Cell Residence Time Research Articles

Design and Characterization of Ocular Inserts Loaded with Dexamethasone for the Treatment of Inflammatory Ophthalmic Disease.

The short precorneal residence time of ophthalmic drops is associated with their low absorption; therefore, the development of ocular inserts capable of prolonging and controlling the ophthalmic release of drugs is an interesting option in the design and development of these drugs. A surface response design was developed, specifically the Central Composite Design (CCD), to produce ophthalmic films loaded with Dexamethasone (DEX) by the solvent evaporation method having experimental levels of different concentrations of previously selected polymers (PVP K-30 and Eudragit RS100.). Once optimization of the formulation was obtained, the in vivo test was continued. The optimal formulation obtained a thickness of 0.265 ± 0.095 mm, pH of 7.11 ± 0.04, tensile strength of 15.50 ± 3.94 gF, humidity (%) of 22.54 ± 1.7, mucoadhesion strength of 16.89 ± 3.46 gF, chemical content (%) of 98.19 ± 1.124, release of (%) 13,510.71, and swelling of 0.0403 ± 0.023 g; furthermore, in the in vivo testing the number and residence time of PMN cells were lower compared to the Ophthalmic Drops. The present study confirms the potential use of polymeric systems using PVPK30 and ERS100 as a new strategy of controlled release of ophthalmic drugs by controlling and prolonging the release of DEX at the affected site by decreasing the systemic effects of the drug.

Activated Carbon Electrodes Obtained from Crude Glycerol for Capacitive Deionization Desalination

The freshwater demand increases over the years to attend agriculture, industry, and human consumption demand. Water desalination by capacitive deionization (CDI) would be an interesting strategy to provide freshwater for populations suffering of water scarcity in arid and semi-arid regions in which brackish groundwater is available. CDI is an electrochemical technique based on the removal of ions using carbon electrodes. Besides low-cost, activated carbons (AC) produced from renewable sources are also desired due to sustainability demands. In parallel, appropriate routes for disposal or reuse of crude glycerol from biodiesel plants are also a major current concern (10 kg of biodiesel generates ~1.0 kg of glycerol). So, considering the water-waste nexus concept, in this work we proposed the use of crude glycerol as precursor to obtain a new sustainable activated carbon (PGAC), which was employed as an electrode for CDI desalination of brackish water. The crude glycerol is firstly converted to polyglycerol, which is carbonized and then chemically activated. The best desalination performance using the PGAC electrodes was achieved using membrane CDI configuration, applying 1.6 V, providing a stable salt adsorption capacity (SAC) of 27.1 mg of NaCl removed per g of PGAC over 50 desalination cycles. At this condition, co-ion repulsion is minimized and the charging efficiency (QE ) remained close to 100%. The high values of SAC and QE , along with the low cost of PGAC electrode, led to a very low specific energy consumption (2.6 J per mg of NaCl removed), compared to other values reported in literature, making it a potential candidate for use in CDI desalination. In order to further improve the desalination performance, a new cell architecture was proposed, named percolation flow cell (PFC). The PFC cell combines the fast mass transfer rates of the flow-through cell (FTC) configuration and longer residence time of flow-by cells (FBC), in which the flow velocity and electric current fields are perpendicular. Taking advantage of the beneficial aspects of the FBC and FTC designs, the desalination carried out using the PFC was enhanced by 170 %, providing a remarkable water desalination rate of 1661 mg g-1 day-1 at 1.0 mA cm-2 and single pass operation (7.0 mL min-1). Despite these advantages, the high pressure drop (0.12 bar cm-1) imposes a challenging issue for the effective application of PFE cells.

Co-feeding strategy alleviates hypoxic stress in large-scale bioreactor for optimal production of secretory recombinant proteins in Pichia pastoris.

The loss of mixing efficiency inherent to bioreactor process operated at large-scale yields to the formation of concentration gradient and thus to heterogeneous culture conditions. For processes operated with methanol feeding, P. pastoris faces oscillatory culture conditions that significantly affect the cell ability to produce secretory recombinant proteins at high yield. Extended cell residence time in microenvironments of high methanol concentration and low oxygen availability that are typically found in the upper part of the bioreactor near the feeding point, triggers the unfolded protein response (UPR) and thus impairs proper protein secretion. Methanol co-feeding with sorbitol was shown herein to reduce the UPR response and to restore productivity of secreted protein.

