Fostering the next generation of molecular diagnostics: 3D Microfluidic RNA-sensing hydrogel biosensors for clinical analysis of miRNA biomarkers

SCIENTIFIC MOTIVATION AND BIOMEDICAL AND CLINICAL NEED. Highly conserved small non-coding microRNAs (miRNAs) regulate gene expression by modulating translational efficacy of their target mRNAs in a tissue-specific manner, thus affecting cellular physiology. Circulating miRNAs identified in cell-free serum are recognised as non-invasive biomarkers for a range of human diseases. Their unique expression profiles represent indicative molecular signatures for neurodegenerative, cardiovascular, autoimmune diseases, and various types of cancers. The detection of specific miRNA expression profiles could therefore be used as biomarkers for the early detection of many important diseases. Detection of changes in the expression levels of free-circulating miRNAs in the blood serum can be used to distinguish diseased patients from healthy individuals, and the non-invasive nature of their sample collection makes them ideal biomarkers to employ for human patients. However, the lack of standardised technologies for qualitative and quantitative measurement of miRNA levels in situ in clinical samples (due to their small size and high sequence homology) is a significant bottleneck in advancing miRNA biomarkers to the clinic. The main challenge in this area is therefore to develop a highly-sensitive technology for the rapid, robust and reliable screening of miRNA biomarkers for future application in clinic and healthcare.
PROJECT OUTLINE. We have recently developed novel peptidyl-oligonucleotide hydrogel biosensors for detection of disease relevant RNA sequences. We have demonstrated at a proof-of-principle level their ability to sense a perfect-match bio-target at picomolar concentrations and discriminate it from single-nucleotide mismatches5. In close collaboration with Manchester BIOGEL Ltd, we now aim to develop a next generation of molecular diagnostics by fabricating a 3D RNA-sensing microfluidic devices based on our peptide-hydrogel biosensor, which could better suit the complexity of biological and clinical samples and allow screening of multiple clinical samples simultaneously. By using an integrative cross-disciplinary approach at the interface of chemical biology, material sciences, structural biology, biopolymer chemistry and architecture, the recruited PhD student will develop a 3D microfluidic diagnostic platform based on peptide-oligonucleotide hydrogels to enable rapid, accurate and reproducible detection of miRNAs directly from clinical samples for early-stage diagnosis of human diseases.
TRAINING PROVIDED BY UoM. This coordinated cross-disciplinary project will be carried out at the interface of chemical biology (EB), synthetic and analytical chemistry (HA), peptide and polymer chemistry (AS), material sciences (AM) and molecular diagnostics (EB). This breadth in the project will help the recruited PhD student to develop a range of interdisciplinary skills and encourage the student to appreciate the value of collaborative and coordinated multidisciplinary approaches for addressing biomedical and clinical grand challenges. The student will be working at the interface between academia and industry (Manchester BIOGEL Ltd) to obtain invaluable experience in knowledge transfer by turning new academic discoveries into commercial success. The Industrial placement at Manchester BIOGEL Ltd will expose the student to the intense commercial environment of the SME business with strict commitments to project delivery and budgetary targets. Such training will support progression into a range of career options within academia or industry (e.g. Big Pharma or small innovative companies), including chemical biology, nanotechnology and nano-medicine, material and analytical sciences and molecular diagnostics. Graduates with skills-sets spanning these areas are rare; therefore, this training will provide a solid platform for the recruited PhD student and promote their further career acceleration and development