Rapid Prototyping of a Nanoparticle Concentrator Using a Hydrogel Molding Method

  1. Human Augmentation Research Center, National Institute of Advanced Industrial Science and Technology, Chiba 277-0882, Japan
  2. Faculty of Science and Technology, Tokyo University of Science, Chiba 278-8510, Japan
  3. Molecular Profiling Research Center for Drug Discovery, National Institute of Advanced Industrial Science and Technology, Tokyo 135-0064, Japan
  4. Future Center Initiative, The University of Tokyo, Chiba 277-0871, Japan
Author to whom correspondence should be addressed.
These authors contributed equally to this work.

Abstract

Nanoparticle (NP) concentration is crucial for liquid biopsies and analysis, and various NP concentrators (NPCs) have been developed. Methods using ion concentration polarization (ICP), an electrochemical phenomenon based on NPCs consisting of microchannels, have attracted attention because samples can be non-invasively concentrated using devices with simple structures. The fabrication of such NPCs is limited by the need for lithography, requiring special equipment and time.
To overcome this, we reported a rapid prototyping method for NPCs by extending the previously developed hydrogel molding method, a microchannel fabrication method using hydrogel as a mold. With this, we fabricated NPCs with both straight and branched channels, typical NPC configurations. The generation of ICP was verified, and an NP concentration test was performed using dispersions of negatively and positively charged NPs.
In the straight-channel NPC, negatively and positively charged NPs were concentrated >50-fold and >25-fold the original concentration, respectively. To our knowledge, this is the first report of NP concentration via ICP in a straight-channel NPC. Using a branched-channel NPC, maximum concentration rates of 2.0-fold and 1.7-fold were obtained with negatively and positively charged NPs, respectively, similar to those obtained with NPCs fabricated through conventional lithography. This rapid prototyping method is expected to promote the development of NPCs for liquid biopsy and analysis.
Micromer Partikel Hydrogel Molding Method

Micromer Partikel Hydrogel Molding Method

Introduction

The concentration of nanoparticles (NPs) is crucial in the field of liquid biopsy and analysis [1,2,3], and various NP concentrators (NPCs) have been developed [3,4,5]. NPCs improve the detection limits of biomarkers (e.g., NPs such as exosomes) for cancer and dementia [5] and the throughput of post-concentration analysis and processing [3]. In recent years, NPCs using ion concentration polarization (ICP), which is an electrochemical phenomenon, have been developed [5]. These devices mainly consist of a microchannel with a built-in selective ion permeation structure (e.g., ion exchange membrane), can concentrate samples non-invasively [6], and have a simple structure because no internal electrodes are required [7,8].
ICP is an electrochemical ion transport phenomenon that occurs near the selective ion transmission structure owing to the application of an electric field [9,10,11,12,13,14]. Due to the generation of ICP in the microchannel, an electrically neutral region, specifically the ion depletion zone (IDZ), which is locally deficient in ions, is formed. The IDZ can eliminate charged substances [15,16].
By utilizing this property, an ICP-based NPC can retain and concentrate the charged substance on the upstream side of the IDZ. Typical types of ICP-based NPCs include those with a straight channel [17] and those with a branched channel [15]. NPCs with a straight channel are used for on-chip batch analysis (where a concentrated sample is retained in a channel) and can concentrate NPs at relatively high concentration rates, whereas it is difficult to collect concentrated samples (which are retained in a channel) outside of the device [18].
NPCs with branched channels are used to continuously concentrate charged substances without the retention of the concentrated sample in a channel. Whereas the concentration rate is lower than that with the straight-channel NPC, the concentrated sample can be recovered from the device [18].
NPCs consisting of microchannels have been fabricated through a variety of rapid prototyping techniques for microchannel fabrication, using transparent, easy-to-process polydimethylsiloxane (PDMS) with low cytotoxicity [19] as a device material [3,4,5]. Photo- and soft-lithography [20] is a conventional rapid prototyping technique that is time-consuming and requires special equipment such as mask aligners, clean rooms, and plasma irradiators [21]. To further facilitate the development of NPCs for liquid biopsy and analysis, an NPC rapid prototyping method that enables us to design, prototype, and evaluate NPCs without special equipment is required.
We have previously reported a method of fabricating PDMS-based microchannels using a hydrogel as a mold (that is, the hydrogel molding method (HGM). The HGM process does not require the special equipment that is used for photo- and soft-lithography. A hydrogel mold used in the HGM can be easily fabricated by casting a wire-shaped hydrogel from capillary tubes (e.g., a glass capillary and a polytetrafluoroethylene tube).
HGM enables the simple and rapid preparation of two-dimensional and three-dimensional PDMS-based microchannels with various cross-sectional shapes (e.g., circles, squares, triangles). Although HGM could impart various properties to microchannels by embedding different materials in PDMS together with a hydrogel mold, HGM has not been applied to the production of such microchannels.
In this study, to overcome the existing issue (i.e., the fabrication of NPCs is limited by the need for lithography, requiring special equipment and time), we developed a rapid prototyping method for NPCs consisting of microchannels using the HGM. In the proposed method, a commercially available ion-exchange membrane (Nafion) was embedded in the device together with the hydrogel mold, and special equipment used for conventional photo- and soft-lithography techniques was not required.
Here, two typical types of devices (an NCP with a straight channel and an NCP with a branched channel) were prepared. First, the fabrication conditions (i.e., temperature and Nafion membrane width) were optimized. Subsequently, the generation of ICP in the prepared NCPs was verified using a fluorescent dye. Finally, the concentration performance of the NCPs was evaluated using NPs.

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