This work was supported by the European Research Council (ERC Starting Grant n&#956;LIPIDS, No. 203428) and ETH Zurich (project number: ETH-49 12-2). The authors of this manuscript would like to thank Bodo Hattendorf for help with the ICP-MS and F. Kurth for cell counting. The authors also would like to thank Christoph B&#228;rtschi and Roland M&#228;der for their support with building the mechanical setup. The clean room facility FIRST at ETH Zurich is acknowledged for support in microfabrication.

<ol>
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The authors declare that they have no competing financial interests.

למרות שהייצור של השבבים הוא אמין מאוד יש כמה נקודות קריטיות במהלך הייצור הדורשים תשומת לב מיוחדת. ראשית, ניקיון באסיפה חשוב מאוד על מנת למנוע זיהום של השבב על ידי אבק. האבק עלול לחסום את הערוצים ולמנוע דור אגל יציב. שנית, חשוב במיוחד שהקצה הוא לחתוך מאונך לערוץ הזרבובי...

<html> ניתוח יסודות של דגימות נוזל על ידי ספקטרומטריית מסת פלזמה בשילוב אינדוקטיבי (ICPMS) מתבצע בדרך כלל תוך שימוש nebulizers בשילוב עם תאי תרסיס כמערכת מבוא 1. במדגם מערכת ההקדמה הזו המדגם הוא ריסס על ידי nebulizer ליצור תרסיס polydisperse. תא תרסיס במורד הזרם משמש לסינון טיפות גדולות. שיטה זו מקושרת עם הצריכה גבוהה מדגם (&gt; 0.3 מיליליטר -1 דקות) 2 ותחבורת מדגם חלקית. לפיכך, הוא הופך להיות מעשי עבור יישומים בהם כרכי מדגם microliter רק זמינים, כמו במחקרים ביולוגיים, זיהוי פלילי, טוקסיקולוגי וקליניים 3. כדי להפחית את צריכת המדגם, nebulizers עם ממדים קטנים יותר זרבובית פותחו 3. עם זאת, גודל הנחיר המופחת מגדיל את הסיכון לסתימה כאשר דגימות של נוזלים ביולוגיים לא מעוכלים או פתרונות מלח מרוכזים צריכים להיות מנותחות 3. &quot;Jove_content&quot;&gt; גישה שונה להקדמת מדגם הוצעה על ידי et al Olesik. 4. המחברים הזריקו נוזל לתוך ICPMS בצורה של microdroplets הבדיד monodisperse, שיוצרו על ידי micropump מונע piezo-חשמלי. למרות שמערכת זו מאוד לא מצאה יישום רחב, זה שיזם את הפיתוח נוסף של הרעיון של הקדמת אגל דיסקרטית בICPMS. היום, piezo-חשמלי המונעים מחלק מערכות, אשר יכולה ליצור טיפות בגודל של 30, 50, 70 ו -100 מיקרומטר ובתדרים של 100-2,000 הרץ, ניתן לרכוש. יכולות להיות מועברים הטיפות לתוך ICPMS עם קרוב ליעילות של 100% 5. מכשירי microdroplet אלה יושמו לכמותית מדידת חלקיקים אחת 5,6 כמו גם אפיון תאים ביולוגיים בודדים 7. מערכת דומה המבוססת על טכנולוגיית הזרקת דיו תרמית 8 נבדקה לצורך הניתוח של דגימות ביולוגיות 9. למרות avaiמערכות הקדמת טיפה אחת lable הן יעילים