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Diagnostic Devices with
Microfluidics
 Devices, Circuits, and Systems

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Diagnostic Devices with
Microfluidics
Edited by
Francesco Piraino • Šeila Selimović

Managing Editor
Krzysztof Iniewski
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Contents

Preface.......................................................................................................................xi
Series Editor............................................................................................................xv
Editors................................................................................................................... xvii
Contributors...........................................................................................................xix

Section I Microfluidic Devices for Diagnostics

1. Handheld Microfluidics for Point-of-Care

In Vitro Diagnostics........................................................................................3
Baichen Li and Zhenyu Li

2. Body-Worn Microfluidic Sensors................................................................21

Mary M. Rodgers, Vinay M. Pai, and Richard S. Conroy

3. Fabrication and Applications of Paper-Based Microfluidics................45

Xuan Mu and Yu Shrike Zhang

4. Printed Wax-Ink Valves for Multistep Assays in Paper

Analytical Devices.........................................................................................65
Jacqueline C. Linnes and Elizabeth Phillips

5. Mycofluidics: Miniaturization of Mycotoxin Analysis..........................75

Jonathan H. Loftus, Gregor S. Kijanka, and Richard O’Kennedy

6. Planar Differential Mobility Spectrometry for

Clinical Breath Diagnostics.........................................................................89
Erkinjon G. Nazarov, Timothy Postlethwaite,
Kenneth Markoski, Sophia Koo, and Jeffrey T. Borenstein

Section II Applications in Disease Detection

7. Rapid Diagnosis of Infectious Diseases Using

Microfluidic Systems...................................................................................145
Hardik Jeetendra Pandya, Mohamed Shehata Draz,
Majid Ebrahimi Warkiani, and Hadi Shafiee

ix
x Contents

8. Microfluidics for Tuberculosis Diagnosis: Advances,

Scalability, and Challenges........................................................................163
Bhavna G. Gordhan and Bavesh D. Kana

Section III Practical Aspects of Developing

a Commercial Diagnostic Device
9. Starting with the End in Mind by Developing Diagnostics
around User Needs......................................................................................207
Mark David Lim

10. Incorporating the Needs of Users into the Development of

Diagnostics for Global Health: A Framework and Two Case
Studies............................................................................................................219
Jacqueline C. Linnes, Elizabeth Johansen, and Ashok A. Kumar

Index......................................................................................................................251
Preface

This book provides insight into the latest developments in point-of-care

(POC) and laboratory diagnostic devices that are based on microfluidic
principles. Microfluidic techniques and devices have had a steadily grow-
ing influence on research in life sciences and bioengineering, leading to their
adoption in modern diagnostic solutions. The goal of this book is to highlight
this growing field and present a selection of important topics, making it an
excellent introductory reading for graduate students in bioengineering and
related disciplines. The book is also suitable for advanced researchers, as a
review of the latest published studies.
The three sections of the book are devoted to the devices for diagnostics,
applications for specific diseases, and practical aspects of developing a diag-
nostic device.
Chapter 1 provides the description of a handheld microfluidic device for
POC in vitro diagnostics. In Chapter 2, recent developments in wearable
microfluidic sensors are highlighted, with a special focus on microfluidic
devices for monitoring physical and physiological activity and noninvasive
collection and analysis of biological fluids, such as breath condensates, sweat,
saliva, and tears. The chapter discusses paper-based microfluidics, which is
an emerging and rapidly developing technology. It harnesses the material
merits of paper as well as the basic concepts of microfluidics. This syner-
gistic combination not only leverages analytical functions and transforms
them into a POC technique, but also renders the configuration of the assay
as simple as possible. It is advantageous to address technical bottlenecks in
current diagnostic assays and to develop novel POC tests. Consequently,
paper-based microfluidics is capable of enhancing the delivery of health-
care interventions to patients, especially in resource-limited settings, show-
ing potential to revolutionize first-line clinical practice. Chapter 3 provides
a background of paper-based microfluidics, reviews the recent advances
in fabrication techniques, and emphasizes its critical applications in a few
specific clinical scenarios, including immunoassay, blood typing, and sickle
disease detection. Chapter 4 describes a method for fabricating paper ana-
lytical devices (PADs) containing wax-ink valves to control the timing of
reagent delivery in multistep assays. Wax-ink valves are printed onto mem-
branes in defined patterns and can be actuated by applying localized heat
to the valves to allow fluid to flow. Here, the authors describe how to use
these valves to enhance the lateral flow immunoassay detection signal water
test kit to detect microbiological contamination. Chapter 5 briefly describes
some of the established methods of mycotoxin analysis and highlights the
limitations of these methods. The need to develop rapid, portable analytical
platforms is emphasized. These platforms must be able to compete with the

