Closed-loop Drug Delivery System Research Articles

Closed-loop automated drug infusion regulator: A clinically translatable, closed-loop drug delivery system for personalized drug dosing

Dosing of chemotherapies is often calculated according to the weight and/or height of the patient or equations derived from these, such as body surface area (BSA). Such calculations fail to capture intra- and interindividual pharmacokinetic variation, which can lead to order of magnitude variations in systemic chemotherapy levels and thus under- or overdosing of patients. We designed and developed a closed-loop drug delivery system that can dynamically adjust its infusion rate to the patient to reach and maintain the drug's target concentration, regardless of a patient's pharmacokinetics (PK). We demonstrate that closed-loop automated drug infusion regulator (CLAUDIA) can control the concentration of 5-fluorouracil (5-FU) in rabbits according to a range of concentration-time profiles (which could be useful in chronomodulated chemotherapy) and over a range of PK conditions that mimic the PK variability observed clinically. In one set of experiments, BSA-based dosing resulted in a concentration 7 times above the target range, while CLAUDIA keeps the concentration of 5-FU in or near the targeted range. Further, we demonstrate that CLAUDIA is cost effective compared to BSA-based dosing. We anticipate that CLAUDIA could be rapidly translated to the clinic to enable physicians to control the plasma concentration of chemotherapy in their patients. This work was supported by MIT's Karl van Tassel (1925) Career Development Professorship and Department of Mechanical Engineering and the Bridge Project, a partnership between the Koch Institute for Integrative Cancer Research at MIT and the Dana-Farber/Harvard Cancer Center.

Performance of closed-loop systems for intravenous drug administration: a systematic review and meta-analysis of randomised controlled trials.

Closed-loop drug delivery systems are autonomous computers able to administer medication in response to changes in physiological parameters (controlled variables). While limited evidence suggested that closed-loop systems can perform better than manual drug administration in certain settings, this technology remains a research tool with an uncertain risk/benefit profile. Our aim was comparing the performance of closed-loop systems with manual intravenous drug administration in adults. We searched MEDLINE, CENTRAL, and Embase from inception until November 2022, without restriction to language. We assessed for inclusion randomised controlled trials comparing closed-loop and manual administration of intravenous drugs in adults, intraoperatively or in the Intensive Care Unit. We identified 32 studies on closed-loop administration of propofol, noradrenaline, phenylephrine, insulin, neuromuscular blockers, and vasodilators. Most studies were at moderate or high risk of bias. The results showed that closed-loop systems reduced the duration of blood pressure outside prespecified targets during noradrenaline (MD 14.9%, 95% CI 9.6-20.2%, I2 = 66.6%) and vasodilators administration (MD 7.4%, 95% CI 5.2-9.7%, I2 = 62.3%). Closed-loop systems also decreased the duration of recovery after propofol (MD 1.3min, 95% CI 0.4-2.1min, I2 = 58.6%) and neuromuscular blockers (MD 9.0min, 95% CI 7.9-10.0min, I2 = 0%). The certainty of the evidence was low or very low for most outcomes. Automatic technology may be used to improve the hemodynamic profile during noradrenaline and vasodilators administration and reduce the duration of postanaesthetic recovery.Registration: This systematic review was registered with PROSPERO (CRD42022336950) on the 7th of June 2022.

Intelligent automated drug administration and therapy: future of healthcare.

In the twenty-first century, the collaboration of control engineering and the healthcare sector has matured to some extent; however, the future will have promising opportunities, vast applications, and some challenges. Due to advancements in processing speed, the closed-loop administration of drugs has gained popularity for critically ill patients in intensive care units and routine life such as personalized drug delivery or implantable therapeutic devices. For developing a closed-loop drug delivery system, the control system works with a group of technologies like sensors, micromachining, wireless technologies, and pharmaceuticals. Recently, the integration of artificial intelligence techniques such as fuzzy logic, neural network, and reinforcement learning with the closed-loop drug delivery systems has brought their applications closer to fully intelligent automatic healthcare systems. This review's main objectives are to discuss the current developments, possibilities, and future visions in closed-loop drug delivery systems, for providing treatment to patients suffering from chronic diseases. It summarizes the present insight of closed-loop drug delivery/therapy for diabetes, gastrointestinal tract disease, cancer, anesthesia administration, cardiac ailments, and neurological disorders, from a perspective to show the research in the area of control theory.

Trance-it to the Future

Trance-it to the Future

Wireless, battery-free and wearable device for electrically controlled drug delivery: sodium salicylate released from bilayer polypyrrole by near-field communication on smartphone.

