4D-printed microdevices for spatiotemporal detection of ctDNA and miRNA in pancreatic cancer: an in-depth review.

Pancreatic cancer is among the most lethal forms of cancer, with a five-year survival rate under 7%, primarily due to its late clinical presentation and rapid disease progression. Although the oncogenic development of pancreatic tumors can span over a decade, early diagnosis remains a major clinical challenge, as current diagnostic approaches-including imaging modalities and blood-based markers like CA19-9-lack the requisite sensitivity for detecting early-stage disease. Liquid biopsy has emerged as a promising, non-invasive diagnostic technique by enabling the detection of circulating tumor-specific nucleic acids, particularly circulating tumor DNA (ctDNA) and microRNAs (miRNAs). However, the practical use of these biomarkers is limited by their low concentrations in early disease stages, molecular fragility, and the demanding nature of current detection methods. The advent of 4D printing-a transformative advancement in additive manufacturing utilizing stimuli-responsive materials-has introduced novel opportunities for biomedical sensing. These responsive microdevices can undergo spatiotemporal changes, allowing for precise, time-regulated capture of molecular targets. This review presents a comprehensive analysis of 4D-printed micro- and nanodevices designed for ctDNA and miRNA detection, with an emphasis on their potential utility in pancreatic cancer diagnostics. We examine material selection, actuation strategies, fluid dynamics, device architecture, and emerging prototypes. Furthermore, the review considers clinical translation challenges, including regulatory pathways and integration into personalized medicine frameworks. In contrast to conventional PCR and NGS techniques-which, despite their high sensitivity, are often hindered by labor-intensive sample preparation, extended processing times, and reduced efficiency in identifying low-abundance biomarkers during the early stages of pancreatic cancer-4D-printed biosensors provide a dynamic, stimuli-responsive approach capable of enabling faster, more selective, and potentially point-of-care detection of ctDNA and miRNA. By combining smart material responsiveness with precise molecular capture mechanisms and compact device architectures, these platforms hold promise for addressing the sensitivity and stability challenges that limit traditional molecular diagnostic methods. Collectively, 4D-printed biosensors represent a promising frontier for advancing the early detection and real-time monitoring of pancreatic cancer.