xi
xii Preface

gold standard techniques in areas such as sensitivity and specificity so that

analysis can be moved from the laboratory to “on-site” monitoring. Current
research on microfluidics-based devices is examined and examples of
devices utilizing microfluidic platforms to offer potential solutions for rapid
analysis are described throughout the chapter. Chapter 6 describes a device
and its technology underpinnings that are capable of revolutionizing clini-
cal breath diagnostics based on a combination of its small size, low power
requirements, ease of use, and applicability to a broad range of clinically rel-
evant biomarker signatures. This technology, based upon the principle of ion
mobility spectrometry, generates signature spectral patterns as distinctive
as mass spectrometry (MS) but with far greater simplicity and adaptability.
The differential mobility spectrometer (DMS) is a portable, handheld device
that generates multidimensional biological spectra from volatile compounds
found in exhaled breath. Current prototype models of the DMS fit in the
palm of the hand, are highly durable, operate at atmospheric pressure, and
can be operated with standard batteries.
Due to numerous advantages, there is great potential for microfluidic tech-
nology to be applied in the development of disposable, inexpensive, portable,
and easy-to-use devices for the detection of infectious diseases in resource-
limited settings. Chapter 7 reviews the application of microfluidic device
and chips for detecting infectious diseases. While no microfluidic diagnostic
platform has been rolled out for TB in endemic countries, significant strides
have been made in the development and implementation of molecular diag-
nostics, which now set the scene for POC microfluidic platforms. Chapter 8
details these molecular diagnostic platforms and follows this with a discus-
sion on the state of the art for TB microfluidic diagnostics that are in develop-
ment. It also outlines the challenges in scaling up of these interventions and
integrating them into healthcare systems.
Chapter 9 highlights considerations for designing a diagnostic device for
use on individual patients or populations by assessing and incorporating
the answers to two fundamental questions—who is asking for the test and
how do test results guide a treatment decision. The methodology described
is a best practice for assessing and ensuring that user needs are central to
the design, development, and evaluation of a new diagnostic tool. The
assessment starts with a clear intended-use statement that is centered on an
actionable decision and justifies the time and cost to obtain a diagnosis. This
definition is used to frame use-cases and user scenarios that identify users
and describe how the test will be implemented, as well as the criteria for
generating an actionable test result. All three of these assessments are then
used to create a list of product attributes that are required to meet the needs
of an end user.
Finally, ensuring that a POC test is designed so that the user can correctly
operate and interpret results is paramount to obtaining a correct diagno-
sis. Designing with end user needs in mind allows researchers to mitigate
potential errors and device failures early in the development process. Yet,
Preface xiii

too often, a lack of knowledge in how to meaningfully engage device users

during the research and design process is a roadblock to progress in early
diagnostic development. This is especially true in designing for global health
settings where resources to access end users may be limited. Chapter 10 out-
lines techniques to incorporate the needs of users into device development
using a framework of human-centered design (HCD). HCD provides a set of
methods to engage with users even before a verified diagnostic device has
been created to develop tests that have improved clinical diagnoses, regula-
tory approval, and commercialization outcomes. Two case studies focused
on incorporating HCD into early-stage diagnostic test development provide
specific examples of methods in use. Finally, common misconceptions about
when and how HCD can be used in diagnostic development are addressed.
We sincerely hope that this book will be a source of inspiration for
new applications and stimulate further development of microsystems
technologies.