Compared with traditional drug delivery methods, transdermal drug delivery has many advantages in avoiding the side effects in gastrointestinal tract, reducing the fluctuations in drug concentration, and improving patients' compliance. Among them, electrically controlled drug delivery is a promising solution. This work presents a wireless, battery-free and wearable device with electrically controlled drug delivery capability. The electronic component of the device is a flexible circuit board with a temperature sensor and a near-field communication module. With the help of smartphone, the device could wirelessly obtain energy and implement data transmission. The drug delivery component is a paper-based electrode modified with polypyrrole, in which non-steroidal anti-inflammatory drug sodium salicylate was encapsulated. The applied potential for electrically controlled drug delivery was more negative than -0.6V. The drug release dose and release rates could be controlled by applying potentials with different amplitudes and durations through this device. It provided a minimalized wearable transdermal drug delivery platform for monitoring diseases such as gout. This wearable device shows promising potential in develop closed-loop drug delivery and monitoring systems for the treatment of various diseases.

An optimal interval type-2 fuzzy logic control based closed-loop drug administration to regulate the mean arterial blood pressure

Background and ObjectiveThe main aim of this work is to present an optimal and robust controller design in order to improve the drug infusion to the automatic control of mean arterial blood pressure in conditions like critically-ill or post-operative or anaesthesia administration. The physiological systems also have uncertainty issues such as parameter variations with time or external disturbances and noise. Therefore, a controlled drug administration is necessary to regulate the mean arterial blood pressure of a person during surgery/observation. Over the years, the proportional-integral-derivative (PID) controller is the most commonly used controller in industries due to its easy structure and simplicity. However, this controller does not meet the desired performance with the complex and uncertain plants. Therefore, a robust controller is required to regulate the physiological variables that are uncertain in nature and can affect the human life. MethodsIn this work, a hybrid control scheme consisting of an interval type-2-fuzzy logic controller which acts as pre-compensator to the traditional PID controller is presented, to regulate the mean arterial blood pressure of a patient by administering the drug sodium nitroprusside in a controlled manner. An effective and well-established nature-inspired optimization technique namely cuckoo search algorithm is employed for obtaining the optimal parameters for the presented scheme. ResultsSimulation results are presented to show the effectiveness and robustness of proposed interval type-2-fuzzy logic controller based PID controller scheme, for maintaining the mean arterial pressure to 100 mmHg within considerable limit through SNP infusion. The results are further compared with other two controllers namely type-1 fuzzy logic based PID and traditional PID controllers for the parameter variations and external noise. ConclusionIn this study, the proposed interval type-2-fuzzy logic controller pre-compensator based PID controller provides an effective control than traditional type-1 fuzzy logic based control scheme and PID controller in terms of overshoot, settling-time and error which are the prime performance objectives of the closed-loop controlled drug delivery of human blood pressure. The presented study provides a firm base for initial design considerations for development of a low-cost closed-loop drug delivery system for blood pressure regulation.

A review on smart bioresponsive drug delivery systems

During the past several decades, many sensing mechanisms have emerged, which provide new control strategies for designing closed-loop drug delivery systems. For such systems, numerous bioresponsive materials are utilized to construct functional modules for the desired devices. The typical closed-loop drug delivery systems recently reported in this review. The stimuli-responsive polymers serve to provide a snapshot of the utility and complexity of polymers that can sense, process, and respond to stimuli in modulating the release of a drug. Stimuli-responsive drug delivery vehicles come in the form of polymersomes, liposomes, micelles and dendrimers. Therapeutics is designed to be controlled released from drug carriers through the structural transformations such as shrinking, swelling, and dissociation or unique responsive cleavage route.

Developing the Subcutaneous Drug Delivery Route

Biopharmaceuticals and biosimilars now represent the majority of the top 10 selling drugs. High development costs and requirement for most to be administered intravenously are noted drawbacks. Recent advances in subcutaneous drug delivery methods offer a viable alternative route for parenteral drug administration. Comparison studies have highlighted equivalent drug efficacies coupled with substantial cost savings. Allied to these developments are new closed-loop drug delivery systems which have the potential to revolutionize the biopharmaceutical sector through active patient engagement. First demonstrated in the insulin marketplace, these efforts represent formal embodiments of the precision medicine approach to disease management. This review will highlight key considerations for subcutaneous drug delivery, including patient preferences, drug formulation and needle and device design. We also provide an overview of the market evolution of subcutaneously administered drugs, highlighting those currently in clinical development, and predict areas for future innovation.

