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Structural systems based on tension and compression play a significant role in maximizing the performance of materials. Among them, structures based on the concept of tensegrity have attracted attention owing to their elegant design features and floating feeling. However, the complex construction of tensegrity-based structures hinders their implementation in practical design and architectural applications. Herein, we propose a novel tensegrity-based unit with simple connectivity and manufacturability. The external form of this unit is similar to that of a space-filling polyhedron. The prototype of the proposed unit is constructed, and the simple tension management of the unit is demonstrated. The mechanical behavior of the assembled structure is investigated by performing loading tests and numerical analyses. The behavior can be accurately predicted and general design can be applied to develop structures for practical applications. [ABSTRACT FROM AUTHOR]

While bioactivity and a favorable safety profile for biotherapeutics is of utmost importance, manufacturability is also worth of consideration to ease the manufacturing process. Manufacturability in the scientific literature is mostly related to stability of formulated drug substances, with limited focus on downstream process‐related manufacturability, that is, how easily can a protein be purified. Process‐related impurities or biological impurities like viruses and host cell proteins (HCP) are present in the harvest which have mostly acid isoelectric points and need to be removed to ensure patient safety. Therefore, during molecule design, the surface charge of the target molecule should preferably differ sufficiently from the surface charge of the impurities to enable an efficient purification strategy. In this feasibility study, we evaluated the possibility of improving manufacturability by adapting the surface charge of the target protein. We generated several variants of a GLP1‐receptor‐agonist‐Fc‐domain‐FGF21‐fusion protein and demonstrated proof of concept exemplarily for an anion exchange chromatography step which then can be operated at high pH values with maximal product recovery allowing removal of HCP and viruses. Altering the surface charge distribution of biotherapeutic proteins can thus be useful allowing for an efficient manufacturing process for removing HCP and viruses, thereby reducing manufacturing costs. [ABSTRACT FROM AUTHOR]

Aligned discontinuous fibre-reinforced composites are becoming more popular because they have the potential to offer stiffness and strength comparable to their continuous counterparts along with better manufacturability. However, the modelling of highly aligned discontinuous fibre composites is still in its infancy. This paper aims to provide a comprehensive review of the available literature to understand how modelling techniques have developed and consider whether all aspects which could affect the performance of aligned discontinuous fibre composites have been addressed. Here, for the first time, a broad view of the advantages, perspectives, and limitations of current approaches to modelling the performance and behaviour of aligned discontinuous fibre composites during alignment, forming, and mechanical loading is provided in one place as a route to design optimisation. [ABSTRACT FROM AUTHOR]

CAD-CAE software companies have introduced numerous tools aimed at facilitating topology optimization through Finite Element Simulation, thereby enhancing accessibility for designers via user-friendly interfaces. However, the imposition of intricate constraint conditions or additional restrictions during calculations may introduce instability into the resultant outcomes. In this paper, an algorithm for updating the design variables called Adaptive Variable Design is proposed to keep the final design space volume of the optimized part consistently under the target value while giving the main algorithm multiple chances to update the optimization parameters and search for a valid design. This algorithm aims to produce results that are more conducive to manufacturability and potentially more straightforward in interpretation. A comparison between several commercial software packages and the proposed algorithm, implemented in MATLAB R2023a, is carried out to prove the robustness of the latter. By simulating identical parts under similar conditions, we seek to generate comparable results and underscore the advantages stemming from the adoption and comprehension of the proposed topology optimization methodology. Our findings reveal that the integrated enhancements within MATLAB pertaining to the topology optimization process yield favourable outcomes with respect to discretization and the manufacturability of the resultant geometries. Furthermore, we assert that the methodology evaluated within MATLAB holds promise for potential integration into commercial packages, thereby enhancing the efficiency of topology optimization processes. [ABSTRACT FROM AUTHOR]

Governments and biopharmaceutical organizations aggressively leveraged expeditious communication capabilities, decision models, and global strategies to make a COVID‐19 vaccine happen within a period of 12 months. This was an unusual effort and cannot be transferred to normal times. However, this focus on a single vaccine has also led to other treatments and drug developments being sidelined. Society expects the pharmaceutical industry to provide an uninterrupted supply of medicines. However, it is often overlooked how complex the manufacture of these compounds is and what logistics are required, not to mention the time needed to develop new drugs. The overarching theme, therefore, is patient access and how we can help ensure access and extend it to low‐ and middle‐income countries. Despite unceasing efforts to make medications available to all patient populations, this must never be done at the expense of patient safety. A major fraction of the costs in biopharmaceutical manufacturing are for drug discovery, process development, and clinical studies. Infrastructure costs are very difficult to quantify because they often depend on whether a greenfield facility or an existing, depreciated facility is used or adapted for a new product. To accelerate process development concepts of platform process and prior knowledge are increasingly leveraged. While more traditional protein therapeutics continue to dominate the field, we are also experiencing the exciting emergence and evolution of other therapeutic formats (bispecifics, tetravalent mAbs, antibody‐drug conjugates, enzymes, peptides, etc.) that offer unique treatment options for patients. Protein modalities are still dominant, but new modalities are being developed that can be learned from including advanced therapeutics‐like cell and gene therapies. The industry must develop a model‐based strategy for process development and technologies such as continuous integrated biomanufacturing must be adopted. The overall conclusion is that the pandemic pace was unsustainable, focused on vaccine delivery at the expense of other modalities/disease targets, and had implications for professional and personal life (work‐life balance). Routinely reducing development time from 10 years to 1 year is nearly impossible to achieve. Environmental aspects of sustainable downstream processing are also described. [ABSTRACT FROM AUTHOR]