Francesco Piraino
Lausanne, Switzerland
Šeila Selimović
Washington, DC

MATLAB® and Simulink® are registered trademarks of The MathWorks, Inc.

For product information, please contact:
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Series Editor

Krzysztof (Kris) Iniewski is managing R&D at Redlen Technologies Inc.,

a start-up company in Vancouver, Columbia, Canada. Redlen’s revolution-
ary production process for advanced semiconductor materials enables a
new generation of more accurate, all-digital, radiation-based imaging solu-
tions. Kris is also a founder of Emerging Technologies CMOS Inc. (www.
etcmos.com), an organization of high-tech events covering communications,
microsystems, optoelectronics, and sensors. In his career, Dr. Iniewski held
numerous faculty and management positions at the University of Toronto,
University of Alberta, SFU, and PMC-Sierra Inc. He has published over 100
research papers in international journals and conferences. He holds 18 inter-
national patents granted in the USA, Canada, France, Germany, and Japan.
He is a frequent invited speaker and has consulted for multiple organiza-
tions internationally. He has written and edited several books for CRC Press,
Cambridge University Press, IEEE Press, Wiley, McGraw-Hill, Artech House,
and Springer. His personal goal is to contribute to healthy living and sustain-
ability through innovative engineering solutions. In his leisurely time, Kris
can be found hiking, sailing, skiing, or biking in beautiful British Columbia.
He can be reached at kris.iniewski@gmail.com.

xv
Editors

Francesco Piraino is currently a research scientist at the Swiss Federal

Institute of Technology in Lausanne (Switzerland). He uses microscale tech-
nologies to develop next-generation microfluidic diagnostics platforms.
Following his graduate studies in Biomedical Engineering at Politecnico di
Milano (Italy) and at Harvard-MIT Division of Health Science & Technology
(USA), he joined the Broad Institute of MIT and Harvard (USA) to develop
devices for single-cell genomics. Dr. Piraino is a trained bioengineer who
has also attended programs at the Universitat de Barcelona (Spain), the City
College of the City University of New York (USA), and the Massachusetts
Institute of Technology (USA). His work aims to solve problems at the
intersection of biomedical engineering and medicine. His research interests
include in vitro diagnostics, tissue engineering, and biomaterials.

Šeila Selimović is director of the NIBIB programs in tissue chips/tissue

preservation technologies and biosensors. Her other scientific interests
include lab-on-a-chip platforms, paper microfluidics, and point-of-care diag-
nostics. In 2015, she was selected as one of the “50 Leaders of Tomorrow”
from among hundreds of young biotech leaders in the Mid-Atlantic region.
Prior to her current position, she was chosen by the American Association
for the Advancement of Science to serve as a Science and Technology Policy
Fellow at the U.S. Department of State, where she covered science diplomacy
issues related to energy security, climate, and innovation. Previously, she
was a postdoctoral research fellow at Harvard Medical School and Brigham
and Women’s Hospital in Boston, Massachusetts. Dr. Selimović’s research
has focused on the development of microfluidic platforms for applications in
biophysics and biological engineering, and her research interests include the
physics of microscale flows, protein crystallization, colloidal suspensions,
and rheology and microrheology. Dr. Selimović earned her PhD and MSc in
physics from Brandeis University, with National Science Foundation sup-
port, and her BA in physics and German from Wellesley College. She is a
member of Sigma Xi.

xvii
Contributors
Jeffrey T. Borenstein
Biomedical Engineering Centre
Draper
Cambridge, Massachusetts
Richard S. Conroy
Office of Strategic Coordination
Division of Program Coordination,
Planning, and Strategic Initiatives
Office of the NIH Director
National Institutes of Health
Bethesda, Maryland
Mohamed Shehata Draz
Department of Medicine
Harvard Medical School
Brigham and Women’s Hospital
Cambridge, Massachusetts
Bhavna G. Gordhan
DST/NRF Centre of Excellence for
Biomedical TB Research
School of Pathology
Faculty of Health Sciences
University of the Witwatersrand
and the National Health
Laboratory Service
Johannesburg, South Africa
Elizabeth Johansen
Diagnostics For All
Salem, Massachusetts
and
Spark Health Design
Hanover, Massachusetts
Bavesh D. Kana
DST/NRF Centre of Excellence for
Biomedical TB Research
School of Pathology
Faculty of Health Sciences
University of the Witwatersrand
and the National Health
Laboratory Service
Johannesburg, South Africa
and
Centre for the AIDS Programme of
Research
Durban, South Africa
Gregor S. Kijanka
Biomedical Diagnostics Institute
Dublin City University
Dublin, Ireland
Sophia Koo
Division of Infectious Diseases
Department of Medicine
Brigham and Women’s Hospital
Boston, Massachusetts
Ashok A. Kumar
Jana Care
Boston, Massachusetts
and
Department of Chemistry and
Chemical Biology
Harvard University
Cambridge, Massachusetts
xix
xx
Baichen Li
Department of Biomedical
Engineering
School of Engineering and Applied
Sciences
The George Washington University
Washington, DC
Zhenyu Li
Department of Biomedical
Engineering
School of Engineering and Applied
Sciences
The George Washington University
Washington, DC
Mark David Lim
Diagnostics, Global Health
Bill and Melinda Gates Foundation
Seattle, Washington
Jacqueline C. Linnes
Weldon School of Biomedical
Engineering
Purdue University
West Lafayette, Indiana
Jonathan H. Loftus
School of Biotechnology
Dublin City University
Dublin, Ireland
Kenneth Markoski
Mechanical Engineering Draper
Cambridge, Massachusetts
Xuan Mu
Division of Engineering in Medicine
Brigham and Women’s Hospital
Harvard Medical School
Cambridge, Massachusetts
Contributors
Erkinjon G. Nazarov
BioMEMS Centre Draper
Tampa, Florida
Richard O’Kennedy
School of Biotechnology and
Biomedical Diagnostics Institute
Dublin City University
Dublin, Ireland
Vinay M. Pai
National Institute of Biomedical
Imaging and Bioengineering
National Institutes of Health
Bethesda, Maryland
Hardik Jeetendra Pandya
Department of Medicine
Harvard Medical School
Brigham and Women’s Hospital
Cambridge, Massachusetts
Elizabeth Phillips
Weldon School of Biomedical
Engineering
Purdue University
West Lafayette, Indiana
Timothy Postlethwaite
Biomedical Solutions Program
Office Draper
Tampa, FL
Mary M. Rodgers
National Institute of Biomedical
Imaging and Bioengineering
National Institutes of Health
Bethesda, Maryland
Hadi Shafiee
Department of Medicine
Harvard Medical School
Brigham and Women’s Hospital
Cambridge, Massachusetts
Contributors xxi

Majid Ebrahimi Warkiani Yu Shrike Zhang

School of Mechanical and Division of Engineering in Medicine
Manufacturing Engineering Brigham and Women’s Hospital
University of New South Wales Harvard Medical School
and Cambridge, Massachusetts
Garvan Institute for Biomedical
Research
Sydney, New South Wales, Australia
and
School of Medical Sciences
Edith Cowan University
Perth, Western Australia, Australia
 Section I

Microfluidic Devices
for Diagnostics
1
Handheld Microfluidics for Point-of-Care
In Vitro Diagnostics*

Baichen Li and Zhenyu Li

CONTENTS
1.1 Introduction.....................................................................................................3
1.2 Design of the Handheld Microfluidic System............................................6
1.2.1 Pneumatic Subsystem�������������������������������������������������������������������������6
1.2.2 Pressure Stabilization in Reservoirs 1 and 2...................................8
1.2.3 Microcontroller-Based Electronic Subsystem...................................9
1.2.4 Android Application........................................................................10
1.2.5 Microfluidic Device Design and Fabrication,
Reagent Containers, and Interfaces................................................10
1.2.6 Simulated Bead-Based Fluorescence Immunoassay
Liquid Handling...............................................................................10
1.3 System Performance..................................................................................... 11
1.3.1 Pneumatic Subsystem...................................................................... 11
1.3.2 Microbead-Based HIV p24 Immunoassay.....................................13
1.3.3 Power Consumption........................................................................15
1.4 Summary........................................................................................................17
Acknowledgments.................................................................................................18
References................................................................................................................18

1.1 Introduction
In vitro diagnostics (IVD) influences 70% of all healthcare decisions accord-
ing to a study (Lewin Group 2005). However, such a universally demanded
service is still largely centralized partly due to the fact that current IVD tech-
nologies are still too complicated, expensive, bulky, and slow for point-of-
care (POC) settings such as emergency rooms, physicians’ offices, patients’
homes, and ultimately on (or in) human bodies. One important goal of

* Part of this chapter was published in Lab on a Chip as a peer-reviewed article (Li et al. 2014).

3
4 Diagnostic Devices with Microfluidics

lab-on-a-chip research is to miniaturize conventional medical diagnostic

instruments, including IVD systems (Manz et al. 1992, Whitesides 2006).
One common feature of traditional IVD instruments is that they all require
complex manipulations of liquid samples such as blood, urine, saliva, and
liquid reagents, and so on. Therefore, it is essential for POC IVD systems to
have built-in liquid-handling capabilities comparable to robotic pipetting
and centrifugation used in conventional clinical labs in order to achieve
truly automated sample-to-answer operations. In the past three decades,
there have been extensive efforts on miniaturizing liquid-handling com-
ponents on chip, such as MEMS valves and pumps (Kwang and Chong
2006, Laser and Santiago 2004), elastomeric on-chip valves and pumps
(Unger et al. 2000), and droplet manipulation systems (Pollack et al. 2000).
However, due to various material, fabrication, integration, and reliability
challenges, few handheld (not to mention fully on-chip) self-contained
microfluidic systems capable of sophisticated liquid handling exist in the
market today except for capillary-driven microfluidics such as lateral flow
tests (Wong and Tse 2009). Most lab-on-a-chip systems still rely on bulky off-
chip components such as compressed pressure sources, syringe pumps, and
electronics to achieve their liquid manipulation functions, which severely
limits the applicability of such systems for POC diagnostics, environmental
monitoring, and bioterrorism detection. Recently, a handheld instrument
was developed that can actuate on-chip elastomeric microvalves using
­solenoid-containing actuation units (Addae-Mensah et al. 2010). Another
promising technique is digital microfluidics, in which droplets are manipu-
lated by electrowetting (Pollack et al. 2000); however, to our knowledge a
handheld digital microfluidic system has not been demonstrated. Braille
display devices have also been used to build portable microfluidic sys-
tems (Gu et al. 2004). In this chapter, we present a smartphone-controlled
handheld microfluidic liquid-handling system recently developed by us. It
combines elastomeric on-chip microfluidic valves, a handheld pneumatic
system, and a smartphone-based control and data processing system. The
handheld pneumatic system provides onboard multiple pressure genera-
tion, stabilization, and control by using a miniature pump, pressure-storage
reservoirs, and small solenoid valves. This system is applicable to both
single-layer, pressure-driven microfluidics and multilayer, elastomeric
microfluidics (Grover et al. 2003, Hansson et al. 1994, Hosokawa, Maeda
2000, Hansen et al. 2004, Thorsen et al. 2002 and Unger et al. 2000), although
the main focus is on the latter. Elastomeric microfluidics refers to microflu-
idic systems with on-chip valves based on the mechanical deformations of
elastomeric membranes or structures, such as multilayer PDMS microflu-
idics (Hosokawa and Maeda 2000, Unger et al. 2000), glass/PDMS/glass
devices (Grover et al. 2003), and other hybrid devices (Hansson et al. 1994).
In a typical elastomeric microfluidic system, often two different pressure
sources are needed: one for actuating on-chip valves, which typically require
a relatively high pressure level (5–10 psi, depending on the membrane
Handheld Microfluidics for Point-of-Care In Vitro Diagnostics 5

property and valve geometry); and the other for driving reagents into micro-
fluidic channels (for typical microfluidic channel dimensions, e.g., 10 μm
high, 100 μm wide, 1–5 psi is sufficient for many applications). Traditionally,
this is achieved by using two pressure regulators connected to a compressed
gas (often nitrogen or air) tank (Unger et al. 2000). However, the sizes and
nature of these components make them unsuitable for building a handheld
system. Although it is possible to use two separate diaphragm pumps to
build such a system, the significant fluctuations of the output pressure of a
diaphragm pump limit its applications.
To address these challenges, we have recently developed a handheld
microfluidic liquid-handling system controlled by a smartphone (Figure 1.1),
which can provide two different stable pressure sources and an array of eight
pneumatic control lines for operating elastomeric microfluidic chips (Li et al.
2014). One pressure source (P1) is set to above 10 psi (maximum 20 psi) to
operate on-chip elastomeric valves, while the other (P2) can be set to any
value between 0 psi and P1 to drive liquid flow, with a precision of ±0.05 psi.
Eight independent pneumatic control lines are available to handle eight dif-
ferent liquid reagents. The size of the resulting system is 6 × 10.5 × 16.5 cm,
and the total weight is 829 g (including battery). The system can operate con-
tinuously for 8.7 h while running a sandwich immunoassay liquid-handling
protocol when powered by a 12.8 V, 1500 mAh lithium battery. This technol-
ogy can serve as a general-purpose, handheld small-volume liquid-handling

FIGURE 1.1
Picture of the smartphone-controlled handheld microfluidic liquid-handling system. The foot-
print of the instrument is 6 × 10.5 × 16.5 cm. Powered by a 12.8 V 1500 mAh lithium battery,
the instrument consumes 2.2 W on average for a typical sandwich immunoassay and lasts for
8.7 h. A multilayer PDMS device with on-chip elastomeric valves is on top of the handheld
instrument.
6 Diagnostic Devices with Microfluidics

platform for many biochemical and cell-based assays such as immunoassay,

fluorescence in situ hybridization (FISH), polymerase chain reaction (PCR),
flow cytometry, DNA/RNA/protein microarrays, and sequencing. The
integration of this system with biosensors may help realize the long-sought
dream of handheld multianalyte in vitro diagnostic (IVD) systems, that
is, something that can be called a medical tricorder (Qualcomm Tricorder
XPRIZE 2014).

1.2 Design of the Handheld Microfluidic System

The overall handheld microfluidic system consists of three subsystems:
(1) a pneumatic pressure generation, stabilization, and control subsystem
(pneumatic subsystem); (2) an electronic printed circuit board (PCB) with
two microcontrollers, a Bluetooth wireless communication module, pres-
sure sensors, and power component drivers (electronic subsystem); and
(3) an elastomeric microfluidic chip (microfluidic chip). The system can
be controlled by a Bluetooth-enabled Android smartphone (e.g., Galaxy
SIII). Each subsystem will be described in more detail in the following
sections.

1.2.1 Pneumatic Subsystem
The pneumatic subsystem is designed to generate two compressed air
pressure sources at different levels (P1: >10 psi; P2: 0 to P1) for operating elas-
tomeric microfluidic chips (or cartridges). