Specific growth rate observer for the growing phase of a Polyhydroxybutyrate production process.

This paper focuses on the specific growth rate estimation problem in a Polyhydroxybutyrate bioplastic production process by industrial fermentation. The kinetics of the process are unknown and there are uncertainties in the model parameters and inputs. During the first hours of the growth phase of the process, biomass concentration can be measured online by an optical density sensor, but as cell density increases this method becomes ineffective and biomass measurement is lost. An asymptotic observer is developed to estimate the growth rate for the case without biomass measurement based on corrections made by a pH control loop. Furthermore, an exponential observer based on the biomass measurement is developed to estimate the growth rate during the first hours, which gives the initial condition to the asymptotic observer. Error bounds and robustness to uncertainties in the models and in the inputs are found. The estimation is independent of the kinetic models of the microorganism. The characteristic features of the observer are illustrated by numerical simulations and validated by experimental results.

Modeling and estimation of production rate for the production phase of non-growth-associated high cell density processes.

This paper addresses the estimation of the specific production rate of intracellular products and the modeling of the bioreactor volume dynamics in high cell density fed-batch reactors. In particular, a new model for the bioreactor volume is proposed, suitable to be used in high cell density cultures where large amounts of intracellular products are stored. Based on the proposed volume model, two forms of a high-order sliding mode observer are proposed. Each form corresponds to the cases with residual biomass concentration or volume measurement, respectively. The observers achieve finite time convergence and robustness to process uncertainties as the kinetic model is not required. Stability proofs for the proposed observer are given. The observer algorithm is assessed numerically and experimentally.

Model-based scale-up methodology for aerobic fed-batch bioprocesses: application to polyhydroxybutyrate (PHB) production.

This work presents a general model-based methodology to scale-up fed-batch bioprocesses. The idea behind this approach is to establish a dynamics hierarchy, based on a model of the process, that allows the designer to determine the proper scale factors as well as at which point of the fed-batch the process should be scaled up. Here, concepts and tools of linear control theory, such as the singular value decomposition of the Hankel matrix, are exploited in the context of process design. The proposed scale-up methodology is first described in a bioprocesses general framework highlighting its main features, key variables and parameters. Then, it is applied to a polyhydroxybutyrate (PHB) fed-batch bioreactor and compared with three empirical criteria, that are traditionally employed to determine the scale factors of these processes, showing the usefulness and distinctive features of this proposal. Moreover, this methodology provides theoretical support to a frequently used empirical rule: scale-up aerobic bioreactors at constant volumetric oxygen transfer coefficient. Finally, similar process dynamic behavior and PHB production set at the laboratory scale are predicted at the new operating scale, while it is also determined that is rarely possible to reproduce similar dynamic behavior of the bioreactor using empirical scale-up criteria.

Auto adaptation of closed-loop insulin delivery system using continuous reward functions and incremental discretization.

Several closed or hybrid loop controllers for Blood Glucose (BG) regulation, which are also known as Artificial Pancreas (AP) Systems or Automated Insulin Delivery systems (AIDs), are in development worldwide. Most AIDs are designed and evaluated for short-term performance, with a particular emphasis on the post-meal period. However, if controllers are not adapted properly to account for variations in physiology that affect Insulin Sensitivity (IS), the AIDs may perform inadequately. In this work, the performance of two Reinforcement Learning (RL) agents trained under both piecewise and continuous reward functions is evaluated in-silico for long-term adaptation of a Fully Automated Insulin Delivery (fAID) system. An automatic adaptive discretization scheme that expands the state space as needed is also implemented to avoid disproportionate state space exploration. The proposed agents are evaluated for long-term adaptation of the Automatic Regulation of Glucose (ARG) algorithm, considering variations in IS. Results show that both RL agents have improved performance compared to a rule-based decision-making approach and the baseline controller for the majority of the adult population. Moreover, the use of a continuous shaped reward function proves to enhance the performance of the agents further than a piecewise one.

First Outpatient Clinical Trial of a Full Closed-Loop Artificial Pancreas System in South America.

BACKGROUND: The first two studies of an artificial pancreas (AP) system carried out in Latin America took place in 2016 (phase 1) and 2017 (phase 2). They evaluated a hybrid algorithm from the University of Virginia (UVA) and the automatic regulation of glucose (ARG) algorithm in an inpatient setting using an AP platform developed by the UVA. The ARG algorithm does not require carbohydrate (CHO) counting and does not deliver meal priming insulin boluses. Here, the first outpatient trial of the ARG algorithm using an own AP platform and doubling the duration of previous phases is presented. METHOD: Phase 3 involved the evaluation of the ARG algorithm in five adult participants (n = 5) during 72 hours of closed-loop (CL) and 72 hours of open-loop (OL) control in an outpatient setting. This trial was performed with an own AP and remote monitoring platform developed from open-source resources, called InsuMate. The meals tested ranged its CHO content from 38 to 120 g and included challenging meals like pasta. Also, the participants performed mild exercise (3-5 km walks) daily. The clinical trial is registered in ClinicalTrials.gov with identifier: NCT04793165. RESULTS: The ARG algorithm showed an improvement in the time in hyperglycemia (52.2% [16.3%] OL vs 48.0% [15.4%] CL), time in range (46.9% [15.6%] OL vs 50.9% [14.4%] CL), and mean glucose (188.9 [25.5] mg/dl OL vs 186.2 [24.7] mg/dl CL) compared with the OL therapy. No severe hyperglycemia or hypoglycemia episodes occurred during the trial. The InsuMate platform achieved an average of more than 95% of the time in CL. CONCLUSION: The results obtained demonstrated the feasibility of outpatient full CL regulation of glucose levels involving the ARG algorithm and the InsuMate platform.

