Highly Sensitive Minimal Residual Disease Detection by Biomimetic Multivalent Aptamer Nanoclimber Functionalized Microfluidic Chip

Abstract

Minimal residual disease (MRD) offers a highly independent prognostic factor for leukemia patients. However, challenges confronting conventional MRD assays are high invasiveness, as well as limited detection sensitivity and clinical applicability. Inspired by the self‐adaptive skeleton and multiple suckers or tendrils of climbing plants, a biomimetic Multivalent Aptamer Nanoclimber (MANC)‐functionalized microfluidic chip (MANC‐Chip) is reported for minimally invasive, highly sensitive and clinically applicable MRD detection in the peripheral blood of T‐cell acute lymphoblastic leukemia patients. The MANCs are synthesized by a simple co‐polymerization reaction. Due to their flexible structure and cooperative multivalent effect, MANCs dramatically enhance the binding affinity of aptamers targeting leukemia cells. A deterministic lateral displacement‐patterned microfluidic chip is designed to further increase the collision probability between MANCs and leukemia cells. Benefiting from the synergistic effect of multivalent binding and enhanced collision, a high capture efficiency of 92.2% for leukemia cells is achieved. Moreover, the captured leukemia cells can be released with high efficiency of 88.9% and high viability of 93.8% via nuclease treatment prior to downstream analysis. Overall, the excellent features of MANC‐Chip make it very useful for precise detection of MRD and better understanding of leukemia.

Multivalent Aptamer Approach: Designs, Strategies, and Applications

“…Conjugating aptamers onto linear scaffolds—either flexible or rigid—allows aptamers to be arranged into linear configurations. The linear scaffolds can be made of polymers [ 53 ] or nucleic acids, such as ssDNA [ 54 , 55 ], double stranded DNA (dsDNA) [ 56 , 57 , 58 ], and DNA nanotubes [ 59 , 60 ]. The physical properties of each scaffold type confer specific advantages to their resultant linear constructs.…”

“…The physical properties of each scaffold type confer specific advantages to their resultant linear constructs. For flexible scaffolds such as ssDNA and polymers, the scaffold chains can easily adapt to the surface topography of targets, while the multivalent aptamers work synergistically, thus enhancing binding avidities [ 53 ]. Linear multivalent aptamers with flexible scaffolds are commonly used for therapeutic [ 4 , 61 ] or detection purposes [ 23 , 53 , 55 ].…”

“…For flexible scaffolds such as ssDNA and polymers, the scaffold chains can easily adapt to the surface topography of targets, while the multivalent aptamers work synergistically, thus enhancing binding avidities [ 53 ]. Linear multivalent aptamers with flexible scaffolds are commonly used for therapeutic [ 4 , 61 ] or detection purposes [ 23 , 53 , 55 ]. Because of these long and flexible aptamer chains, the linear multivalent aptamers can reach tens of micrometers into the sample solutions, providing sufficient interactions with targets for more enhanced target capturing [ 55 ].…”

Exosome: From leukemia progression to a novel therapeutic approach in leukemia treatment

“…It needs an immunophenotype identification of disease before the utilization and also it can analyze viable cells through 48 hr postsampling 158 . MFC is a fast technique and gives reliable information about leukemic cells but high cast with low reproducibility makes it limited 159 . Despite of high sensitivity of ASO‐PCR, it is very time consuming and each patient need a specific primer 160 .…”

Split Aptamers Immobilized on Polymer Brushes Integrated in a Lab-on-Chip System Based on an Array of Amorphous Silicon Photosensors: A Novel Sensor Assay

“…More importantly, due to their small size, microfluidic platforms improve the transport of the analyte molecules to the biorecognition elements improving the sensor response time and in some cases the sensitivity [ 15 ]. Aptamers have been immobilized into microfluidic devices using different nanomaterials [ 16 ] such as nanoparticles [ 17 ], graphene oxide [ 18 ], self-assembled monolayers and polymer brushes for the detections of different targets such as small molecules and biomarkers [ 14 , 19 , 20 , 21 , 22 , 23 ], pathogens [ 24 ], and cancer cells [ 25 , 26 , 27 ]. The nanomaterials applied in the above systems act as transducing agents and the signal deriving from the interaction of the target and the immobilized aptamers is detected.…”