Biosensor integrated subcutaneous organ-on-chip development for understanding subcutaneous drug performance.

The diversity of the human genome combined with ADME factors such as body weight, fat content, and the efficiency of organ function, leads to substantial difference in the bioavailability, pharmacokinetics and clinical efficacy of therapeutic interventions delivered via the subcutaneous route. This in practice means the dose at which the treatment is effective, induces toxicity and the rate at which it is absorbed, excreted and metabolised varies significantly between individuals. Biopharmaceutics in drug development primarily concerns itself with events that occur prior to systemic absorption of a drug compound. Whilst we have moved into an era where we are now beginning to measure the differences in bioavailability between patients, there is now a large knowledge gap regarding the underlying physiological factors within subcutaneous tissue prior to systemic absorption of a compound. Our ability to tailor the medicine dose and determine its effectiveness considering this human physiology has been limited by a lack of technological innovation.
The aim of this PhD is to address this technological gap by developing new Healthcare Technology based on merging electrochemical sensing technology with 3D cell culture models of subcutaneous tissue to facilitate a better understanding of some of the physiological liabilities present within subcutaneous drug delivery, for example a detrimental immune response following subcutaneous.
injection (1, 2). This aim will be achieved by developing electrochemical sensors for cytokines (1), adipokines(3) and key biomarkers of cellular function. The granular, real-time information obtained from the electrochemical sensors for a key biomarkers will enable us to generate a time course profile understanding of the underlying cellular processes following subcutaneous drug product administration.
The project will involve extensive Complex Product Characterization with the product in this case considered to be the 3D cell culture device with integrated electrochemical sensors. This will require characterization in the form of monolayer vs 3D cell culture in general terms, e.g., cell viability, cell function, morphology, and additionally with the integrated electrochemical sensors, and if the performance of the sensors can be applied to both monolayer and 3D cell culture settings. The results of the project will be used in Predictive Pharmaceutical Sciences to try and obtain granular understanding of how the main new modalities that are delivered subcutaneously behave in relation to one another, e.g. what are the main liabilities of oligonucleotides compared to peptides. This is currently a large knowledge gap, and one that is essential to understanding to influence regulators regarding new modalities.
The FDA Modernization Act 2.0 states the use of advanced in vitro tools to being central to their vision for drug development moving forward (4), along with artificial intelligence/digital science predictive tools. However, without the key understanding of the physiology at play, creating accurate advanced in vitro tools that recapitulate the hallmark components of subcutaneous physiology in relation to the modality remains a daunting task.
This project can look towards both the underlying biological factors at play in following subcutaneous injection, either on a molecular or functional level, whilst also looking at the properties of the drug product itself. This presents a unique opportunity for a truly translational PhD project that spans disciplines, and multiple components of the late stage drug development pipeline. Scientific progress driven through this PhD will greatly help AstraZeneca accelerate the development of subcutaneous drug products to ensure safe, effective products reach our patients.