Bipolar Membrane Capacitive Deionization for pH-Assisted Ionic Separations

Selective ionic separations represent an increasingly important technical area for the strategic interests of the U.S. economy─for example, securing critical minerals and materials and circular economy aspirations that include recovering organic acids from processed biomass. This work disseminates bipolar membrane (BPM) capacitive deionization for selective ionic separations from multicomponent, ionic species mixtures. The selective separations are guided by the Pourbaix diagram and acid–base equilibria principles. BPM capacitive deionization was demonstrated to generate alkaline or acidic process streams depending upon the location of the BPM in the electrochemical cell. The role of system operating parameters, such as the cell voltage, residence time, and feed concentration on effluent stream pH was studied. It was observed that the pH adjustment in BPM-CDI/MCDI (MCDI, membrane capacitive deionization) was more sensitive to the cell voltage when compared to the process stream residence time and salt feed concentration. The BPM-MCDI gave over 6 times higher percentage of copper(II) removal when compared to sodium ion removal from brine mixtures. Finally, BPM-MCDI demonstrated over 40% greater removal for copper ions from brine mixtures and fivefold higher removal for itaconic acid from brine mixtures when benchmarked against a traditional flow-by-MCDI setup.

A time-step-robust algorithm to compute particle trajectories in 3-D unstructured meshes for Lagrangian stochastic methods

Abstract The purpose of this paper is to propose a time-step-robust cell-to-cell integration of particle trajectories in 3-D unstructured meshes in particle/mesh Lagrangian stochastic methods. The main idea is to dynamically update the mean fields used in the time integration by splitting, for each particle, the time step into sub-steps such that each of these sub-steps corresponds to particle cell residence times. This reduces the spatial discretization error. Given the stochastic nature of the models, a key aspect is to derive estimations of the residence times that do not anticipate the future of the Wiener process. To that effect, the new algorithm relies on a virtual particle, attached to each stochastic one, whose mean conditional behavior provides free-of-statistical-bias predictions of residence times. After consistency checks, this new algorithm is validated on two representative test cases: particle dispersion in a statistically uniform flow and particle dynamics in a non-uniform flow.

Is heterogeneity in large-scale bioreactors a real problem in recombinant protein synthesis by Pichia pastoris?

Culture medium heterogeneity is inherent in industrial bioreactors. The loss of mixing efficiency in a large-scale bioreactor yields to the formation of concentration gradients. Consequently, cells face oscillatory culture conditions that may deeply affect their metabolism. Herein, cell response to transient perturbations, namely high methanol concentration combined with hypoxia, has been investigated usinga two stirred-tank reactor compartiments(STR-STR) scale-down system and a Pichia pastoris strain expressing the gene encoding enhanced green fluorescent protein (eGFP) under the control of the alcohol oxidase 1 (AOX1) promoter. Cell residence times under transient stressing conditions were calculated based on the typical hydraulic circulation times of bioreactors of tens and hundreds cubic metres. A significant increase in methanol and oxygen uptake rates was observed as the cell residence time was increased. Stressful culture conditions impaired biomass formation and triggered cell flocculation. More importantly, both expression levels of genes under the control of pAOX1 promoter and eGFP specific fluorescence were higher in those oscillatory culture conditions, suggesting that those a priori unfavourable culture conditions in fact benefit to recombinant protein productivity. Flocculent cells were also identified as the most productive as compared to ovoid cells. KEY POINTS: • Transient hypoxia and high methanol trigger high level of recombinant protein synthesis • In Pichia pastoris, pAOX1 induction is higher in flocculent cells • Medium heterogeneity leads to morphological diversification.

CFD supported scale up of perfusion bioreactors in biopharma

The robust scale up of perfusion systems requires comparable conditions over all scales to ensure equivalent cell culture performance. As cells in continuous processes circulate outside the bioreactor, performance losses may arise if jet flow and stirring cause a direct connection between perfusion feed and return. Computational fluid dynamics can be used to identify such short circuit flows, assess mixing efficiencies, and eventually adapt the perfusion setup. This study investigates the scale up from a 2 L glass bioreactor to 100 L and 500 L disposable pilot scale systems. Highly resolved Lattice Boltzmann Large Eddy simulations were performed in single phase and mixing efficiencies (Emix) furthermore experimentally validated in the 2 L system. This evaluation gives insight into the flow pattern, the mixing behavior and information on cell residence time inside the bioreactors. No geometric adaptations in the pilot scale systems were necessary as Emix was greater than 90% for all conditions tested. Two different setups were evaluated in 2 L scale where the direction of flow was changed, yielding a difference in mixing efficiency of 10%. Nevertheless, since Emix was confirmed to be >90% also for both 2 L setups and the determined mixing times were in a similar range for all scales, the 2 L system was deemed to be a suitable scale down model. The results demonstrate how computational fluid dynamic models can be used for rational process design of intensified production processes in the biopharmaceutical industry.

Controlling bead and cell mobility in a recirculating hanging-drop network.

Integrating flowing cells, such as immune cells or circulating tumour cells, within a microphysiological system is crucial for body-on-a-chip applications. However, ensuring unimpeded recirculation of cells is a significant challenge. Closed microfluidic devices have a no-slip boundary condition along channel walls and a defined chip geometry (laminar flow) that hinders the ability to freely control cell flow. Open microfluidic devices, where the bottom device boundary is an air-liquid interface (ALI), e.g., hanging drop networks (HDNs), offer the advantage of an easily-actuatable fluid-phase geometry, where cells can either flow or stagnate. In this paper, we optimized a hanging-drop-integrated pneumatic-pump system for closed-loop recirculation of particles (i.e., beads or cells). Experiments with both beads and cells in cell culture medium initially resulted in particle stagnation, which was suggestive of a pseudo-no-slip boundary condition at the ALI. Transmission electron microscopy and dynamic light scattering measurements of the ALI suggested that aggregation of submicron-scale cell-culture-medium components is the cause of the pseudo-no-slip boundary condition. We used the finite element method to study the forces on particles at the ALI and to optimize HDN design (drop aperture) and operation (drop height) parameters. Based on this analysis, we report a phase diagram delineating the conditions for free flow or stagnation of particles at the ALI of hanging drops. Using our experimental setup with 3.5 mm drop apertures, we conducted particle flow experiments while actuating drop heights. We confirmed the ability to control the flow or stagnation of particles by actuating the height of hanging drops: a drop height over 300 μm led to particle stagnation and a drop height under 300 μm allowed for particle flow. This particle-flow control, combined with the ease of integrating scaffold-free organ models (microtissues or organoids) in HDNs, constitutes the basis for an experimental setup enabling the control of the residence time of single cells around 3D organ models.

Determination of biokinetic coefficients of an aerobic system for potato starch removal

This study presents an aerobic laboratory scale-reactor completely mixed performance for starch wastewater treatment. The reactor was operated for 119 days divided into 5 operational phases which included the start-up and the variation of cell-residence time. In order to determine the biokinetic coefficients for starch removal, the cell-residence time was varied between 20 to 4 days, and the system operation was set hydraulic retention time of 24 hours with a completely mixed reactor setup. The chemical oxygen demand concentration was 1000mg/L in the inflow of the reactor and dissolved oxygen remained above 2mg/L. In this experimentation time, the parameters such as pH, chemical oxygen demand (in the influent and effluent), dissolved oxygen and Mixed liquor suspended solids were monitored. The calculation of biokinetic constants was done by an approximate method, using the graphical Lineweaver-Burk method. The biokinetic coefficients determined were for Maximum substrate removal rate , Half saturation rate constant or affinity constant ( sludge yield coefficient (Y), and Microbial decay or indigenous respiration rate . The results showed that Y, , and ( were in the range of 0,3- 0,7 mgSSV/mgBOD5, 2- 8 Day1 and 40-120 mg/L (COD- BOD5), respectively. Values of the coefficients were within the range of those reported for conventional activated sludge processes.

Gelatin Microspheres Loaded with Wharton's Jelly Mesenchymal Stem Cells Promote Acute Full-Thickness Skin Wound Healing and Regeneration in Mice.