Advances in bioresponsive closed-loop drug delivery systems

Controlled drug delivery systems are able to improve efficacy and safety of therapeutics by optimizing the duration and kinetics of release. Among them, closed-loop delivery strategies, also known as self-regulated administration, have proven to be a practical tool for homeostatic regulation, by tuning drug release as a function of biosignals relevant to physiological and pathological processes. A typical example is glucose-responsive insulin delivery system, which can mimic the pancreatic beta cells to release insulin with a proper dose at a proper time point by responding to plasma glucose levels. Similar self-regulated systems are also important in the treatment of other diseases including thrombosis and bacterial infection. In this review, we survey the recent advances in bioresponsive closed-loop drug delivery systems, including glucose-responsive, enzyme-activated, and other biosignal-mediated delivery systems. We also discuss the future opportunities and challenges in this field.

DIGITAL HOSPITAL ; AN EXAMPLE OF BEST PRACTICE

Digital Hospital is a concept contributing to enhancing personnel productivity, facilitating hospital operations, improving the process quality and ensuring patient safety by integrating cutting-edge technologies such as medical devices, smart information systems, facility control and automatic conveyor systems, location-based services, sensors and digital communication tools into health processes. The primary aim of this study is to address the theoretical and practical aspects of “Digital (paperless) hospital” concept, which is addressed in a limited number of studies, and investigate the digital hospital practices of Izmir Tire Public Hospital and Giresun Tirebolu Public Hospital, which entered into the list of top digital hospitals in Europe as examples of best practices. The study was prepared based on the interviews with the managers of Tire Public Hospital and Tirebolu Public Hospital awarded with digital hospital certificates by HIMMS (International Accrediting Agency) in 2016. 18 hospitals received “Stage 6” and one hospital (Tire Public Hospital) received the top-level “Stage 7” digital hospital certificate, which was awarded to four hospitals in Europe by 2016 in Turkey. In the hospital transforming into a top level digital hospital and offering services with this concept; speed and efficiency of business processes increase, paper and document expenses are cut to zero, human-made errors are minimized. Diagnosis and treatment processes are provided not only within the hospital walls but also to long distances. By the help of digital hospitals health data are immediately and retrospectively retrieved at any time by the authorized body, other health institutions and patients and can be forwarded via sensors, cameras and early warning systems without requiring follow-up by humans, fast and right decisions can be given thanks to decision support systems, and the right medicine is administered to the right patient, at right doses and at the right time by the Closed Loop Drug Delivery System. With the widespread access to digital hospitals, it will be possible to benefit from all these advantages and offer the most effective and efficient healthcare services to the patients within the shortest time. Hospital personnel will have less workload and be less likely to make mistakes.

Particle filter algorithms for identification of minimally parametrized Wiener models of drug administration effect

Closed-loop drug administration is performed by a feedback controller keeping the patient response around a pre-set level in the face of process disturbance and uncertainty. To guarantee the safe operating envelope of the closed-loop drug delivery system, controller design for performance and robustness is typically based on a mathematical model of the plant. Minimally parametrized Wiener models comprising a linear dynamic block and a smooth output nonlinearity have been shown to accurately capture the patient-specific pharmacokinetics and pharmacodynamics in closed-loop drug administration. Due to the nonlinear model dynamics, identification techniques based on linear or linearized models yield biased parameter estimates and thus introduce superfluous uncertainty. The present paper compares the performance of three nonlinear system identification algorithms: an extended Kalman filter, a conventional particle filter (PF), and a PF making use of a orthonormal basis to estimate the probability density function from the particle set. A database of patient models estimated under PID-controlled neuromuscular blockade during general anesthesia is utilized, along with the clinical measurements. The bias and variance of the estimated models are related to the computational complexity of the identification algorithms, highlighting the superiority of the PFs in this safety-critical application.

PATIENT VARIABILITY AND UNCERTAINTY QUANTIFICATION IN ANESTHESIA: PART I – PKPD MODELING AND IDENTIFICATION

The outcome of any surgery is particularly dependent on the adequate delivery of anesthetic drugs. Not surprisingly clinical researchers have been trying to automatize their delivery in order to provide anesthesiologists with titration tools that can target the exact needs of each individual patient. As compared to today's population-normed drug delivery strategy closed-loop drug delivery systems would provide patients with customized pharmacological action, thereby improving surgery outcome. While some anesthesia closed-loop designs have already shown promising results within controlled clinical protocols, the pharmacological variability that exists between patients needs to be addressed within a mathematical framework to prove the stability of the control laws, and gain faster and wider acceptance of these systems by the clinical community and regulatory committees. This paper is the first of a series of 2 papers addressing the issue of pharmacological variability, and how this variability translates into quantifiable system uncertainty. In this work, we focus essentially on deriving patient-specific models to assess inter-patient variability. These models will serve as basis for illustrating the uncertainty quantification approach proposed in the accompanying paper.