As the occurrences of cancer rise and the requirement for biotherapeutics increases, there is a growing demand for cost‐efficient methods to manufacture mammalian cell‐based biopharmaceuticals. Currently, the most cost‐efficient manufacturing solution is the cultivation of cells in perfusion mode. Perfusion allows for high cell densities of up to 200 million viable cells per mL (MVC mL−1) to be achieved, resulting in an increase in yield and volumetric productivity, which is the production of product per unit volume and time. However, culturing in perfusion mode requires large volumes of media, which is a significant expense in process development. Therefore, methods that allow rapid optimization of perfusion media are desirable to decrease operating costs and increase productivity. In this work, a quasi‐perfusion methodology using microwell plates (MWP) is used for media optimization to culture CHO‐S cells producing IgG1 monoclonal antibodies (mAb) known as trastuzumab, which have clinical applications treating HER2+ breast cancer. Results show blending glucose‐rich supplements and sodium butyrate with perfusion‐specific base media can lead to an 8‐fold increase in monoclonal antibody titre compared with traditional fed‐batch media. The original and optimized media were then scaled‐up to a custom made, mini bioreactor (MBR) running in perfusion mode. Two‐fold higher cell density is achieved in the MBR compared with the MWP, however, when normalizing for cell density, mAb productivity is comparable between the two methodologies. The combined MWP and 250 mL MBR methodology is an optimization tool that enables process development cost savings due to reduced volume of media utilization. [ABSTRACT FROM AUTHOR]

Additive manufacturing (AM) enables new possibilities for the design and manufacturing of complex metal architectures. Incorporating lattice structures into complex part geometries can enhance strength-to-weight and surface area-to-volume ratios for valuable components, particularly in industries such as medical devices and aerospace. However, lattice structures and their interconnections may result in unsupported down-skin surfaces, potentially limiting their manufacturability by metal AM technologies, such as laser powder bed fusion (LPBF). This study aimed to examine the correlation between down-skin surface area and the manufacturability of lattice structures fabricated using LPBF. Image processing algorithms were used to analyze down-skin surface areas of seven unique lattice designs and to devise quantitative metrics (such as down-skin surface area, discrete surface count, surface interconnectivity, down-skin ratio, over-print/under-print volumes, etc.) to evaluate LPBF manufacturability. The seven lattice designs were subsequently manufactured using maraging steel via LPBF and then examined using imaging using X-ray micro-computed tomography (XCT). The geometric accuracy of the lattice designs was compared with XCT scans of the manufactured lattices by employing a voxel-based image comparison technique. The results indicated a strong relationship between down-skin surface area, surface interconnectivity, and the manufacturability of a given lattice design. The digital manufacturability evaluation workflow was also applied to a medical device design, further affirming its potential industrial utility for complex geometries. [ABSTRACT FROM AUTHOR]

Titanium dioxide (TiO2) is used primarily as an opacifier in solid dosage forms and is present in the majority of tablet and capsule dosage forms on the market. The IQ* TiO2 Working Group has previously shown that titanium dioxide has unique properties which are necessary for its function in these formulations and noted that, as the potential replacements lack the semi-conductor properties, high refractive index and whiteness of E171, it might be hard to replicate these properties with alternative materials. In this paper we detail the results of readiness surveys and practical assessments that have been conducted with alternative materials by IQ member companies. A range of technical challenges and regulatory hurdles were identified which mean that, in the short term, it may be difficult to replace titanium dioxide with the currently available alternative materials while readily achieving the same drug product quality attributes, especially for some of the marketed formulations that titanium dioxide is currently used for. We note the higher technical complexity, due to the variability, color fading and identified scale up risk, of E171 free film coatings and the likely impact on development costs and timelines. We also highlight several regulatory hurdles that would have to be overcome if a titanium dioxide replacement was required for some markets but was not mandated by others. [ABSTRACT FROM AUTHOR]

Curvilinear design was applied to standard cell layout to improve electrical characteristics and reduce manufacturing costs. Its implementation was intelligently co-optimized with 1-D Manhattan shapes and photolithography process to preserve the standard cell area equivalent to that of 1-D Manhattan-only designs. B-spline curve representation was employed to realize the curvilinear design. Curvilinear pathfinding was carried out through the Voronoi diagram to find the optimum routing path, and the A* routing algorithm to determine the shortest path. In the curvilinear-designed standard cells, the majority of standard cells exhibited reduced total metal length, decreased number of vias, and eliminated the need for an extra metal layer when compared to 1-D Manhattan-only standard cell designs. Manufacturability of curvilinear designs was evaluated, and potential solutions are proposed in the context of design rule, design rules check (DRC) and optical proximity correction (OPC). DRC and OPC were carried out within the currently employed electronic design automation (EDA) tools to verify the curvilinear designs. [ABSTRACT FROM AUTHOR]