Reaction rate reconstruction from biomass concentration measurement in bioreactors using modified second-order sliding mode algorithms.

This paper deals with the estimation of unknown signals in bioreactors using sliding observers. Particular attention is drawn to estimate the specific growth rate of microorganisms from measurement of biomass concentration. In a recent article, notions of high-order sliding modes have been used to derive a growth rate observer for batch processes. In this paper we generalize and refine these preliminary results. We develop a new observer with a different error structure to cope with other types of processes. Furthermore, we show that these observers are equivalent, under coordinate transformations and time scaling, to the classical super-twisting differentiator algorithm, thus inheriting all its distinctive features. The new observers' family achieves convergence to time-varying unknown signals in finite time, and presents the best attainable estimation error order in the presence of noise. In addition, the observers are robust to modeling and parameter uncertainties since they are based on minimal assumptions on bioprocess dynamics. In addition, they have interesting applications in fault detection and monitoring. The observers performance in batch, fed-batch and continuous bioreactors is assessed by experimental data obtained from the fermentation of Saccharomyces Cerevisiae on glucose.

Practical constraint definition in safety schemes for artificial pancreas systems.

INTRODUCTION: Artificial pancreas systems usually define an insulin-on-board constraint (IOB¯) for safety schemes to limit the insulin infusion and avoid hypoglycemia during the closed-loop performance. Several methods have been proposed with impractical considerations requiring information from the prandial events or complex procedures for ambulatory use. METHODS: This paper presents a simple method that consists of two novel rules that allow finding an IOB¯ based only on common clinical parameters that do not require patient intervention. The method robustness was evaluated using a control system coupled to a safety layer under demanding scenarios implemented on the FDA-approved simulator for preclinical studies. RESULTS: The method maintains a safe performance, even in the face of interpatient variability, hybrid and fully automatic implementations of an artificial pancreas system, and uncertain settings. Both proposed rules work as effectively or even better and without the patient intervention than other methods that have already been clinically validated. CONCLUSION: This method can be used to define a constant IOB¯ that ensures performance and safety of the control system, even under scenarios with incorrect clinical data. Unlike other methods, this method only requires reliable information that is easily obtained from the patient, such as their total daily dose of insulin or body mass.

A Dual-Hormone Multicontroller for Artificial Pancreas Systems.

Artificial pancreas (AP) algorithms can be divided into single-hormone (SH) and dual-hormone (DH). SH algorithms regulate glycemia using insulin as their control input. On the other hand, DH algorithms also use glucagon to counteract insulin. While SH-AP systems are already commercially available, DH-AP systems are still in an earlier research phase. DH-AP systems have been questioned since the added complexity of glucagon infusion does not always guarantee hypoglycemia prevention and might significantly raise insulin delivery. In this work, a DH multicontroller is proposed based on a SH linear quadratic gaussian (LQG) algorithm with an additional LQG controller to deliver glucagon. This strategy has a switched structure that allows activating one of the following three controllers when necessary: a conservative insulin LQG controller to modulate basal delivery ( K1), an aggressive insulin LQG controller to counteract meals ( K2), or a glucagon LQG controller to avoid imminent hypoglycemia ( K3). Here, an in silico study of the benefits of incorporating controller K3 is carried out. Intra-patient variability and mixed meals are considered. Results indicate that the proposed switched, dual-hormone strategy yields to a reduction in hypoglycemia without increasing hyperglycemia, with no significant rise in insulin delivery.

Extended SEIR Model for Health Policies Assessment Against the COVID-19 Pandemic: the Case of Argentina.

This work presents an extended and age-band compartmentalised SEIR model that allows describing the spread evolution of SARS-CoV-2 and evaluating the effect of different detection rates, vaccination strategies or immunity periods. The model splits up the population into fifteen age groups of 5 years each, linked through a statistical interaction matrix that includes seventeen health states within each age group. An age-dependent transmission rate takes into account infectious between the groups as well the effect of interventions such as quarantines and mobility restrictions. Further, the proposal includes a nonlinear switched controller for model tuning purposes guarantying a simple and fast adjusting process. To illustrate the model potentials, the particular case of COVID-19 evolution in Argentina is analysed by simulation of three scenarios: (i) different detection levels combined with mobility restrictions, (ii) vaccination campaigns with re-opening of activities and (iii) vaccination campaigns with possible reinfections. The results exhibit how the model can aid the authorities in the decision making process.

Non-pharmaceutical intervention to reduce COVID-19 impact in Argentina.

This work is focused on the multilevel control of the population confinement in the city of Buenos Aires and its surroundings due to the pandemic generated by the COVID-19 outbreak. The model used here is known as SEIRD and two objectives are sought: a time-varying identification of the infection rate and the inclusion of a controller. A control differential equation has been added to regulate the transitions between confinement and normal life, according to five different levels. The plasma treatment from recovered patients has also been considered in the control algorithm. Using the proposed strategy the ICU occupancy is reduced, and as a consequence, the number of deaths is also decreased.