Objective: At present, there is an urgent need to develop a novel and practical therapeutic approach to accelerate the healing of acute wounds. Mesenchymal stem cell (MSC)-based therapy is emerging as a promising therapeutic approach for acute skin wounds. However, there are still challenges in clinical application of this strategy, such as low survivability, low retention time, and less engraftment in skin wounds. Approach: Wharton's jelly mesenchymal stem cells (WJMSCs) were seeded into three-dimensional (3D) gelatin microspheres (GMs) to identify the biocompatibility of GMs. WJMSCs were embedded in GMs and then encapsulated with Pluronic F-127 (PF-127) and sodium ascorbyl phosphate (SAP) combination to transplant onto acute full-thickness skin wound in mice. Histology, immunohistochemistry, and immunofluorescence assay were used to investigate the skin wound healing, dermis regeneration, collagen deposition, cell proliferation, and neovascularization. Results: Three-dimensional GM had strong biocompatibility, compared with two-dimensional adherent culturing, GM loading increased the cell viability and proliferation ability of WJMSCs. WJMSCs+GM+PF-127+SAP transplantation increased skin wound healing rate, dermis regeneration, and type III collagen deposition through improving macrophage polarization, cell proliferation, neovascularization, cell retention, and engraftment at skin wound site. Innovation: The effective 3D encapsulation technology for WJMSCs solved the main problems of cell activity and residence time during MSC transplantation. WJMSCs+GM+PF-127+SAP transplantation will be a new and effective MSC biomaterials-based therapeutic strategy for acute skin traumatic wounds. Conclusion: WJMSCs+GM+PF-127+SAP transplantation facilitated acute full-thickness skin wound healing and regeneration and might be a new and effective therapy for acute skin traumatic wounds.

A Novel Resource Oriented DMA Framework for Internet of Medical Things Devices in 5G Network

The Internet of Medical Things (IoMT) mobile devices such as ambulance, medical done, and emergency mobile medical equipment face severe signal distortions due to interference, end-to-end packet loss, handoff delays, and lower throughputs during mobility. Network mobility basic support protocol (NBSP) has been proposed using the IP-based Wi-Fi solution to solve these issues. However, the weak signal, extra signaling overhead, and higherdelays were identified during handover due to patients' excessive requisites, resulting in radio link failure. Therefore, this article proposes a novel resource-efficient flow-enabled distributed mobility anchoring (FDMA) framework enhancing the functionalities of the centralized network entities and mobility entities.The performance of the proposed FDMA framework is evaluated and compared with the standard NBSP and proxy NEMO (PNEMO) scheme in terms of the variable number of cell residence time and mobile routers, where the proposed framework outperformed NBSP and PNEMO schemes for IoMT Mobile devices in 5G network.

Performance and kinetics of a fluidized bed anaerobic reactor treating distillery effluent

Abstract The kinetic analysis of an anaerobic fluidized bed bioreactor treating distillery effluent was carried out. Natural zeolite was used as biomass carrier at various organic loading rates and hydraulic retention times (HRT). The degradation followed first order kinetics and fitted Michaelis–Menten kinetic model for substrate utilization. The kinetic analysis showed that 9% of the TOC was nonbiodegradable which corresponds to about 14% COD. The non-biodegradable component was responsible for the dark-brown color of the distillery effluent and therefore there was a need for employing a post-treatment technology for their removal. Biomass yield was found to be 0.4658 g/g while endogenic microorganisms decay coefficient was 0.0293, which suggested that there was a need to install a sludge handling unit prior to post-treatment. The maximum micro-organisms’ growth rate was found to be 0.136 d−1 while the specific growth rate of the micro-organisms reduced with an increase in HRT at constant feed concentration. The specific substrate utilization rate was found to increase linearly with an increase in the ration of food to micro-organisms and the mean cell residence time was found to be at least 2.5 times the HRT due to application of zeolite as microbial support in the reactor.

Oceanic carbon capture through electrochemically induced in situ carbonate mineralization using bipolar membrane

Bipolar membrane electrodialysis (BPMED) can provide a sustainable route to capture the oceanic-dissolved inorganic carbon (DIC) using an electrochemical pH-swing concept. Previous works demonstrated how gaseous CO2 (through acidification) can be obtained from ocean water, and how carbonate minerals can be provided via ex situ alkalinization. In this work, we present, for the first time, the in situ mineralization via the alkalinization route using both real and synthetic seawater. An in situ pH-swing, inside of the BPMED cell, allows reducing the energy consumption of the oceanic-DIC capture. We demonstrate that, by accurately controlling the applied current density and cell residence time, the energy required for the process can be indeed lowered through facilitating an optimized pH in the cell (i.e., base-pH 9.6–10). Within this alkaline pH-window, we capture between 60% (for real seawater) up to 85% (for synthetic seawater) of the DIC from the feed, together with minor Mg(OH)2 precipitates. The CaCO3(s) production increases linearly with the applied current density, with a theoretical maximum extraction of 97 %. The energy consumption is dominated by the ohmic losses and BPM-overpotential. Through tuning the current density and flow rate, we optimised the energy consumption by applying a mild in situ pH-swing of ca. pH 3.2 – 9.75 (for real seawater). As a result, aragonite was extracted by using of 318 ± 29 kJ mol−1 CaCO3(s) (i.e., ca. 0.88 kWh kg−1 CaCO3(s)) from real seawater in a cell containing ten bipolar – cation exchange membrane cell pairs, which is less than half of the previously lowest energy consumption for carbonate mineralization from (synthetic) seawater.