מאוד, יכול לשמש לכרכי מדגם קטנים ומבטיחות לניתוח של חלקיקים ותאים, יש להם כמה מגבלות. לגודל נחיר קבוע, גודל הטיפה יכול להיות מגוון רק מעט (אלא אם כן הגדרות מותאמות אישית המשמשות 10). שינויים של התכונות הפיסיקליות של הנוזלים (pH, תוכן מלח) יכולים לשנות את מאפייני אגל (גודל, מהירות זריקה). כמו כן, מכשירים אלה הם יקרים למדי, נוטים לסתימה וקשה לנקות. שיטה נוספת ליצירת טיפות ידועה בתחום מיקרופלואידיקה רביב 11. בשנים האחרונות מיקרופלואידיקה רביב צברה ריבית ל( ביולוגית) תגובות כימיות 12-15 וללימודי תא בודדים 16,17. בנוסף, טכניקה זו יושמה להחדרת דגימות בספקטרומטר מסת יינון electrospray 18,19 ולהכנת דגימות בdesorption / ionizatio לייזר בסיוע מטריקסספקטרומטר מסת n 20,21. לאחרונה, הצגנו מערכת מבוססת microfluidic להקדמת מדגם ב -22 ICPMS. המרכיב המרכזי של מערכת המבוא שלנו הוא פליטת אגל שבב הנוזל סייע (אדה). שבב זה מורכב מפולי (dimethylsiloxane) (PDMS) לחלוטין. בצומת הערוץ הראשונה לזרום התמקדות הוא משמש לייצור טיפות monodisperse של תמיסה מימית מדגם (איור 1). למטרה זו (נקודת רתיחה של C ° 58-60 23) בתנודתיות הגבוהה וperfluorohexane מוביל immiscible שלב (PFH) משמשת (איור 1). תכונות אלה מאפשרות PFH דור אגל יציב והסרת מהירה של השלב המוביל. שינויים במאפיינים של מדגם השפעת נוזל שיטת הדור הזה פחות, בהשוואה לגנרטורים טיפה אחרות. גודל הטיפה הוא מתכוונן על פני טווח רחב על ידי שינוי שיעורי הזרימה של השלב המימי וPFH. בsecondar במורד הזרםצומת y, יותר PFH מתווספת להגדיל את מהירות הזרימה לשנייה במרחק של לפחות 1 -1. במהירות זו הנוזל יכול להיפלט מהשבב במטוס יציב וישר (איור 1) ללא הרס אגל (איור הבלעה 1). עיצוב כפול צומת זו מאפשר שליטה על יציבות הסילון העצמאית של דור אגל. הטיפות מועברות לICPMS עם מערכת תחבורה מותאמת אישית. מערכת זו כוללת צינור נופל וdesolvator קרום להסיר את PFH. השאריות מיובשות של הטיפות מימיות מיוננות לאחר מכן בפלזמה של ICPMS ואמצעי גלאי מסת היונים. החלק הקדמי של השבב הוא להבטיח קשר הדוק עם מערכת תחבורת אגל בצורת חבית. הפליטה של ​​המדגם המימי כמו טיפות בPFH מועילה, משום שמגע עם הזרבובית הוא נמנע. זה משמעותי מוריד את הסיכון לסתימת נחיר, מה שיכול להיות בעיה בעבודה עם השעיות תא או שיתוףפתרונות מלח ncentrated. שבבי אדה, מפוברקים על ידי PDMS יתוגרפיה הרכה, זולים (2 עלות חומר כ $ לכל שבב), חד פעמיות וקלים לשנות. בשילוב עם הייצור שדורש רק כמות קטנה של עבודה ידנית כל ניסוי ניתן לבצע עם שבב חדש. לכן, ניקוי מפרך אין צורך וזיהום לחצות ממוזער. כאן, הייצור של שבב אדה על ידי יתוגרפיה הרכה ובקשתה לICPMS מתוארים. דוגמאות למדידות עם תמיסה מימית והשעית תא מוצגות.

<table><tbody><tr><td>Silicon wafer 100 mm</td><td>Si-Mat (Kaufering, Germany)</td><td></td><td></td></tr><tr><td>SU-8 2002</td><td>Microchem Corp. (Massachusetts, U.S.A.)</td><td></td><td></td></tr><tr><td>SU-8 2050</td><td>Microchem Corp. (Massachusetts, U.S.A.)</td><td></td><td></td></tr><tr><td>Acetone</td><td>Merk VWR (Darmstadt, Germany)</td><td>100014</td><td></td></tr><tr><td>MR-developer 600</td><td>Microresist Technology GmbH (Berlin, Germany)</td><td></td><td></td></tr><tr><td>Isopropanol</td><td>Merk VWR (Darmstadt, Germany)</td><td>109634</td><td></td></tr><tr><td>1&lt;em&gt;H&lt;/em&gt;,1&lt;em&gt;H&lt;/em&gt;,2&lt;em&gt;H&lt;/em&gt;,2&lt;em&gt;H&lt;/em&gt;-perfluorodecyltrichlorosilane</td><td>ABCR-Chemicals (Karlsruhe, Germany)</td><td>AB111155</td><td></td></tr><tr><td>Sylgard 184 silicone elastomer kit (PDMS)</td><td>Dow Corning (Michigan, U.S.A.)</td><td>39100000</td><td></td></tr><tr><td>Perfluorohexane 99%</td><td>Sigma-Aldrich (Missouri, U.S.A.)</td><td>281042</td><td></td></tr><tr><td>FC-40</td><td>ABCR-Chemicals (Karlsruhe, Germany)</td><td>AB103511</td><td></td></tr><tr><td>Phosphate-buffered saline&amp;nbsp;</td><td>Life Technologies (Paisley, U.K.)&amp;nbsp;</td><td>10010-015</td><td></td></tr><tr><td>Red blood cells in phosphate-buffered saline</td><td>Rockland Immunochemicals Inc. (Pennsylvania, U.S.A.)&amp;nbsp;</td><td>R400-0100</td><td></td></tr><tr><td>Single-element standard solutions Na, Fe</td><td>Inorganic Ventures (Virginia, U.S.A.)</td><td></td><td></td></tr><tr><td>Multielement standard solution&amp;nbsp;</td><td>Merck Millipore (Massachusetts, U.S.A.)</td><td>IV</td><td></td></tr><tr><td>Nitric acid</td><td>Sub-boiled</td><td></td><td></td></tr><tr><td>Ultrahigh-purity water</td><td>Merck Millipore (Massachusetts, U.S.A.)</td><td></td><td></td></tr><tr><td>Hot plate HP 160 III BM</td><td>Sawatec (Sax, Switzerland)</td><td></td><td>used for wafer preparation</td></tr><tr><td>Spin modules SM 180 BM</td><td>Sawatec (Sax, Switzerland)</td><td></td><td>used for wafer preparation</td></tr><tr><td>High resolution film photomask</td><td>Microlitho (Essex, U.K.)</td><td></td><td></td></tr><tr><td>Step profiler Dektak XT advanced</td><td>Bruker&amp;nbsp; (Massachusetts, U.S.A.)</td><td></td><td></td></tr><tr><td>Hot plate MR 3002</td><td>Heidolph (Schwabach, Germany)</td><td></td><td>used for replica molding&amp;nbsp;</td></tr><tr><td>1.5 mm biopsy puncher</td><td>Miltex (Pennsylvania, U.S.A.)</td><td>33-31AA/33-31A</td><td></td></tr><tr><td>Spin coater&amp;nbsp; WS-400 BZ-6NPP/LITE</td><td>Laurell (Pennsylvania, U.S.A.)</td><td></td><td>used for adhesive bonding</td></tr><tr><td>Syringe pump neMESYS</td><td>Cetoni (Korbussen, Germany)</td><td></td><td></td></tr><tr><td>1 ml syringe&amp;nbsp;</td><td>Codan (Lensahn, Germany)&amp;nbsp;</td><td>62.1002</td><td></td></tr><tr><td>5 ml syringe&amp;nbsp;</td><td>B. Braun (Melsungen, Germany)&amp;nbsp;</td><td>4606051V</td><td></td></tr><tr><td>PTFE tubing&amp;nbsp;</td><td>PKM SA (Lyss, Switzerland)&amp;nbsp;</td><td>PTFE-AWG-TFT20.N</td><td></td></tr><tr><td>Quadrupole-based ICPMS ELAN6000</td><td>PerkinElmer (Massachusetts, U.S.A.)&amp;nbsp;</td><td></td><td></td></tr><tr><td>Membrane desolvator CETAC6000AT+</td><td>CETAC Technologies (Nebraska, U.S.A.)&amp;nbsp;</td><td></td><td>only the desolvator unit is used</td></tr><tr><td>High speed camera Miro M110</td><td>Vision Research (New Jersey, U.S.A.)</td><td></td><td></td></tr><tr><td>Data analysis program Origin pro</td><td>OriginLab Corp. (Massachusetts, U.S.A.)</td><td>version 8.6</td><td></td></tr><tr><td>Microscope</td><td>Olympus (Tokyo, Japan)</td><td>IX71</td><td></td></tr></tbody></table>

a microfluidic chip for icpms sample introduction

פרוטוקול זה דן בייצור ושימוש בשבב חד פעמי עלות הנמוכה microfluidic כמערכת מבוא לדוגמה עבור ספקטרומטריית מצמידים אינדוקטיבי פלזמה המונית (ICPMS). השבב מייצר טיפות מדגם מימיות monodisperse בperfluorohexane (PFH). גודל ותדירות של הטיפות מימיות יכולים להיות מגוון בטווח של 40 עד 60 מיקרומטר ובין 90 ל -7,000 הרץ, בהתאמה. הטיפות נפלטות מהשבב עם זרימה שנייה של PFH ולהישאר שלמים בפליטה. מערכת desolvation שהותקן מסירה PFH ומעבירה את הטיפות לתוך ICPMS. כאן, אותות יציבים מאוד עם חלוקת עוצמת צרה ניתן למדוד, המראים את monodispersity של הטיפות. אנו מראים כי מערכת ההקדמה יכולה לשמש כדי לקבוע כמותית ברזל בתאי דם אדום אחת שור. בעתיד, היכולות של מכשיר ההקדמה יכולות בקלות להיות מורחבות על ידי האינטגרציה של מודולים microfluidic נוספים.

המערכת הוצגה יכולה להיות מועסק על מנת למדוד כמויות קטנות של פתרונות או השעיות המכילות תאים או חלקיקים. דוגמאות למדידה ואפיון פתרון סטנדרטיים של תאים בודדים מוצגות כאן. ניתן למצוא דוגמאות נוספות בet al Verboket. 22. בדרך כלל את...

Watch this Scientific Journal Video about A Microfluidic Chip for ICPMS Sample Introduction at JoVE.com

A Microfluidic Chip for ICPMS Sample Introduction

אנו מציגים מערכת מבוא מדגם אגל דיסקרטית לספקטרומטריית מצמידים אינדוקטיבי פלזמה המונית (ICPMS). הוא מבוסס על שבב microfluidic זול וחד פעמי שיוצר טיפות monodisperse ביותר בטווח גודל של 40-60 מיקרומטר בתדרים בין 90 ל -7,000 הרץ.

שבב microfluidic למבוא לדוגמא ICPMS

This protocol discusses the fabrication and usage of a disposable low cost microfluidic chip as sample introduction system for inductively coupled plasma ...

a-microfluidic-chip-for-icpms-sample-introduction

Research

JoVE Journal

Bioengineering

11.1K Views.  ETH Zurich.  אנו מציגים מערכת מבוא מדגם אגל דיסקרטית לספקטרומטריית מצמידים אינדוקטיבי פלזמה המונית (ICPMS). הוא מבוסס על שבב microfluidic זול וחד פעמי שיוצר טיפות monodisperse ביותר בטווח גודל של 40-60 מיקרומטר בתדרים בין 90 ל -7,000 הרץ. 

Video: A Microfluidic Chip for ICPMS Sample Introduction

A Microfluidic-based Hydrodynamic Trap for Single Particles

The ability to confine and manipulate single particles in free solution is a key enabling technology for fundamental and applied science. Methods for particle trapping based on optical, magnetic, electrokinetic, and acoustic techniques have led to major advancements in physics and biology ranging from the molecular to cellular level. In this article, we introduce a new microfluidic-based technique for particle trapping and manipulation based solely on hydrodynamic fluid flow. Using this method, we demonstrate trapping of micro- and nano-scale particles in aqueous solutions for long time scales. The hydrodynamic trap consists of an integrated microfluidic device with a cross-slot channel geometry where two opposing laminar streams converge, thereby generating a planar extensional flow with a fluid stagnation point (zero-velocity point). In this device, particles are confined at the trap center by active control of the flow field to maintain particle position at the fluid stagnation point. In this manner, particles are effectively trapped in free solution using a feedback control algorithm implemented with a custom-built LabVIEW code. The control algorithm consists of image acquisition for a particle in the microfluidic device, followed by particle tracking, determination of particle centroid position, and active adjustment of fluid flow by regulating the pressure applied to an on-chip pneumatic valve using a pressure regulator. In this way, the on-chip dynamic metering valve functions to regulate the relative flow rates in the outlet channels, thereby enabling fine-scale control of stagnation point position and particle trapping. The microfluidic-based hydrodynamic trap exhibits several advantages as a method for particle trapping. Hydrodynamic trapping is possible for any arbitrary particle without specific requirements on the physical or chemical properties of the trapped object. In addition, hydrodynamic trapping enables confinement of a "single" target object in concentrated or crowded particle suspensions, which is difficult using alternative force field-based trapping methods. The hydrodynamic trap is user-friendly, straightforward to implement and may be added to existing microfluidic devices to facilitate trapping and long-time analysis of particles. Overall, the hydrodynamic trap is a new platform for confinement, micromanipulation, and observation of particles without surface immobilization and eliminates the need for potentially perturbative optical, magnetic, and electric fields in the free-solution trapping of small particles.

In this article, we present a microfluidic-based method for particle confinement based on hydrodynamic flow. We demonstrate stable particle trapping at a fluid stagnation point using a feedback control mechanism, thereby enabling confinement and micromanipulation of arbitrary particles in an integrated microdevice.

Microfluidic מבוססי הידרודינמית מלכודת חלקיקים יחיד

The ability to confine and manipulate single particles in free solution is a key enabling technology for fundamental and applied science.  Methods for ...

