Bioengineering — Open Access Journal

Translational research for new drugs, medical devices, and diagnostics encompasses aspects of both basic science and clinical research, requiring multidisciplinary skills and resources that are not all readily available in either a basic laboratory or clinical setting alone. We propose that, to be successful, “translational” research ought to be understood as a defined process from basic science through manufacturing, regulatory, clinical testing all the way to market. The authors outline a process which has worked well for them to identify and commercialize academic innovation. The academic environment places a high value on novelty and less value on whether, among other things, data are reproducible, scalable, reimbursable, or have commercial freedom to operate. In other words, when investors, strategic companies, or other later stage stakeholders evaluate academic efforts at translational research the relative lack of attention to clinical, regulatory, reimbursement, and manufacturing and intellectual property freedom to operate almost universally results in more questions and doubts about the potential of the proposed product, thereby inhibiting further interest. This contrasts with industry-based R&D, which often emphasizes manufacturing, regulatory and commercial factors. Academics do not so much choose to ignore those necessary and standard elements of translation development, but rather, they are not built into the culture or incentive structure of the university environment. Acknowledging and addressing this mismatch of approach and lack of common language in a systematic way facilitates a more effective “translation” handoffs of academic project concepts into meaningful clinical solutions help translational researchers more efficiently develop and progress new and better medical products which address validated needs. The authors provide an overview and framework for academic researchers to use which will help them define the elements of a market-driven translational program (1) problem identification and validation; (2) defining the conceptual model of disease; and (3) risk evaluation and mitigation strategies. Full article

The separation of blood components (WBCs, RBCs, and platelets) is important for medical applications. Recently, standing surface acoustic wave (SSAW) microfluidic devices are used for the separation of particles. In this paper, the design analysis of SSAW microfluidics is presented. Also, the analysis of SSAW force with Rayleigh angle effect and its attenuation in liquid-loaded substrate, viscous drag force, hydrodynamic force, and diffusion force are explained and analyzed. The analyses are provided for selecting the piezoelectric material, width of the main microchannel, working area of SAW, wavelength, minimum input power required for the separation process, and widths of outlet collecting microchannels. The design analysis of SSAW microfluidics is provided for determining the minimum input power required for the separation process with appropriated the displacement contrast of the particles.The analyses are applied for simulation the separation of blood components. The piezoelectric material, width of the main microchannel, working area of SAW, wavelength, and minimum input power required for the separation process are selected as LiNbO₃, 120 μm, 1.08 mm², 300 μm, 371 mW. The results are compared to other published results. The results of these simulations achieve minimum power consumption, less complicated setup, and high collecting efficiency. All simulation programs are built by MATLAB. Full article

Successful scale-up of bioprocesses requires that laboratory-scale performance is equally achieved during large-scale production to meet economic constraints. In industry, heuristic approaches are often applied, making use of physical scale-up criteria that do not consider cellular needs or properties. As a consequence, large-scale productivities, conversion yields, or product purities are often deteriorated, which may prevent economic success. The occurrence of population heterogeneity in large-scale production may be the reason for underperformance. In this study, an in silico method to predict the formation of population heterogeneity by combining computational fluid dynamics (CFD) with a cell cycle model of Pseudomonas putida KT2440 was developed. The glucose gradient and flow field of a 54,000 L stirred tank reactor were generated with the Euler approach, and bacterial movement was simulated as Lagrange particles. The latter were statistically evaluated using a cell cycle model. Accordingly, 72% of all cells were found to switch between standard and multifork replication, and 10% were likely to undergo massive, transcriptional adaptations to respond to extracellular starving conditions. At the same time, 56% of all cells replicated very fast, with µ ≥ 0.3 h⁻¹ performing multifork replication. The population showed very strong heterogeneity, as indicated by the observation that 52.9% showed higher than average adenosine triphosphate (ATP) maintenance demands (12.2%, up to 1.5 fold). These results underline the potential of CFD linked to structured cell cycle models for predicting large-scale heterogeneity in silico and ab initio. Full article