Reaction mechanism development and investigation on the convergence influence in a 1D catalyst model for a γ-alumina stabilized three-way catalyst

Accurate and computational cost-effective modeling tools for the optimization of processes and devices of all kinds are needed in nearly all scientific fields. While experimental optimization entails high expenses in terms of cost and time virtual optimization may be a promising alternative. In this work, the suitability and accuracy of a 1D heterogeneous catalytic model is investigated. First, the influence of cell discretization and residence time on the convergence in a 1D catalyst model are investigated. Second, the catalyst model is investigated and validated with use of a stoichiometric steady state three-way catalyst experiment. With the help of these investigations the reaction mechanism is further developed and new reaction rates for two reactions are presented. The modeling results are compared to a 2D simulation approach in terms of computational time and catalyst conversion behavior. The presented model is capable to capture the experimental results with a drastically reduced computational time in comparison to the 2D simulation presented in literature.

Aeration and non-aeration cycles (AE/NA) time: influence in combined organic matter and nitrogen removal and features of biofilm

ABSTRACT This research aimed the performance evaluation of a structured bed reactor with different cycles of Intermittent Aeration (IA)(SBRRIA) in the municipal sewage treatment and the verification of the effect of IA cycles on the total nitrogen (TN) removal and organic matter (COD). Three IA cycles were evaluated: phase I (4 h AE (aeration on) – 2 h NA (aeration off)); II (2 h AE–1 h NA) and III (2 h AE–2 h NA), with Hydraulic Retention Time of 16 h. The best nitrogen removal was obtained during phase II, with the lowest non-aeration time: efficiency of nitrification, denitrification, TN and COD removal of 80 ± 15%, 82 ± 12%, 67 ± 6% and 94 ± 7%, respectively. The mean cell residence time was 19, 26 and 33 d in phases I, II and III, respectively. The statistical analysis applied to the AE/NA profiles showed that the time of AE and NA in the cycles did not influence nitrogen and organic matter removal. Thus, this indicates the recirculation and the gradient formed in the support material facilitate the process of Simultaneous Nitrification and Denitrification. The lowest concentration of nitrifying and denitrifying microorganisms was obtained in effluent and sludge at the end of phase III. From the TP (Total Proteins)/TPS (Total Polysaccharides) ratio obtained (0.8 ± 0.1, 1.3 ± 0.1 e 1.5 ± 0.1 in phases I, II and III), it was possible to conclude that the biofilm in phase I was more porous, with a thin layer if compared to that in phase II and III.

Vegetable and fruit market wastes as an appropriate source for biogas production via anaerobic digestion process

Abstract Urban waste management is a critical issue in today’s world. On the other hand, energy supply is a significant need, especially from renewable sources. In this paper, an efficient method is studied for the production of biogas from vegetable and fruit market wastes. A comprehensive study is presented on the production of methane in biogas from vegetable and fruit market wastes. For this purpose, a reactor was designed and vegetable and fruit market wastes were used as feed of the reactor for biogas production. For supplying the moisture during the gas formation, the feed was mixed with distilled water in 1:1 ratio. The mean cell residence time was set at 25 days. The results showed an intense sensitivity of the microorganism to the pH of the reactor. In acidic media, the produced biogas was very lower than neutral and slightly basic media. In addition, the percentage of the methane in the biogas showed to be increased by increasing pH from 6.3 to 7.6.

Polymeric Microspheres Containing Human Vocal Fold Fibroblasts for Vocal Fold Regeneration.

Most acellular injectable biomaterials for vocal fold (VF) wound treatment have limited regenerative potential due to their fast enzymatic degradation and limited recruitment of native cells postinjection. The injection of cells as therapeutic treatment often results in apoptosis due to stresses within the needle and the immune response of the host. Degradable microspheres may improve treatment effectiveness by increasing cell residence time, shielding cells during injection, and offering early protection against the immune system response. The objective of the present study was to investigate the potential of human VF fibroblasts encapsulated in polymeric microspheres as an injectable therapeutic treatment in vitro. Alginate, alginate-poly-L-lysine, and alginate-chitosan microspheres were fabricated using electrospraying and characterized in terms of biocompatibility, swelling, and mechanical properties as well as cytokine production. Alginate microspheres were found to have the most desirable properties for VF regeneration. They were resistant to mechanical challenges. They were found to have a stiffness similar to that reported for native VF-lamina propria. They were found to be biocompatible and increased the proliferation of fibroblasts. Human VF fibroblasts encapsulated in alginate microspheres induced the production of interleukin (IL)-8 and IL-4 at 24 hours. The alginate microspheres fabricated in this study were found to offer potential advantages, as cell delivery tool. This study highlights the importance of combining biomaterials and cells to expedite the wound-healing process through cytokine production. Future work is aimed to further analysis of the wound-healing properties the microspheres. NA Laryngoscope, 131:1828-1834, 2021.