ABSTRACT While bioactivity and a favorable safety profile for biotherapeutics is of utmost importance, manufacturability is also worth of consideration to ease the manufacturing process. Manufacturability in the scientific literature is mostly related to stability of formulated drug substances, with limited focus on downstream process‐related manufacturability, that is, how easily can a protein be purified. Process‐related impurities or biological impurities like viruses and host cell proteins (HCP) are present in the harvest which have mostly acid isoelectric points and need to be removed to ensure patient safety. Therefore, during molecule design, the surface charge of the target molecule should preferably differ sufficiently from the surface charge of the impurities to enable an efficient purification strategy. In this feasibility study, we evaluated the possibility of improving manufacturability by adapting the surface charge of the target protein. We generated several variants of a GLP1‐receptor‐agonist‐Fc‐domain‐FGF21‐fusion protein and demonstrated proof of concept exemplarily for an anion exchange chromatography step which then can be operated at high pH values with maximal product recovery allowing removal of HCP and viruses. Altering the surface charge distribution of biotherapeutic proteins can thus be useful allowing for an efficient manufacturing process for removing HCP and viruses, thereby reducing manufacturing costs.

Bispecific antibodies (bsAb) and multispecific antibodies (msAb) encompass a diverse variety of formats that can concurrently bind multiple epitopes, unlocking mechanisms to address previously difficult-to-treat or incurable diseases. Early assessment of candidate developability enables demotion of antibodies with low potential and promotion of the most promising candidates for further development. Protein-based therapies have a stringent set of developability requirements in order to be competitive (e.g. high-concentration formulation, and long half-life) and their assessment requires a robust toolkit of methods, few of which are validated for interrogating bsAbs/msAbs. Important considerations when assessing the developability of bsAbs/msAbs include their molecular format, likelihood for immunogenicity, specificity, stability, and potential for high-volume production. Here, we summarize the critical aspects of developability assessment, and provide guidance on how to develop a comprehensive plan tailored to a given bsAb/msAb.

ABSTRACTOptimal combinations of paratopes assembled into a biparatopic antibody have the capacity to mediate high-grade target cross-linking on cell membranes, leading to degradation of the target, as well as antibody and payload delivery in the case of an antibody-drug conjugate (ADC). In the work presented here, molecular docking suggested a suitable paratope combination targeting c-MET, but hydrophobic patches in essential binding regions of one moiety necessitated engineering. In addition to rational design of HCDR2 and HCDR3 mutations, site-specific spiking libraries were generated and screened in yeast and mammalian surface display approaches. Comparative analyses revealed similar positions amendable for hydrophobicity reduction, with a broad combinatorial diversity obtained from library outputs. Optimized variants showed high stability, strongly reduced hydrophobicity, retained affinities supporting the desired functionality and enhanced producibility. The resulting biparatopic anti-c-MET ADCs were comparably active on c-MET expressing tumor cell lines as REGN5093 exatecan DAR6 ADC. Structural molecular modeling of paratope combinations for preferential inter-target binding combined with protein engineering for manufacturability yielded deep insights into the capabilities of rational and library approaches. The methodologies of in silico hydrophobicity identification and sequence optimization could serve as a blueprint for rapid development of optimal biparatopic ADCs targeting further tumor-associated antigens in the future.

The article aims to model the processing industry of Ukraine in the direction of increasing its economic efficiency according to the criteria of manufacturability and self-sufficiency (i.e. reducing import dependence). The regularities of the impact of technology and import dependence on the functional efficiency of the economy's industrial sector are revealed. The authors' hypothesis that higher economic efficiency in processing is explained by its greater focus on high-tech processes and production with a greater degree of the processing of raw materials, as well as a lower level of dependence on imported components, has been empirically proven. With the help of correlation-regression analysis, dependence between change in structural parameters (the share of high- and medium-high-tech industries in terms of output and the share of imports for intermediate consumption) and efficiency (the share of GVA in output) is substantiated. Deterministic economic-mathematical models (solved by linear programming) for optimising output and GVA in the processing industry and intermediate consumption were built according to the criteria of increasing manufacturability and reducing import dependence, both towards increasing efficiency. Such intermediate consumption (in terms of imported and domestic components of costs) was modelled, under which the indicator of the share of GVA of Ukraine would correspond to the level in Poland. The optimised data obtained form the basis for strategic planning, as they show what the output (by manufacturability) and intermediate consumption should be to ensure the desired level of economic efficiency of the Ukrainian processing industry. [ABSTRACT FROM AUTHOR]

Uralmashplant PJSC has developed original technical solutions to ensure the connection reliability of mating structural elements operating under conditions of increased loads throughout the entire life cycle. The connection basic design diagram is recommended for use in the design of various equipment for transmitting torque without vibrations, overloads and emergency situations, as well as eliminating circular and longitudinal displacements of the connected parts relative to each other. [ABSTRACT FROM AUTHOR]

Mechanical metamaterials are artificial structures that possess exceptional mechanical properties that are not naturally occurring. The complex geometrical and topological features of these metamaterials pose significant challenges to both structure design and manufacturing, despite the recent rapid development of additive manufacturing (AM) techniques. Thus, an effective framework for designing 3D metamaterials with desired mechanical properties, while also ensuring AM manufacturability, is urgently needed. In this paper, an AM manufacturability-aware deep generative model-based design framework is proposed for designing 3D metamaterial units for target properties. To accomplish this, we propose using Variational Autoencoder (VAE) as the feature extractor, which maps the 3D metamaterial geometries to a low-dimensional latent feature space. The latent feature space is concurrently linked to discriminators/regressors to predict manufacturability metrics and mechanical properties. We demonstrate that the proposed design framework is capable of designing high-performance metamaterial units with various user-defined manufacturability metrics. To showcase the effectiveness of the proposed design framework, three design cases with different objective functions are presented, and the final optimal designs are validated by comparing them to state-of-the-art designs or the optimal designs obtained by topology optimization methods. [ABSTRACT FROM AUTHOR]

The article aims to model the processing industry of Ukraine in the direction of increasing its economic efficiency according to the criteria of manufacturability and self-sufficiency (i.e. reducing import dependence). The regularities of the impact of technology and import dependence on the functional efficiency of the economy’s industrial sector are revealed. The authors’ hypothesis that higher economic efficiency in processing is explained by its greater focus on high-tech processes and production with a greater degree of the processing of raw materials, as well as a lower level of dependence on imported components, has been empirically proven. With the help of correlation-regression analysis, dependence between change in structural parameters (the share of high- and medium-high-tech industries in terms of output and the share of imports for intermediate consumption) and efficiency (the share of GVA in output) is substantiated. Deterministic economic-mathematical models (solved by linear programming) for optimising output and GVA in the processing industry and intermediate consumption were built according to the criteria of increasing manufacturability and reducing import dependence, both towards increasing efficiency. Such intermediate consumption (in terms of imported and domestic components of costs) was modelled, under which the indicator of the share of GVA of Ukraine would correspond to the level in Poland. The optimised data obtained form the basis for strategic planning, as they show what the output (by manufacturability) and intermediate consumption should be to ensure the desired level of economic efficiency of the Ukrainian processing industry.

AbstractRecent years have seen the development of a variety of mammalian library approaches for display and secretion mode. Advantages include library approaches for engineering, preservation of precious immune repertoires and their repeated interrogation, as well as screening in final therapeutic format and host. Mammalian display approaches for antibody optimization exploit these advantages, necessitating the generation of large libraries but in turn enabling early screening for both manufacturability and target specificity. For suitable libraries, high antibody integration rates and resulting monoclonality need to be balanced – we present a solution for sufficient transmutability and acceptable monoclonality by applying an optimized ratio of coding to non-coding lentivirus. The recent advent of microfluidic-assisted hit discovery represents a perfect match to mammalian libraries in secretion mode, as the lower throughput fits well with the facile generation of libraries comprising a few million functional clones. In the presented work, Chinese Hamster Ovary cells were engineered to both express the target of interest and secrete antibodies in relevant formats, and specific clones were strongly enriched by high throughput screening for autocrine cellular binding. The powerful combination of mammalian secretion libraries and microfluidics-assisted hit discovery could reduce attrition rates and increase the probability to identify the best possible therapeutic antibody hits faster.

Aligned discontinuous fibre-reinforced composites are becoming more popular because they have the potential to offer stiffness and strength comparable to their continuous counterparts along with better manufacturability. However, the modelling of highly aligned discontinuous fibre composites is still in its infancy. This paper aims to provide a comprehensive review of the available literature to understand how modelling techniques have developed and consider whether all aspects which could affect the performance of aligned discontinuous fibre composites have been addressed. Here, for the first time, a broad view of the advantages, perspectives, and limitations of current approaches to modelling the performance and behaviour of aligned discontinuous fibre composites during alignment, forming, and mechanical loading is provided in one place as a route to design optimisation.

The concept of chiplet was proposed in the post-Moore era. How to layout the multiple chips with different processes and sizes in the package structure is a problem that needs to be considered as different layouts may significantly affect the manufacturability during the packaging process. XDFOI-O is a 2.5D organic interposer structure with a significant coefficient of thermal expansion mismatch in it. Different layouts may cause excessive stress concentration in the package structure, as well as large wafer warpage, which can affect the normal operations of the production line. Stress accumulation on specific chiplet during the wafer thinning process is another manufacturability problem, leading to chip cracking. Prospective finite element analysis can be applied to evaluate the various layouts. In simulation work, different placement processes of dummy chips as stiffeners, as well as different chiplet thicknesses and underfill coverage, can be used as factors for simulation studies, thereby making a reference for further chiplet package design. [ABSTRACT FROM AUTHOR]

The studies were carried out in 2017–2022 in the Khabarovsk krai to identify the diversity of the collection material of 170 samples of soybeans of various ecological and geographical origin with the prospect of their further use in the breeding process when creating new varieties. The weather conditions of 2017 and 2018 were the closest to the climatic norm with HTC 2.1 and 2.2, respectively. The years 2019 (HTC = 3.0), 2020 (HTC = 2.7) and 2022 (HTC = 2.5) were characterized by excessive humidity. On the contrary, 2021 was the hottest and driest year (HTC = 0.9). Basically, the collection was represented by varieties from the Russian Federation (46.5%) and European countries (34.1%) with a growing season period ranging from 93 to 149 days. Twenty-two varieties with a growing season of up to 100 days were selected as the source material in breeding for early maturity and five highly productive varieties with a seed weight per plant of more than 33 g. According to the number of beans per plant (more than 80 pcs.), five midearly and two midripening variety samples were identified, by seed weight (more than 250 g), eight and nine variety samples, respectively. Three variety samples, forming three–four beans in a productive joint, were identified in the midearly ripening group. It is necessary to expand the search for high-protein forms, involving well-known sources in the study. Accessions K-6777, K-9837 (Germany), K-4842 (Russian Federation), K-9922 (France), K-5564 (China), K-6795 (Poland), which showed the best performance in terms of a set of traits, are of particular interest. [ABSTRACT FROM AUTHOR]

Recent years have seen the development of a variety of mammalian library approaches for display and secretion mode. Advantages include library approaches for engineering, preservation of precious immune repertoires and their repeated interrogation, as well as screening in final therapeutic format and host. Mammalian display approaches for antibody optimization exploit these advantages, necessitating the generation of large libraries but in turn enabling early screening for both manufacturability and target specificity. For suitable libraries, high antibody integration rates and resulting monoclonality need to be balanced - we present a solution for sufficient transmutability and acceptable monoclonality by applying an optimized ratio of coding to non-coding lentivirus. The recent advent of microfluidic- assisted hit discovery represents a perfect match to mammalian libraries in secretion mode, as the lower throughput fits well with the facile generation of libraries comprising a few million functional clones. In the presented work, Chinese Hamster Ovary cells were engineered to both express the target of interest and secrete antibodies in relevant formats, and specific clones were strongly enriched by high throughput screening for autocrine cellular binding. The powerful combination of mammalian secretion libraries and microfluidics-assisted hit discovery could reduce attrition rates and increase the probability to identify the best possible therapeutic antibody hits faster. [ABSTRACT FROM AUTHOR]

As in all sectors of science and industry, artificial intelligence (AI) is meant to have a high impact in the discovery of antibodies in the coming years. Antibody discovery was traditionally conducted through a succession of experimental steps: animal immunization, screening of relevant clones, in vitro testing, affinity maturation, in vivo testing in animal models, then different steps of humanization and maturation generating the candidate that will be tested in clinical trials. This scheme suffers from different flaws, rendering the whole process very risky, with an attrition rate over 95%. The rise of in silico methods, among which AI, has been gradually proven to reliably guide different experimental steps with more robust processes. They are now capable of covering the whole discovery process. Amongst the players in this new field, the company MAbSilico proposes an in silico pipeline allowing to design antibody sequences in a few days, already humanized and optimized for affinity and developability, considerably de-risking and accelerating the discovery process.

CAD-CAE software companies have introduced numerous tools aimed at facilitating topology optimization through Finite Element Simulation, thereby enhancing accessibility for designers via user-friendly interfaces. However, the imposition of intricate constraint conditions or additional restrictions during calculations may introduce instability into the resultant outcomes. In this paper, an algorithm for updating the design variables called Adaptive Variable Design is proposed to keep the final design space volume of the optimized part consistently under the target value while giving the main algorithm multiple chances to update the optimization parameters and search for a valid design. This algorithm aims to produce results that are more conducive to manufacturability and potentially more straightforward in interpretation. A comparison between several commercial software packages and the proposed algorithm, implemented in MATLAB R2023a, is carried out to prove the robustness of the latter. By simulating identical parts under similar conditions, we seek to generate comparable results and underscore the advantages stemming from the adoption and comprehension of the proposed topology optimization methodology. Our findings reveal that the integrated enhancements within MATLAB pertaining to the topology optimization process yield favourable outcomes with respect to discretization and the manufacturability of the resultant geometries. Furthermore, we assert that the methodology evaluated within MATLAB holds promise for potential integration into commercial packages, thereby enhancing the efficiency of topology optimization processes.

Additive manufacturing of bio-ceramics using LCD stereolithography allows the creation of ceramic parts with unprecedented resolution for various medical applications. However, the potential of this technology can only be fully harnessed if the manufacturability of critical geometries is accurately characterized. Thus, this contribution provides a guide with examples for the characterization and analysis of the printability of β-tricalcium phosphate-filled resins using LCD stereolithography. Characterized features include the minimum bore diameter, the minimum wall thickness of free-standing walls and cylindrical pins, the maximum unsupported bridging and overhang and the maximum abrupt thickness changes of cylindrical components. The analysis addresses limitations and factors affecting manufacturability of bio-ceramic-filled resins, and gives recommendations for design and processing parameters. In addition, TGA analysis is presented as a guide for the selection of suitable debinding and sintering schedules for an optimized microstructure and functionality.

ABSTRACTT-cell-engaging bispecific antibodies (T-bsAbs) are promising immunotherapies for cancer treatment due to their capability of redirecting T-cells toward destroying tumor cells. Numerous T-bsAb formats have been developed, each with advantages and disadvantages in terms of developability, immunogenicity, effector functions, and pharmacokinetics. Here, we systematically compared T-bsAbs produced using eight different formats, evaluating the effect of molecular design of T-bsAbs on their manufacturability and functionality. These eight T-bsAb formats were constructed using antigen-binding fragments (Fabs) and single-chain variable fragments (scFvs) of antibodies linked to the crystallizable fragment (Fc) domain of immunoglobulin G. To ensure a fair comparison of growth and production data, we used recombinase-mediated cassette exchange technology to generate the T-bsAb-producing CHO cell lines. The produced T-bsAbs were assessed for their purification profile and recovery, binding capability, and biological activities. Our findings indicated that the manufacturability of bsAbs was adversely affected with increased number of scFv building blocks, while the functionality was affected by the combination of multiple factors, including the binding affinity and avidity of targeting moieties and the flexibility and geometry of formats. These results provide valuable insights into the impact of the format design on the optimal production and function of T-bsAbs.

ABSTRACTWith the growing significance of antibodies as a therapeutic class, identifying developability risks early during development is of paramount importance. Several high-throughput in vitro assays and in silico approaches have been proposed to de-risk antibodies during early stages of the discovery process. In this review, we have compiled and collectively analyzed published experimental assessments and computational metrics for clinical antibodies. We show that flags assigned based on in vitro measurements of polyspecificity and hydrophobicity are more predictive of clinical progression than their in silico counterparts. Additionally, we assessed the performance of published models for developability predictions on molecules not used during model training. We find that generalization to data outside of those used for training remains a challenge for models. Finally, we highlight the challenges of reproducibility in computed metrics arising from differences in homology modeling, in vitro assessments relying on complex reagents, as well as curation of experimental data often used to assess the utility of high-throughput approaches. We end with a recommendation to enable assay reproducibility by inclusion of controls with disclosed sequences, as well as sharing of structural models to enable the critical assessment and improvement of in silico predictions.

ABSTRACTAntibody drugs should exhibit not only high-binding affinity for their target antigens but also favorable physicochemical drug-like properties. Such drug-like biophysical properties are essential for the successful development of antibody drug products. The traditional approaches used in antibody drug development require significant experimentation to produce, optimize, and characterize many candidates. Therefore, it is attractive to integrate new methods that can optimize the process of selecting antibodies with both desired target-binding and drug-like biophysical properties. Here, we summarize a selection of techniques that can complement the conventional toolbox used to de-risk antibody drug development. These techniques can be integrated at different stages of the antibody development process to reduce the frequency of physicochemical liabilities in antibody libraries during initial discovery and to co-optimize multiple antibody features during early-stage antibody engineering and affinity maturation. Moreover, we highlight biophysical and computational approaches that can be used to predict physical degradation pathways relevant for long-term storage and in-use stability to reduce the need for extensive experimentation.

The assessment of manufacturability of fiberglass parts in small-scale and repair production is presented. The objects of study are materials based on epoxy binders, the curing of which occurs at elevated temperatures. To compare the manufacturability of various molding processes, composites based on dispersed fillers and thermoplastic matrices are also considered. The results of expert assessments of manufacturability are presented, which show that molding processes, consisting of technological operations that are similar in content, differ significantly from each other in cost and material intensity. [ABSTRACT FROM AUTHOR]

Urgency of the research. The contradiction between technological and biological as a marker of scientific and technological shifts of modern civilization is a modification of the conflict / contradiction of two cultures – technical and spiritual culture. If the first is undergoing an unprecedented development, then it is the spiritual culture that needs special attention, which is connected with the rethinking of the existing system of values, namely humanistic guidelines as a matrix responsible for the idea of preserving humanity. Such humanistic constants as responsibility, openness, freedom, tolerance, compassion, the ability to compromise, moderation are primarily those components without which science, scientific activity remains the embodiment of the instrumental mind, turning into selfworth. Target setting. Science as a sociocultural phenomenon is one of the main factors of modern transformation. Understanding the meaning of the latter unfolds in the coordinates “efficiency – success – productivity”, which correlates with the problem of truth / falsity of scientific knowledge, which can be understood as a problem of scientificity and non-scientific nature. If classical science was defined in the system of cause-andeffect relationships / linearity, nonclassical science became possible in a dialectical dimension, then post-nonclassical science unfolds in the coordinates of multiplicity / plurality / variability, which makes it impossible to have a single paradigm. The specified polyparadigmality articulates the problem of non-scientific knowledge and its importance in overcoming the absolutization of scientific centrism, which acquires special importance in the situation of technological modernity. Actual scientific researches and issues analysis. The works of T. Kuhn, I. Lakatos, K. Popper, B. Russell, P. Feyerabend, and others are devoted to the study of modes of scientific and nonscientific knowledge. Among Ukrainian researchers, it is worth mentioning I. Zagriichuk, S. Krymsky, M. Popovych, L. Drotyanko, I. Chornomordenko. The research objective. Turning to non-scientific knowledge in the challenges of technological modernity presupposes the following tasks: to investigate nonscientific knowledge in the context of the opposition “Science – Humanity’s”; to reveal the meaning of non-scientific knowledge as a condition for preventing the monologism of science; determine the relationship between scientific and nonscientific knowledge as an opportunity to create a single integrated platform that overcomes the discontinuity / dualism of two cultures, thereby actualizing the internal potential for the development of humanity as a world community The statement of basic materials. The article is devoted to the study of the problem of scientific and non-scientific knowledge, which is fundamentally related to the understanding of the possible horizons of human activity, which appears as a result of the latter’s self-development. Modern civilization, as a technological one, has not resolved the conflict between scientific and technical development and the value system, which gives rise to a multitude of contradictions, one of which is the “lagging behind” of the humanitarian component from the intensive development of the technological component. Conclusions. The question of the relationship between scientific and nonscientific knowledge, about the possible prospects for the further development of humanity, about the possibility of a single integral platform that overcomes the discontinuity / dualism of two cultures at the beginning of the 21st century, is taking on a new configuration. It is about the existing potential of non-scientific knowledge in the current situation, primarily the strengthening of interaction between the elements of the “philosophy – science – education” system, because the lack of internal coordination can lead to the formation of a technocratic culture. The connection of humanities and natural sciences is a project of realizing the sustainable development of humanity and is a condition for the preservation of the essence of man. [ABSTRACT FROM AUTHOR]

This study presents a new robust formulation for the topology optimization of compliant mechanisms, addressing the design challenges while considering manufacturability, static strength, and fatigue failure. A three-field density projection is implemented to control the minimum size of both real-phase and null-phase material structures to meet the manufacturing process requirements. The static strength is evaluated via the sum of the amplitude and the mean absolute value of the signed von Mises stress. The fatigue failure is solved via the modified Goodman criterion. The real output displacement is optimized by adding artificial springs to the prescribed value. This approach is implemented based on an improved solid isotropic material with penalization (SIMP) interpolation method to describe and solve the optimization model and derive the shape sensitivity of the optimization problem. Finally, two numerical examples are applied to illustrate the effectiveness of the presented method. [ABSTRACT FROM AUTHOR]

Additive Manufacturing (AM) is the process of joining materials by selectively depositing them layer upon layer for the purpose of manufacturing parts or assemblies which are based on a 3D digital model. The nature of these processes results in the morphing of complex component geometries, enabling a high degree of design freedom and resulting in lightweight structures with increased performance. These processes, however, experience many limitations regarding manufacturability. The aim of this study is to develop a method and tool that optimizes the design of a component to avoid overhanging geometries and the need for supports during the Additive Manufacturing process. A workflow consisting of steps for topology optimization, orientation optimization, material addition, and machine code generation is described and implemented using Rhinoceros 3D and Grasshopper software. The proposed workflow is compared to a conventional workflow regarding manufacturing Key Performance Indicators (KPIs) such as part volume, support volume, and build time. A significant reduction is observed regarding all the KPIs by using the proposed method. Examining the results from both the conventional workflow and the proposed one, it is clear that the latter has unquestionable advantages in terms of effectiveness. In the particular case study presented, a total volume reduction of around 80% is observed. The reduction in the total volume (including the required support volume) leads to a significant reduction in the material used as well as in the build time, consequently resulting in cost reduction. [ABSTRACT FROM AUTHOR]

Natural Killer (NK) cells are a type of innate lymphoid cells that play a crucial role in immunity by killing virally infected or tumor cells and secreting cytokines and chemokines. NK cell-mediated immunotherapy has emerged as a promising approach for cancer treatment due to its safety and effectiveness. NK cell engagers (NKCEs), such as BiKE (bispecific killer cell engager) or TriKE (trispecific killer cell engager), are a novel class of antibody-based therapeutics that exhibit several advantages over other cancer immunotherapies harnessing NK cells. By bridging NK and tumor cells, NKCEs activate NK cells and lead to tumor cell lysis. A growing number of NKCEs are currently undergoing development, with some already in clinical trials. However, there is a need for more comprehensive studies to determine how the molecular design of NKCEs affects their functionality and manufacturability, which are crucial for their development as off-the-shelf drugs for cancer treatment. In this review, we summarize current knowledge on NKCE development and discuss critical factors required for the production of effective NKCEs. [ABSTRACT FROM AUTHOR]

Introduction. Modern methods of executing total building renovation are based on the principles of flow and scientific methods of labour organisation, developed with due regard for the specific features of certain types of repair and construction works technologies. The following labour-intensiveness and duration of work, material-intensiveness, cost and production cost of constructions are considered as the main indicators of work production technology in the course of overhaul repair. Each of these indicators has corresponding reserves, which are identified and used to improve the manufacturability of production of each type of work, as well as on the building as a whole.Materials and methods. The article is based on the method of assessing the effectiveness of various options to reduce the duration of work, which directly affects the change in technological parameters. A ranking among contractors has been carried out to identify the reserves for increasing labour productivity, as well as to identify bona fide contractors for customers.Results. The developed methodology of evaluation of manufacturability of overhaul works allows contractors to justify for customers the proposals on reduction of terms and cost of overhaul works. The use of the developed organizational and technological mechanism in practice of interaction of all participants of capital repair process will allow not only to achieve the highest indicators, but also will serve as a basis for actualization of normative documents on total building renovation.Conclusions. The method of efficiency estimation of different variants of work time reduction and related changes of technological parameters according to Wald, Savage and Hurwitz criteria allowed to establish the most preferable construction-technological solution. The developed rating assessment of contractors will, on the basis of achieved results, enable to reveal reserves of increasing labour productivity in the course of repair-construction works and to encourage these organizations to be more preferable in carrying out competitive procedures of selecting contractors by the customer. The identified reserves of reducing the duration of overhaul works are used as a basis for the formation of measures to improve the manufacturability of works.

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Copyright of Automobile Technology & Material is the property of Automobile Technology & Material Editorial Office and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Copyright of Herald of Journalism / Habaršy Žurnalistika Seriâsy is the property of Al-Farabi Kazakh National University and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Continuum topology optimization considering the vibration response is of great value in the engineering structure design. The aim of this study is to address the topological design optimization of harmonic excitation structures with minimum length scale control to facilitate structural manufacturing. A structural topology design based on discrete variables is proposed to avoid localized vibration modes, gray regions and fuzzy boundaries in harmonic excitation topology optimization. The topological design model and sensitivity formulation are derived. The requirement of minimum size control is transformed into a geometric constraint using the discrete variables. Consequently, thin bars, small holes, and sharp corners, which are not conducive to the manufacturing process, can be eliminated from the design results. The present optimization design can efficiently achieve a 0–1 topology configuration with a significantly improved resonance frequency in a wide range of excitation frequencies. Additionally, the optimal solution for harmonic excitation topology optimization is not necessarily symmetric when the load and support are symmetric, which is a distinct difference from the static optimization design. Hence, one-half of the design domain cannot be selected according to the load and support symmetry. Numerical examples are presented to demonstrate the effectiveness of the discrete variable design for excitation frequency topology optimization, and to improve the design manufacturability. [ABSTRACT FROM AUTHOR]