Microfluidic Chips Controlled with Elastomeric Microvalve Arrays

Miniaturized microfluidic systems provide simple and effective solutions for low-cost point-of-care diagnostics and high-throughput biomedical assays. Robust flow control and precise fluidic volumes are two critical requirements for these applications. We have developed microfluidic chips featuring elastomeric polydimethylsiloxane (PDMS) microvalve arrays that: 1) need no extra energy source to close the fluidic path, hence the loaded device is highly portable; and 2) allow for microfabricating deep (up to 1 mm) channels with vertical sidewalls and resulting in very precise features.

The PDMS microvalves-based devices consist of three layers: a fluidic layer containing fluidic paths and microchambers of various sizes, a control layer containing the microchannels necessary to actuate the fluidic path with microvalves, and a middle thin PDMS membrane that is bound to the control layer. Fluidic layer and control layers are made by replica molding of PDMS from SU-8 photoresist masters, and the thin PDMS membrane is made by spinning PDMS at specified heights. The control layer is bonded to the thin PDMS membrane after oxygen activation of both, and then assembled with the fluidic layer. The microvalves are closed at rest and can be opened by applying negative pressure (e.g., house vacuum). Microvalve closure and opening are automated via solenoid valves controlled by computer software.

Here, we demonstrate two microvalve-based microfluidic chips for two different applications. The first chip allows for storing and mixing precise sub-nanoliter volumes of aqueous solutions at various mixing ratios. The second chip allows for computer-controlled perfusion of microfluidic cell cultures.

The devices are easy to fabricate and simple to control. Due to the biocompatibility of PDMS, these microchips could have broad applications in miniaturized diagnostic assays as well as basic cell biology studies.

We demonstrate protocols for manufacturing and automating elastomeric polydimethylsiloxane (PDMS)-based microvalve arrays that need no extra energy to close and feature photolithographically defined precise volumes. A parallel subnanoliter-volume mixer and an integrated microfluidic perfusion system are presented.

שבבי microfluidic מבוקרת עם מערכים Microvalve אלסטומרי

Miniaturized microfluidic systems provide simple and effective solutions for low-cost point-of-care diagnostics and high-throughput biomedical assays.  ...

Biology

On-chip Isotachophoresis for Separation of Ions and Purification of Nucleic Acids

Electrokinetic techniques are a staple of microscale applications because of their unique ability to perform a variety of fluidic and electrophoretic processes in simple, compact systems with no moving parts. Isotachophoresis (ITP) is a simple and very robust electrokinetic technique that can achieve million-fold preconcentration1,2 and efficient separation and extraction based on ionic mobility.3 For example, we have demonstrated the application of ITP to separation and sensitive detection of unlabeled ionic molecules (e.g. toxins, DNA, rRNA, miRNA) with little or no sample preparation4-8 and to extraction and purification of nucleic acids from complex matrices including cell culture, urine, and blood.9-12
ITP achieves focusing and separation using an applied electric field and two buffers within a fluidic channel system. For anionic analytes, the leading electrolyte (LE) buffer is chosen such that its anions have higher effective electrophoretic mobility than the anions of the trailing electrolyte (TE) buffer (Effective mobility describes the observable drift velocity of an ion and takes into account the ionization state of the ion, as described in detail by Persat et al.13). After establishing an interface between the TE and LE, an electric field is applied such that LE ions move away from the region occupied by TE ions. Sample ions of intermediate effective mobility race ahead of TE ions but cannot overtake LE ions, and so they focus at the LE-TE interface (hereafter called the "ITP interface"). Further, the TE and LE form regions of respectively low and high conductivity, which establish a steep electric field gradient at the ITP interface. This field gradient preconcentrates sample species as they focus. Proper choice of TE and LE results in focusing and purification of target species from other non-focused species and, eventually, separation and segregation of sample species.
We here review the physical principles underlying ITP and discuss two standard modes of operation: "peak" and "plateau" modes. In peak mode, relatively dilute sample ions focus together within overlapping narrow peaks at the ITP interface. In plateau mode, more abundant sample ions reach a steady-state concentration and segregate into adjoining plateau-like zones ordered by their effective mobility. Peak and plateau modes arise out of the same underlying physics, but represent distinct regimes differentiated by the initial analyte concentration and/or the amount of time allotted for sample accumulation.
We first describe in detail a model peak mode experiment and then demonstrate a peak mode assay for the extraction of nucleic acids from E. coli cell culture. We conclude by presenting a plateau mode assay, where we use a non-focusing tracer (NFT) species to visualize the separation and perform quantitation of amino acids.

Isotachophoresis (ITP) is a robust electrokinetic separation and preconcentration technique with applications ranging from toxin detection to sample preparation. We review the physical principles of ITP and the methodology of applying this technique to two specific example applications: separation and detection of small molecules and purification of nucleic acids from cell culture lysate.

על שבב Isotachophoresis להפרדה של יוני וטיהור של חומצות גרעין

Electrokinetic techniques are a staple of microscale applications because of their unique ability to perform a variety of fluidic and electrophoretic ...

Creating Sub-50 Nm Nanofluidic Junctions in PDMS Microfluidic Chip via Self-Assembly Process of Colloidal Particles

Polydimethylsiloxane (PDMS) is the prevailing building material to make microfluidic devices due to its ease of molding and bonding as well as its transparency. Due to the softness of the PDMS material, however, it is challenging to use PDMS for building nanochannels. The channels tend to collapse easily during plasma bonding. In this paper, we present an evaporation-driven self-assembly method of silica colloidal nanoparticles to create nanofluidic junctions with sub-50 nm pores between two microchannels. The pore size as well as the surface charge of the nanofluidic junction is tunable simply by changing the colloidal silica bead size and surface functionalization outside of the assembled microfluidic device in a vial before the self-assembly process. Using the self-assembly of nanoparticles with a bead size of 300 nm, 500 nm, and 900 nm, it was possible to fabricate a porous membrane with a pore size of ~45 nm, ~75 nm and ~135 nm, respectively. Under electrical potential, this nanoporous membrane initiated ion concentration polarization (ICP) acting as a cation-selective membrane to concentrate DNA by ~1,700 times within 15 min. This non-lithographic nanofabrication process opens up a new opportunity to build a tunable nanofluidic junction for the study of nanoscale transport processes of ions and molecules inside a PDMS microfluidic chip.

We propose a simple self-assembly technique of silica colloidal nanoparticles to create a nanofluidic junction between two microchannels in polydimethylsiloxane (PDMS). Using this technique, a nanoporous bead membrane with a pore size down to ~45 nm was built inside a microchannel and applied to electrokinetic preconcentration of DNA samples.

יצירת צומת תת-50 ננומטר ננו-נוזלי ב PDMS Microfluidic שבב באמצעות תהליך ההרכבה העצמית של חלקיקים קולואיד

Polydimethylsiloxane (PDMS) is the prevailing building material to make microfluidic devices due to its ease of molding and bonding as well as its ...

Engineering

A Microfluidic Chip for the Versatile Chemical Analysis of Single Cells

We present a microfluidic device that enables the quantitative determination of intracellular biomolecules in multiple single cells in parallel. For this purpose, the cells are passively trapped in the middle of a microchamber. Upon activation of the control layer, the cell is isolated from the surrounding volume in a small chamber. The surrounding volume can then be exchanged without affecting the isolated cell. However, upon short opening and closing of the chamber, the solution in the chamber can be replaced within a few hundred milliseconds. Due to the reversibility of the chambers, the cells can be exposed to different solutions sequentially in a highly controllable fashion, e.g. for incubation, washing, and finally, cell lysis. The tightly sealed microchambers enable the retention of the lysate, minimize and control the dilution after cell lysis. Since lysis and analysis occur at the same location, high sensitivity is retained because no further dilution or loss of the analytes occurs during transport. The microchamber design therefore enables the reliable and reproducible analysis of very small copy numbers of intracellular molecules (attomoles, zeptomoles) released from individual cells. Furthermore, many microchambers can be arranged in an array format, allowing the analysis of many cells at once, given that suitable optical instruments are used for monitoring. We have already used the platform for proof-of-concept studies to analyze intracellular proteins, enzymes, cofactors and second messengers in either relative or absolute quantifiable manner.

In this article we present a microfluidic chip for single cell analysis. It allows the quantification of intracellular proteins, enzymes, cofactors, and second messengers by means of fluorescent assays or immunoassays.&#160;

שבב microfluidic לניתוח הכימי תכליתי של תאים בודדים

We present a microfluidic device that enables the quantitative determination of intracellular biomolecules in multiple single cells in parallel. For this ...

Microfluidic Chips for In Situ Crystal X-ray Diffraction and In Situ Dynamic Light Scattering for Serial Crystallography

This protocol describes fabricating microfluidic devices with low X-ray background optimized for goniometer based fixed target serial crystallography. The devices are patterned from epoxy glue using soft lithography and are suitable for in situ X-ray diffraction experiments at room temperature. The sample wells are lidded on both sides with polymeric polyimide foil windows that allow diffraction data collection with low X-ray background. This fabrication method is undemanding and inexpensive. After the sourcing of a SU-8 master wafer, all fabrication can be completed outside of a cleanroom in a typical research lab environment. The chip design and fabrication protocol utilize capillary valving to microfluidically split an aqueous reaction into defined nanoliter sized droplets. This loading mechanism avoids the sample loss from channel dead-volume and can easily be performed manually without using pumps or other equipment for fluid actuation. We describe how isolated nanoliter sized drops of protein solution can be monitored in situ by dynamic light scattering to control protein crystal nucleation and growth. After suitable crystals are grown, complete X-ray diffraction datasets can be collected using goniometer based in situ fixed target serial X-ray crystallography at room temperature. The protocol provides custom scripts to process diffraction datasets using a suite of software tools to solve and refine the protein crystal structure. This approach avoids the artefacts possibly induced during cryo-preservation or manual crystal handling in conventional crystallography experiments. We present and compare three protein structures that were solved using small crystals with dimensions of approximately 10-20 &#181;m grown in chip. By crystallizing and diffracting in situ, handling and hence mechanical disturbances of fragile crystals is minimized. The protocol details how to fabricate a custom X-ray transparent microfluidic chip suitable for in situ serial crystallography. As almost every crystal can be used for diffraction data collection, these microfluidic chips are a very efficient crystal delivery method.

Microfluidic Chips for In Situ Crystal X-ray Diffraction and In Situ Dynamic Light Scattering for Serial Crystallography

This protocol describes in detail how to fabricate and operate microfluidic devices for X-ray diffraction data collection at room temperature. Additionally, it describes how to monitor protein crystallization by dynamic light scattering and how to process and analyze obtained diffraction data.

Microfluidic שבבים עבור בחיי עיר קריסטל רנטגן עקיפה ו בחיי עיר פיזור אור דינאמי עבור קריסטלוגרפיה טורי

This protocol describes fabricating microfluidic devices with low X-ray background optimized for goniometer based fixed target serial crystallography. The ...

Chemistry

A Microfluidic-based Electrochemical Biochip for Label-free DNA Hybridization Analysis

Miniaturization of analytical benchtop procedures into the micro-scale provides significant advantages in regards to reaction time, cost, and integration of pre-processing steps. Utilizing these devices towards the analysis of DNA hybridization events is important because it offers a technology for real time assessment of biomarkers at the point-of-care for various diseases. However, when the device footprint decreases the dominance of various physical phenomena increases. These phenomena influence the fabrication precision and operation reliability of the device. Therefore, there is a great need to accurately fabricate and operate these devices in a reproducible manner in order to improve the overall performance. Here, we describe the protocols and the methods used for the fabrication and the operation of a microfluidic-based electrochemical biochip for accurate analysis of DNA hybridization events. The biochip is composed of two parts: a microfluidic chip with three parallel micro-channels made of polydimethylsiloxane (PDMS), and a 3 x 3 arrayed electrochemical micro-chip. The DNA hybridization events are detected using electrochemical impedance spectroscopy (EIS) analysis. The EIS analysis enables monitoring variations of the properties of the electrochemical system that are dominant at these length scales. With the ability to monitor changes of both charge transfer and diffusional resistance with the biosensor, we demonstrate the selectivity to complementary ssDNA targets, a calculated detection limit of 3.8 nM, and a 13% cross-reactivity with other non-complementary ssDNA following 20 min&#160;of incubation. This methodology can improve the performance of miniaturized devices by elucidating on the behavior of diffusion at the micro-scale regime and by enabling the study of DNA hybridization events.

We present a microfluidic-based electrochemical biochip for DNA hybridization detection. Following ssDNA probe functionalization, the specificity, sensitivity, and detection limit are studied with complementary and non-complementary ssDNA targets. Results illustrate the influence of the DNA hybridization events on the electrochemical system, with a detection limit of 3.8 nM.

Biochip אלקטרוכימי מבוסס Microfluidic לניתוח הכלאה DNA ללא תווית

Miniaturization of analytical benchtop procedures into the micro-scale provides significant advantages in regards to reaction time, cost, and integration ...

A Microfluidic Platform for Precision Small-volume Sample Processing and Its Use to Size Separate Biological Particles with an Acoustic Microdevice

A major advantage of microfluidic devices is the ability to manipulate small sample volumes, thus reducing reagent waste and preserving precious sample. However, to achieve robust sample manipulation it is necessary to address device integration with the macroscale environment. To realize repeatable, sensitive particle separation with microfluidic devices, this protocol presents a complete automated and integrated microfluidic platform that enables precise processing of 0.15&#8211;1.5 ml samples using microfluidic devices. Important aspects of this system include modular device layout and robust fixtures resulting in reliable and flexible world to chip connections, and fully-automated fluid handling which accomplishes closed-loop sample collection, system cleaning and priming steps to ensure repeatable operation. Different microfluidic devices can be used interchangeably with this architecture. Here we incorporate an acoustofluidic device, detail its characterization, performance optimization, and demonstrate its use for size-separation of biological samples. By using real-time feedback during separation experiments, sample collection is optimized to conserve and concentrate sample. Although requiring the integration of multiple pieces of equipment, advantages of this architecture include the ability to process unknown samples with no additional system optimization, ease of device replacement, and precise, robust sample processing.

This protocol describes a system architecture for performing automated small volume (0.15&#8211;1.5 ml) particle separations using a microfluidic device, and discusses methods to optimize acoustofluidic device performance and operation.

פלטפורמת microfluidic לעיבוד מדגם Precision הקטן-נפח ושימוש בו לגודל חלקיקים הביולוגיים נפרדים עם Microdevice אקוסטי

A major advantage of microfluidic devices is the ability to manipulate small sample volumes, thus reducing reagent waste and preserving precious sample. ...

Fabrication of a Dipole-assisted Solid Phase Extraction Microchip for Trace Metal Analysis in Water Samples

This paper describes a fabrication protocol for a dipole-assisted solid phase extraction (SPE) microchip available for trace metal analysis in water samples. A brief overview of the evolution of chip-based SPE techniques is provided. This is followed by an introduction to specific polymeric materials and their role in SPE. To develop an innovative dipole-assisted SPE technique, a chlorine (Cl)-containing SPE functionality was implanted into a poly(methyl methacrylate) (PMMA) microchip. Herein, diverse analytical techniques including contact angle analysis, Raman spectroscopic analysis, and laser ablation-inductively coupled plasma-mass spectrometry (LA-ICP-MS) analysis were employed to validate the utility of the implantation protocol of the C-Cl moieties on the PMMA. The analytical results of the X-ray absorption near-edge structure (XANES) analysis also demonstrated the feasibility of the Cl-containing PMMA used as an extraction medium by virtue of the dipole-ion interactions between the highly electronegative C-Cl moieties and the positively charged metal ions.

The fabrication protocol of a dipole-assisted solid phase extraction microchip for the trace metal analysis is presented.

המצאה של Microchip הפקת דיפול בסיוע שלב מוצק עבור ניתוח מתכת עקבות בדגימות מים

This paper describes a fabrication protocol for a dipole-assisted solid phase extraction (SPE) microchip available for trace metal analysis in water ...

Fast Enzymatic Processing of Proteins for MS Detection with a Flow-through Microreactor

The vast majority of mass spectrometry (MS)-based protein analysis methods involve an enzymatic digestion step prior to detection, typically with trypsin. This step is necessary for the generation of small molecular weight peptides, generally with MW &#60; 3,000-4,000 Da, that fall within the effective scan range of mass spectrometry instrumentation. Conventional protocols involve O/N enzymatic digestion at 37 &#186;C. Recent advances have led to the development of a variety of strategies, typically involving the use of a microreactor with immobilized enzymes or of a range of complementary physical processes that reduce the time necessary for proteolytic digestion to a few minutes (e.g., microwave or high-pressure). In this work, we describe a simple and cost-effective approach that can be implemented in any laboratory for achieving fast enzymatic digestion of a protein. The protein (or protein mixture) is adsorbed on C18-bonded reversed-phase high performance liquid chromatography (HPLC) silica particles preloaded in a capillary column, and trypsin in aqueous buffer is infused over the particles for a short period of time. To enable on-line MS detection, the tryptic peptides are eluted with a solvent system with increased organic content directly in the MS ion source. This approach avoids the use of high-priced immobilized enzyme particles and does not necessitate any aid for completing the process. Protein digestion and complete sample analysis can be accomplished in less than ~3 min and ~30 min, respectively.

A quick protocol for proteolytic digestion with an in-house built flow-through tryptic microreactor coupled to an electrospray ionization (ESI) mass spectrometer is presented. The fabrication of the microreactor, the experimental setup and the data acquisition process are described.

עיבוד אנזימתי תענית חלבונים עבור איתור MS עם microreactor זרימה דרך

The vast majority of mass spectrometry (MS)-based protein analysis methods involve an enzymatic digestion step prior to detection, typically with trypsin. ...