Cyanobacteria, as photoautotrophic organisms, provide the opportunity to convert CO2 to biomass with light as the sole energy source. Like many other prokaryotes, especially under nutrient deprivation, most cyanobacteria are able to produce polyhydroxyalkanoates (PHAs) as intracellular energy and carbon storage compounds. In contrast to heterotrophic PHA producers, photoautotrophic cyanobacteria do not consume sugars and, therefore, do not depend on agricultural crops, which makes them a green alternative production system. This review summarizes the recent advances in cyanobacterial PHA production. Furthermore, this study reports the working experience with different strains and cultivating conditions in a 200 L pilot plant. The tubular photobioreactor was built at the coal power plant in Dürnrohr, Austria in 2013 for direct utilization of flue gases. The main challenges were the selection of robust production strains, process optimization, and automation, as well as the CO2 availability. Full article

The effects of microwave-assisted alkali pre-treatment on pellets’ characteristics and enzymatic saccharification for bioethanol production using lignocellulosic biomass of canola straw and oat hull were investigated. The ground canola straw and oat hull were immersed in distilled water, sodium hydroxide and potassium hydroxide solutions at two concentrations (0.75% and 1.5% w/v) and exposed to microwave radiation at power level 713 W and three residence times (6, 12 and 18 min). Bulk and particle densities of ground biomass samples were determined. Alkaline-microwave pre-treated and untreated samples were subjected to single pelleting test in an Instron universal machine, pre-set to a load of 4000 N. The measured parameters, pellet density, tensile strength and dimensional stability were evaluated and the results showed that the microwave-assisted alkali pre-treated pellets had a significantly higher density and tensile strength compared to samples that were untreated or pre-treated by microwave alone. The chemical composition analysis showed that microwave-assisted alkali pre-treatment was able to disrupt and break down the lignocellulosic structure of the samples, creating an area of cellulose accessible to cellulase reactivity. The best enzymatic saccharification results gave a high glucose yield of 110.05 mg/g dry sample for canola straw ground in a 1.6 mm screen hammer mill and pre-treated with 1.5% NaOH for 18 min, and a 99.10 mg/g dry sample for oat hull ground in a 1.6 mm screen hammer mill and pre-treated with 0.75% NaOH for 18 min microwave-assisted alkali pre-treatments. The effects of pre-treatment results were supported by SEM analysis. Overall, it was found that microwave-assisted alkali pre-treatment of canola straw and oat hull at a short residence time enhanced glucose yield. Full article

This paper presents the design optimization of diaphragms for a micro-shock tube-based drug delivery device. The function of the diaphragm is to impart the required velocity and direction to the loosely held drug particles on the diaphragm through van der Waals interaction. The finite element model-based studies involved diaphragms made up of copper, brass and aluminium. The study of the influence of material and geometric parameters serves as a vital tool in optimizing the magnitude and direction of velocity distribution on the diaphragm surface. Experiments carried out using a micro-shock tube validate the final deformed shape of the diaphragms determined from the finite element simulation. The diaphragm yields a maximum velocity of 335 m/s for which the maximum deviation of the velocity vector is 0.62°. Drug particles that travel to the destination target tissue are simulated using the estimated velocity distribution and angular deviation. Further, a theoretical model of penetration helps in the prediction of the drug particle penetration in the skin tissue like a target, which is found to be 0.126 mm. The design and calibration procedure of a micro-shock tube device to alter drug particle penetration considering the skin thickness and property are presented. Full article

In this study, an umbrella-shaped device that is used for osteonecrosis treatment is simulated. The femoral head is subjected to various complex loadings as a result of a person’s daily movements. Implant devices used in the body are made of shape memory alloy materials because of their remarkable resistance to wear and corrosion, good biocompatibility, and variable mechanical properties. Since this NiTi umbrella-shaped implant is simultaneously under several loadings, a 3-D model of shape memory alloy is utilized to investigate the behavior of the implant under different conditions. Shape memory and pseudo-elasticity behavior of NiTi is analyzed using a numerical model. The simulation is performed within different temperatures and in an isothermal condition with varied and complex loadings. The objective of this study is to evaluate the performance of the device under thermal and multi-axial forces via numerically study. Under tensile loading, the most critical points are on the top part of the implant. It is also shown that changes in temperature have a minor effect on the Von Mises stress. Applied forces and torques have significant influence on the femoral head. Simulations results indicate that the top portion of the umbrella is under the most stress when embedded in the body. Consequently, the middle, curved portion of the umbrella is under the least amount of stress. Full article

Sugarcane bagasse was torrefied to improve its quality in terms of properties prior to gasification. Torrefaction was undertaken at 300 °C in an inert atmosphere of N₂ at 10 °C·min⁻¹ heating rate. A residence time of 5 min allowed for rapid reaction of the material during torrefaction. Torrefied and untorrefied bagasse were characterized to compare their suitability as feedstocks for gasification. The results showed that torrefied bagasse had lower O–C and H–C atomic ratios of about 0.5 and 0.84 as compared to that of untorrefied bagasse with 0.82 and 1.55, respectively. A calorific value of about 20.29 MJ·kg⁻¹ was also measured for torrefied bagasse, which is around 13% higher than that for untorrefied bagasse with a value of ca. 17.9 MJ·kg⁻¹. This confirms the former as a much more suitable feedstock for gasification than the latter since efficiency of gasification is a function of feedstock calorific value. SEM results also revealed a fibrous structure and pith in the micrographs of both torrefied and untorrefied bagasse, indicating the carbonaceous nature of both materials, with torrefied bagasse exhibiting a more permeable structure with larger surface area, which are among the features that favour gasification. The gasification process of torrefied bagasse relied on computer simulation to establish the impact of torrefaction on gasification efficiency. Optimum efficiency was achieved with torrefied bagasse because of its slightly modified properties. Conversion efficiency of the gasification process of torrefied bagasse increased from 50% to approximately 60% after computer simulation, whereas that of untorrefied bagasse remained constant at 50%, even as the gasification time increased. Full article

An improved state estimation technique for bioprocess control applications is proposed where a hybrid version of the Unscented Kalman Filter (UKF) is employed. The underlying dynamic system model is formulated as a conventional system of ordinary differential equations based on the mass balances of the state variables biomass, substrate, and product, while the observation model, describing the less established relationship between the state variables and the measurement quantities, is formulated in a data driven way. The latter is formulated by means of a support vector regression (SVR) model. The UKF is applied to a recombinant therapeutic protein production process using Escherichia coli bacteria. Additionally, the state vector was extended by the specific biomass growth rate µ in order to allow for the estimation of this key variable which is crucial for the implementation of innovative control algorithms in recombinant therapeutic protein production processes. The state estimates depict a sufficiently low noise level which goes perfectly with different advanced bioprocess control applications. Full article

This paper presents a systematic investigation into monomer development during mixed culture Polyhydroxyalkanoates (PHA) accumulation involving concurrent active biomass growth and polymer storage. A series of mixed culture PHA accumulation experiments, using several different substrate-feeding strategies, was carried out. The feedstock comprised volatile fatty acids, which were applied as single carbon sources, as mixtures, or in series, using a fed-batch feed-on-demand controlled bioprocess. A dynamic trend in active biomass growth as well as polymer composition was observed. The observations were consistent over replicate accumulations. Metabolic flux analysis (MFA) was used to investigate metabolic activity through time. It was concluded that carbon flux, and consequently copolymer composition, could be linked with how reducing equivalents are generated. Full article

Thisstudy aims to compute 50 Hz electric field interferences on pacemakers for diverse lead configurations and implantation positions. Induced phenomena in a surface-based virtual human model (standing male grounded with arms closed, 2 mm resolution) are computed for vertical exposure using CST EM^® 3D software, with and without an implanted pacemaker. Induced interference voltages occurring on the pacemaker during exposure are computed and the results are discussed. The bipolar mode covers 99% of the implanted pacing leads in the USA and Europe, according to statistics. The tip-to-ring distance of a lead may influence up to 46% of the induced voltage. In bipolar sensing mode, right ventricle implantation has a 41% higher induced voltage than right atrium implantation. The induced voltage is in average 10 times greater in unipolar mode than in bipolar mode, when implanted in the right atrium or right ventricle. The electric field threshold of interference for a bipolar sensing mode in the worst case setting is 7.24 kV·m⁻¹, and 10 times higher for nominal settings. These calculations will be completed by an in vitro study. Full article

