT concentrations in the bath, the yarns exhibit good biocompatibility and the ability to guide cell elongation and alignment. We also report the design and fabrication of a vascular scaffold by knitting the yarns into a textile fabric and combining the textile fabric with gelatin. The scaffold has similar mechanical properties to native vessels and supports cell proliferation. This work demonstrates that the wet electrospun polymer/CNT yarns are good candidates for constructing vascular scaffolds and provides a novel method to incorporate CNTs or other functional materials into biopolymers for tissue engineering applications.

Application of textile technology in tissue engineering: A review.

One of the key elements in tissue engineering is to design and fabricate scaffolds with tissue-like properties. Among various scaffold fabrication methods, textile technology has shown its unique advantages in mimicking human tissues' properties such as hierarchical, anisotropic, and strain-stiffening properties. As essential components in textile technology, textile patterns affect the porosity, architecture, and mechanical properties of textile-based scaffolds. However, the potential of various textile patterns has not been fully explored when fabricating textile-based scaffolds, and the effect of different textile patterns on scaffold properties has not been thoroughly investigated. This review summarizes textile technology development and highlights its application in tissue engineering to facilitate the broader application of textile technology, especially various textile patterns in tissue engineering. The potential of using different textile methods such as weaving, knitting, and braiding to mimic properties of human tissues is discussed, and the effect of process parameters in these methods on fabric properties is summarized. Finally, perspectives on future directions for explorations are presented. STATEMENT OF SIGNIFICANCE: Recently, biomedical engineers have applied textile technology to fabricate scaffolds for tissue engineering applications. Various textile methods, especially weaving, knitting, and braiding, enables engineers to customize the physical, mechanical, and biological properties of scaffolds. However, most textile-based scaffolds only use simple textile patterns, and the effect of different textile patterns on scaffold properties has not been thoroughly investigated. In this review, we cover for the first time the effect of process parameters in different textile methods on fabric properties, exploring the potential of using different textile methods to mimic properties of human tissues. Previous advances in textile technology are presented, and future directions for explorations are presented, hoping to facilitate new breakthroughs of textile-based tissue engineering.

Active Image Synthesis for Efficient Labeling.

The great success achieved by deep neural networks attracts increasing attention from the manufacturing and healthcare communities. However, the limited availability of data and high costs of data collection are the major challenges for the applications in those fields. We propose in this work AISEL, an active image synthesis method for efficient labeling, to improve the performance of the small-data learning tasks. Specifically, a complementary AISEL dataset is generated, with labels actively acquired via a physics-based method to incorporate underlining physical knowledge at hand. An important component of our AISEL method is the bidirectional generative invertible network (GIN), which can extract interpretable features from the training images and generate physically meaningful virtual images. Our AISEL method then efficiently samples virtual images not only further exploits the uncertain regions but also explores the entire image space. We then discuss the interpretability of GIN both theoretically and experimentally, demonstrating clear visual improvements over the benchmarks. Finally, we demonstrate the effectiveness of our AISEL framework on aortic stenosis application, in which our method lowers the labeling cost by 90 percent while achieving a 15 percent improvement in prediction accuracy.

3D Printing, Computational Modeling, and Artificial Intelligence for Structural Heart Disease.

Structural heart disease (SHD) is a new field within cardiovascular medicine. Traditional imaging modalities fall short in supporting the needs of SHD interventions, as they have been constructed around the concept of disease diagnosis. SHD interventions disrupt traditional concepts of imaging in requiring imaging to plan, simulate, and predict intraprocedural outcomes. In transcatheter SHD interventions, the absence of a gold-standard open cavity surgical field deprives physicians of the opportunity for tactile feedback and visual confirmation of cardiac anatomy. Hence, dependency on imaging in periprocedural guidance has led to evolution of a new generation of procedural skillsets, concept of a visual field, and technologies in the periprocedural planning period to accelerate preclinical device development, physician, and patient education. Adaptation of 3-dimensional (3D) printing in clinical care and procedural planning has demonstrated a reduction in early-operator learning curve for transcatheter interventions. Integration of computation modeling to 3D printing has accelerated research and development understanding of fluid mechanics within device testing. Application of 3D printing, computational modeling, and ultimately incorporation of artificial intelligence is changing the landscape of physician training and delivery of patient-centric care. Transcatheter structural heart interventions are requiring in-depth periprocedural understanding of cardiac pathophysiology and device interactions not afforded by traditional imaging metrics.

Functionalized carbon-nanotube sheet/bismaleimide nanocomposites: mechanical and electrical performance beyond carbon-fiber composites.

Since their discovery in 1991, carbon nanotubes (CNTs) have been considered as the next-generation reinforcement materials to potentially replace conventional carbon fibers for producing super-high-performance lightweight composites. Herein, it is reported that sheets of millimeter-long multi-walled CNTs with stretch alignment and epoxidation functionalization reinforce bismaleimide resin, which results in composites with an unprecedentedly high tensile strength of 3081 MPa and modulus of 350 GPa, well exceeding those of state-of-the-art unidirectional carbon-fiber-reinforced composites. The results also provide important experimental evidence of the impact of functionalization and the effect of alignment reported previously on the mechanical performance and electrical conductivity of the nanocomposites.

Carbon nanotube buckypaper to improve fire retardancy of high-temperature/high-performance polymer composites.

Mixed single-walled and multi-walled carbon nanotube membrane (buckypaper) was incorporated onto the surface of polyimide/carbon fibre composites via a compression moulding process. Flammability was investigated by cone calorimeter tests under an external radiant heat flux of 50 kW m(-2). The burning residue was analysed with scanning electron microscopy and thermogravimetric analysis. The buckypaper survived the burning test and decreased the peak heat release rate by 40%, reduced the total heat release by 26%, produced 82% less smoke release and resulted in 33% less mass loss. The directly mixed carbon nanotubes (5 wt% multi-walled carbon nanotubes) yielded 38% less peak heat release rate, only 3.7% less total heat release, 28% more smoke release and no change in mass loss. Compared to direct mixing of carbon nanotubes into the resin, the use of buckypaper is more efficient in fire retardancy improvement; it yielded further delay of ignition, lower heat release rate, further reduced heat release, lower mass loss and less smoke release. The buckypaper worked as an excellent physical barrier, obstructing the flow of heat and oxygen to the inner polymer resin. The as-prepared buckypaper greatly improved the fire retardancy of polyimide matrix carbon fibre composites.

Emitter spacing effects on field emission properties of laser-treated single-walled carbon nanotube buckypapers.

Carbon nanotube (CNT) emitters on buckypaper were activated by laser treatment and their field emission properties were investigated. The pristine buckypapers and CNT emitters' height, diameter, and spacing were characterized through optical analysis. The emitter spacing directly impacted the emission results when the laser power and treatment times were fixed. The increasing emitter density increased the enhanced field emission current and luminance. However, a continuous and excessive increase of emitter density with spacing reduction generated the screening effect. As a result, the extended screening effect from the smaller spacing eventually crippled the field emission effectiveness. Luminance intensity and uniformity of field emission suggest that the highly effective buckypaper will have a density of 2500 emission spots cm(-2), which presents an effective field enhancement factor of 3721 and a moderated screening effect of 0.005. Proper laser treatment is an effective post-treatment process for optimizing field emission, luminance, and durability performance for buckypaper cold cathodes.