Protein delivery with infusion pumps.

When a therapeutic effect is optimized by precise control of specific temporal patterns of plasma levels, infusion offers distinct advantages over oral administration, bolus injection, or depot delivery of polypeptides. The limitations of oral delivery are well known, and although research is under way into development of carrier systems that prevent degradation of labile agents, it is unlikely that the variances in absorption will meet the need for precise control. Depot delivery from subcutaneous or intramuscular implants presents a difficult situation when local tissue reactions to the agent sometimes occur. Removal of a depot system in the event of adverse reactions presents additional difficulties. Bolus injections are unable to sustain constant plasma levels unless the drug half-life is long or the injections are frequently administered. Insulin injections, for example, would be required every 30-60 minutes to approximate the plasma levels provided by a continuous infusion; such frequent injections would not be practical on a 24-hour basis. For the developer of new polypeptides, parenteral administration offers the most direct route to the marketplace. The step from periodic injections to tightly controlled infusion is a logical progression as compared with modification of the molecules or vehicles to obtain equivalent profiles. In Table II several different types of devices that can be used for infusion of proteins are compared. Microelectronics have played a major role in the miniaturization of infusion devices and undoubtedly will continue to do so. Micromachining, a spin-off technology of integrated circuit manufacture, will also find application in small infusion devices. In the future, we will have cost-effective disposable devices (Saaman et al., 1994) built on this technology that are programmable and thus can be adapted to meet each individual therapeutic need (Horres, 1994). We can also expect to see more closed-loop drug delivery systems where biosensors and infusion devices are combined to optimize a particular therapy. Recent positive results obtained in diabetics by a decade on tight glucose control may forecast a resurgence of popularity of insulin pumps. At the other end of the spectrum, low-cost, small, and simple-to-use osmotically powered systems are close to being marketed; these systems will make infusion almost as convenient as transdermal patches. We will also see major advances in how drugs and devices are interfaced. Prefilled and ready-to-use drug cartridges have proven to be efficient in surgical and emergency medicine and can greatly improve most infusion applications. It is anticipated that coded, prefilled cartridges or pouches will be automatically, recognized by preprogrammed pumps to reduce operator labor and entry error.

A model for the design and evaluation of algorithms for closed-loop cardiovascular therapy.

Developing a clinically useful closed-loop drug delivery system can be extremely time consuming and costly. One approach to reducing the time and cost associated with developing closed-loop systems is to reduce the number of animal experiments and perform an extensive set of simulation studies. Through simulations, a closed-loop controller's performance can be evaluated over a complete spectrum of the patient population, including boundary conditions. Simulation studies are repeatable, offering significant advantages in comparing modifications in control algorithms. Finally, simulation studies can be performed in a fraction of the time required for animal studies, at a fraction of the cost. We have developed a simulator, that included a nonlinear pulsatile-flow cardiovascular model, a physiological regulatory mechanism, and the pharmacology of four frequently titrated cardiovascular drugs. This simulator has already been used in the design and evaluation of two closed-loop algorithms-a self-tuning regulator (STR) and a multiple model adaptive controller (MMAC)-for blood pressure control during and after cardiac surgery.

DYNAMIC FEEDBACK AND THE DESIGN OF CLOSED-LOOP DRUG DELIVERY SYSTEMS

A closed-loop drug delivery system is constructed in which external negative feedback is used to regulate the dynamics of a time-delayed negative feedback mechanism which regulates hormone concentration. This results in a control system composed of two time-delayed negative feedback loops arranged in parallel. Stability regions in parameter space and the location of steady states are determined for the cases when the time delays are equal and when they are unequal. The advantage of this paradigm for drug delivery is that both the steady states and stability of the multiple loop feedback system can be influenced in a precisely controllable manner.

A ß-Robust Controller for Closed Loop Drug Delivery Systems: Application to the Infusion of Atracurium in General Anesthesia

A ß-Robust Controller for Closed Loop Drug Delivery Systems: Application to the Infusion of Atracurium in General Anesthesia