Interactions of nanoparticles with biological matter—both somatically and in nature—draw scientists’ attention. Nanoparticulate systems are believed to be our saviors, acting as versatile drug delivery vehicles. However, they can also cause life-threatening bodily damage. One of the most important properties of nanocrystalline cerium dioxide is its antioxidant activity, which decreases the abundance of reactive oxygen species during inflammation. In this paper, we report on synergistic effects of inorganic cerium oxide (IV) nanoparticles conjugated with the antioxidative enzymes superoxide dismutase and catalase on scavenging oxygen and nitrogen radicals. Full article

Hybridoma cells are commonly grown for the production of monoclonal antibodies (MAb). For monitoring and control purposes of the bioreactors, dynamic models of the cultures are required. However these models are difficult to infer from the usually limited amount of available experimental data and do not focus on target protein production optimization. This paper explores an experimental case study where hybridoma cells are grown in a sequential batch reactor. The simplest macroscopic reaction scheme translating the data is first derived using a maximum likelihood principal component analysis. Subsequently, nonlinear least-squares estimation is used to determine the kinetic laws. The resulting dynamic model reproduces quite satisfactorily the experimental data, as evidenced in direct and cross-validation tests. Furthermore, model predictions can also be used to predict optimal medium renewal time and composition. Full article

Bioactive glasses are able to bond to bone and stimulate the growth of new tissue while dissolving over time, which makes them ideal materials for regenerative medicine. The advent of mesoporous glasses, which are typically synthesized via sol-gel routes, allowed researchers to develop a broad and versatile class of novel biomaterials that combine superior bone regenerative potential (compared to traditional melt-derived glasses) with the ability of incorporating drugs and various biomolecules for targeted therapy in situ. Mesoporous glass particles can be directly embedded as a bioactive phase within a non-porous (e.g., microspheres), porous (3D scaffolds) or injectable matrix, or be processed to manufacture a surface coating on inorganic or organic (macro)porous substrates, thereby obtaining hierarchical structures with multiscale porosity. This review provides a picture of composite systems and coatings based on mesoporous glasses and highlights the challenges for the future, including the great potential of inorganic–organic hybrid sol-gel biomaterials. Full article

Cells respond to their mechanical environment in different ways: while their response in terms of differentiation and proliferation has been widely studied, the question of the direction in which cells align when subject to a complex mechanical loading in a 3D environment is still widely open. In the present paper, we formulate the hypothesis that the cells orientate in the direction of unitary stretch computed from the right Cauchy-Green tensor in a given mechanical environment. The implications of this hypothesis are studied in different simple cases corresponding to either the available in vitro experimental data or physiological conditions, starting from finite element analysis results to computed preferential cellular orientation. The present contribution is a first step to the formulation of a deeper understanding of the orientation of cells within or at the surface of any 3D scaffold subject to any complex load. It is believed that these initial preferential directions have strong implications as far as the anisotropy of biological structures is concerned. Full article

Several methodologies have been devised for the design of nanomaterials. The “Holy Grail” for materials scientists is the cost-effective, eco-friendly synthesis of nanomaterials with controlled sizes, shapes and compositions, as these features confer to the as-produced nanocrystals unique properties making them appropriate candidates for valuable bio-applications. The present review summarizes published data regarding the production of nanomaterials with special features via sustainable methodologies based on the utilization of natural bioresources. The richness of the latter, the diversity of the routes adopted and the tuned experimental parameters have led to the fabrication of nanomaterials belonging to different chemical families with appropriate compositions and displaying interesting sizes and shapes. It is expected that these outstanding findings will encourage researchers and attract newcomers to continue and extend the exploration of possibilities offered by nature and the design of innovative and safer methodologies towards the synthesis of unique nanomaterials, possessing desired features and exhibiting valuable properties that can be exploited in a profusion of fields. Full article

RNA nanotechnology is attracting a great deal of attention recently. As the multiple roles that RNA plays in molecular biology and physiological regulation become clearer, there are many opportunities for engineering RNA-Nanoparticle Complexes (RNA-NPCs). The high “engineerability” of RNA-NPCs comes from the ability to modify the RNA and NP chemistry. For example, the NP can be derived from materials with anticancer activity and the RNA delivered by it, designed to target cell signaling pathways that contribute to the molecular basis of these diseases. Despite this rapid advancement and the availability of new quantification and characterization techniques, a key challenge is to develop a better understanding of the RNA-nanobio interface; that is, the interactions of RNA with NP (RNA-nanobio interface) and how that impacts the structure, function, delivery, and activity of the RNA. Here, we attempt to summarize the state-of-the-art in this new and exciting field, and to lay out potential directions for bioengineering research on RNA-NPCs. Full article

The cell membrane is the interface that volumetrically isolates cellular components from the cell’s environment. Proteins embedded within and on the membrane have varied biological functions: reception of external biochemical signals, as membrane channels, amplification and regulation of chemical signals through secondary messenger molecules, controlled exocytosis, endocytosis, phagocytosis, organized recruitment and sequestration of cytosolic complex proteins, cell division processes, organization of the cytoskeleton and more. The membrane’s bioelectrical role is enabled by the physiologically controlled release and accumulation of electrochemical potential modulating molecules across the membrane through specialized ion channels (e.g., Na⁺, Ca²⁺, K⁺ channels). The membrane’s biomechanical functions include sensing external forces and/or the rigidity of the external environment through force transmission, specific conformational changes and/or signaling through mechanoreceptors (e.g., platelet endothelial cell adhesion molecule (PECAM), vascular endothelial (VE)-cadherin, epithelial (E)-cadherin, integrin) embedded in the membrane. Certain mechanical stimulations through specific receptor complexes induce electrical and/or chemical impulses in cells and propagate across cells and tissues. These biomechanical sensory and biochemical responses have profound implications in normal physiology and disease. Here, we discuss the tools that facilitate the understanding of mechanosensitive adhesion receptors. This article is structured to provide a broad biochemical and mechanobiology background to introduce a freshman mechano-biologist to the field of mechanotransduction, with deeper study enabled by many of the references cited herein. Full article

Novel strategies are required to manufacture customized oral solid dosage forms for personalized medicine applications. 3D Pharming, the direct printing of pharmaceutical tablets, is an attractive strategy, since it allows for the rapid production of solid dosage forms containing custom drug dosages. This study reports on the design and characterization of a biocompatible photocurable pharmaceutical polymer for inkjet 3D printing that is suitable for hydrophilic active pharmaceutical ingredients (API). Specifically, hyaluronic acid was functionalized with norbornene moieties that, in the presence of poly(ethylene) glycol dithiol, Eosin Y as a photoinitiator, and a visible light source, undergoes a rapid step-growth polymerization reaction through thiol-ene chemistry. The engineered bioink was loaded with Ropinirole HCL, dispensed through a piezoelectric nozzle onto a blank preform tablet, and polymerized. Drug release analysis of the tablet resulted in 60% release within 15 min of tablet dissolution. The study confirms the potential of inkjet printing for the rapid production of tablets through the deposition of a photocurable bioink designed for hydrophilic APIs. Full article

The current work investigates the capability of a tailored multivariate curve resolution–alternating least squares (MCR-ALS) algorithm to analyse glucose, phosphate, ammonium and acetate dynamics simultaneously in an E. coli BL21 fed-batch fermentation. The high-cell-density (HCDC) process is monitored by ex situ online attenuated total reflection (ATR) Fourier transform infrared (FTIR) spectroscopy and several in situ online process sensors. This approach efficiently utilises automatically generated process data to reduce the time and cost consuming reference measurement effort for multivariate calibration. To determine metabolite concentrations with accuracies between ±0.19 and ±0.96·gL^−l, the presented utilisation needs primarily—besides online sensor measurements—single FTIR measurements for each of the components of interest. The ambiguities in alternating least squares solutions for concentration estimation are reduced by the insertion of analytical process knowledge primarily in the form of elementary carbon mass balances. Thus, in this way, the established idea of mass balance constraints in MCR combines with the consistency check of measured data by carbon balances, as commonly applied in bioprocess engineering. The constraints are calculated based on online process data and theoretical assumptions. This increased calculation effort is able to replace, to a large extent, the need for manually conducted quantitative chemical analysis, leads to good estimations of concentration profiles and a better process understanding. Full article