This research addresses the challenge of detecting and monitoring pure β emitters in the nuclear industry through the development and evaluation of a novel Lab-on-a-Chip (LoC) system. The work focuses on overcoming limitations in small sample volumes, the short range of β particles in matter, and the integration of microfluidic systems with detectors. Two prototype microfluidic detection units (MDU) are designed to efficiently detect and monitor pure β emitters. The research is motivated by the increasing demand for accurate, real-time monitoring of difficult-to-measure radionuclides in the nuclear industry, aiming to improve safety, regulatory compliance, and operational efficiency. The thesis presents an overview of difficult-to-measure radionuclides and monitoring in throughout the nuclear lifecycle, emphasises the benefits of LoC technology, and highlights the need for tailored solutions in the industry. It examines existing microfluidic systems for radionuclide detection, identifies the lack of dedicated platforms for in situ detection of difficult to-measure radionuclides, and discusses future development plans based on optical detection methods. The thesis provides theoretical background on β emission, Cherenkov radiation, and microfluidic parameters. These parameters have been modelled and experimentally validated on simple and complex microfluidic systems with radiological (Cherenkov radiation) and non radiological (chemiluminescence) testing. Coupling of numerical modelling and experimental validation has led to the establishment of best practices to optimise the optical output of the MDU and demonstrates the prototype’s sensitivity to β particles. The research evaluates the MDU’s sensitivity to various β-emitting radionuclides and determines the limit of detection of the system and the minimum detectable activity. The thesis concludes by discussing the outlook of this technology and its potential to address the industry’s needs while aligning with sustainable innovation and green chemistry principles.