Safety, Toxicity, and Regulation of Biomaterials: A Systematic Review of Global Frameworks and Emerging Challenges

ABSTRACT Biomaterials are natural or synthetic materials designed to interact with biological systems for medical, environmental, or industrial applications. Despite their expanding market and crucial healthcare role, ensuring safety and establishing consistent regulatory frameworks remains challenging. Regulatory inconsistencies impede innovation, increase development costs, and potentially compromise patient safety. To systematically examine toxicity concerns and regulatory frameworks governing biomaterials across major regions (USA, EU, India, China & Australia) and evaluate international standards from OECD and ISO organizations. We aimed to identify regulatory gaps, assess challenges posed by advanced materials, and propose solutions for harmonized global regulation. A comprehensive systematic review was conducted following PRISMA guidelines. Multiple electronic databases were searched to identify relevant studies examining biomaterial toxicity assessment methods and regulatory frameworks. Studies were screened based on predetermined eligibility criteria focusing on regulatory standards, toxicity evaluation methods, and safety protocols. Data extraction encompassed regulatory requirements, testing methodologies, and approval pathways. Analysis revealed significant regulatory heterogeneity across jurisdictions, with traditional testing methods inadequately addressing risks from advanced materials including nanomaterials and 3D‐printed tissues. Major gaps included absence of unified global approaches, insufficient evaluation methods for complex dynamic biomaterials undergoing transformation in vivo, and lack of systematic long‐term monitoring systems. Substantial improvements are achievable through innovative approaches including computational modeling for expedited approvals, smart implants incorporating embedded sensors for real‐time monitoring, and establishment of international databases to eliminate redundant testing. These recommendations could enhance regulatory efficiency, improve patient safety, and facilitate global harmonization while accelerating access to life‐saving technologies.