Investment casting is usually employed for producing industrial castings for different sectors including aerospace, automobile, bio-medical, chemical, defense and many more. Frequently, decision to manufacture any industrial component using investment casting process is mainly driven by many factors associated with geometry, desired features as well as manufacturability of industrial components. In this work, five-layered hierarchical structure-based novel Cumulative Complexity Index (CCI) has been developed for making appropriate decision to select investment casting process for manufacturing any industrial component. Top layer is comprised of CCI that is further categorized into three categories of Complexity Index (CI) including characteristics of geometry characteristics, desired features and manufacturability of an industrial component. The CIs are categorized into various 19 elements and further into 52 attributes. These attributes with 212 meta-attributes are employed to compute CCI (in the scale from 0 to 100). As the value of CCI is higher, complexity involved in manufacturing industrial component using investment casting is higher. The proposed concept of CCI is tested on different industrial case studies, and found very useful in making decision to select investment casting process for manufacturing those industrial components. This can be easily embedded with any existing tool on design for casting. [ABSTRACT FROM AUTHOR]

Introduction. The issue of revising the existing regulatory documents at the stage of operation of residential buildings becomes relevant due to the need to take into account scientific and technological achievements in the field of standardization. The emergence of new building materials, technological methods of manufacturing structures, methods of performing repair and construction work leads to the need for an ongoing update of the regulatory framework of construction. The object of the study is a set of regulatory documents focused on the stage of operation of construction facilities. The purpose of the work is to prepare proposals for updating, correcting and supplementing the regulatory framework governing the stage of operation of construction facilities.Materials and methods. The task of this work is to analyze the domestic regulatory framework affecting the concept of ope­ration of construction facilities, to make a classification of requirements for capital construction facilities at this stage and to structure regulatory technical documents.Results. Proposals were developed to adjust, supplement and update the regulatory framework of the operation stage.Conclusions. Within the framework of this study, regulatory technical and methodological documents affecting the concept of the stage of operation of buildings and structures are systematized and analyzed; a list of regulatory documents requiring adjustments and additions is made.

When using the technology of long-line formwork-free shaping for the manufacture of reinforced concrete structures, industrial engineering can be conducted in accordance with the requirements of modern regulatory documents. This allows projects to be developed individually, and production lines can be readjusted in a short time in accordance with emerging needs. In this regard, the possibility of using reinforced concrete posts produced by the technology of long-line formwork-free shaping for 0.4-10 kV overhead line supports is being considered. The designs of such supports are developed on the standard basis of the product range. The problem of establishing the minimum number (two) of cross-sections with different geometric dimensions for all brands of the offered posts is solved, subject to the operational requirements and technological specifications of production. The cross-sections of the proposed posts represent trapeziums, with the dimensions of the upper bases smaller than the dimensions of the lower bases in order to maintain the shape of the freshly formed concrete body of the posts made using long-line formwork-free shaping technology. For posts up to 11.0 m long, a solid cross-section with trapezoid edges is proposed: h = 245 mm; b = 150 mm (an upper base); b1 = 180 mm (a lower base). In the middle part of the cross-section of posts with a length of 11.0 to 16.4 m there is a cavity along the entire length of the posts. Cross-sectional dimensions of such posts are h = 300 mm; b = 205 mm, b1 = 235 mm. Long-line formwork-free shaping technology provides for the reinforcement of prestressed structures with high-strength wire or rope reinforcement. The proposed posts are rein-forced with 5Вр1400 rods, therefore, during their operation, the formation of cracks in the tensile zone of concrete is not fore-seen. The rods are located in groups at all corner sections along the cross-section of the post with an equal number of rods in each group, taking into account the technological features of the long-line formwork-free shaping. For the proposed cross-section of hollow posts, produced by long-line formwork-free shaping for 0.4–10 kV overhead line supports, a patent for autility model has been obtained from the Agency for Intellectual Property of Uzbekistan. Qualitative characteristics of the posts for overhead line supports are low material consumption, versatility, manufacturability, innovation, which lies in the fact that their implementation is associated with the design, manufacture and testing of experimental products for use by specific consumers, i. e. with the commercialization.

Feature recognition and manufacturability analysis from computer-aided design (CAD) models are indispensable technologies for better decision making in manufacturing processes. It is important to transform the knowledge embedded within a CAD model to manufacturing instructions for companies to remain competitive as experienced baby-boomer experts are going to retire. Automatic feature recognition and computer-aided process planning have a long history in research, and recent developments regarding algorithms and computing power are bringing machine learning (ML) capability within reach of manufacturers. Feature recognition using ML has emerged as an alternative to conventional methods. This study reviews ML techniques to recognize objects, features, and construct process plans. It describes the potential for ML in object or feature recognition and offers insight into its implementation in various smart manufacturing applications. The study describes ML methods frequently used in manufacturing, with a brief introduction of underlying principles. After a review of conventional object recognition methods, the study discusses recent studies and outlooks on feature recognition and manufacturability analysis using ML. [ABSTRACT FROM AUTHOR]