Analytical solution of reactive hybrid cells in series (HCIS) model for pollution transport through the rivers

ABSTRACT The application of accurate transport models is critical in tracer routing through river reaches. Reactive models are widely used because of the reaction and degradation properties of some pollutants with bed and bank materials, and cell-based theoretical models are among the most popular for contaminant transport simulation. This study investigates the reactive form of cells in a series model. A new analytical equation is proposed that includes a degradation term for sudden mass release in a river reach. To consider the inaccuracy of previously proposed equations, we attempted to rearrange separate transport actions such as advection, dispersion and degradation through the cells of a length unit. The cell residence times of mixed cells were equated, and the degradation action was only forced to the second cell. The parameter number of the solution was lower than in previously proposed models. Synthetic datasets of the advection–dispersion–degradation equation were used to examine model performance. The model was found to work well in the first and later units. The numerical convolution method was used in the second to fourth units, and it also fitted synthetic data. The previously proposed equation of reactive HCISD was imprecise in the convolution method.

A Seamless Mobility Management Protocol in 5G Locator Identificator Split Dense Small Cells

Network densification with Small Cells (SCs) has emerged as a key technique to increase the 5G network capacity. However, in a densified network, fast mobile nodes will experience frequent handovers with a high signaling load, handover latency, and packet loss, due to the short cell radius. Indeed, Distributed Mobility Management (DMM) protocols aim to solve the shortcomings of centralized mobility management solutions such as poor scalability and non-optimal routing. However, when the cell residence time is short, DMM protocols might suffer from increased costs and limited performance. This paper proposes a localized mobility management protocol in 5G dense SCs, based on the locator identifier separation protocol, local mobility anchoring, and fast handovers concepts. The proposed scheme divides a local domain into several location service areas, each controlled by a local anchor. We provide the analytical models of several handover metrics, namely the average total signaling cost, the data delivery cost, the handover latency, and the packet loss. Numerical and simulation results show significant cost savings, up to 30 percent in signaling overhead, up to 53 percent of packet loss, and up to 90 percent of processing load reduction at the core of the network compared to the existing lisp mobile node protocol.

Scale-down studies for the scale-up of a recombinant Corynebacterium glutamicum fed-batch fermentation: loss of homogeneity leads to lower levels of cadaverine production.

BACKGROUNDThe loss of efficiency and performance of bioprocesses on scale‐up is well known, but not fully understood. This work addresses this problem, by studying the effect of some fermentation gradients (pH, glucose and oxygen) that occur at the larger scale in a bench‐scale two‐compartment reactor [plug flow reactor (PFR) + stirred tank reactor (STR)] using the cadaverine‐producing recombinant Corynebacterium glutamicum DM1945 Δact3 Ptuf‐ldcC_OPT. The new scale‐down strategy developed here studied the effect of increasing the magnitude of fermentation gradients by considering not only the average cell residence time in the PFR (), but also the mean frequency at which the bacterial cells entered the PFR () section of the two‐compartment reactor.RESULTSOn implementing this strategy the cadaverine production decreased on average by 26%, 49% and 59% when the was increased from 1 to 2 min and then 5 min respectively compared to the control fermentation. The carbon dioxide productivity was highest (3.1‐fold that of the control) at a of 5 min, but no losses were observed in biomass production. However, the population of viable but non‐culturable cells increased as the magnitude of fermentation gradients was increased. The new scale‐down approach was also shown to have a bigger impact on fermentation performance than the traditional one.CONCLUSIONThis study demonstrated that C. glutamicum DM1945 Δact3 Ptuf‐ldcC_OPT physiological response was a function of the magnitude of fermentation gradients simulated. The adaptations of a bacterial cell within a heterogeneous environment ultimately result in losses in fermentation productivity as observed here. © 2019 The Authors. Journal of Chemical Technology & Biotechnology published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry.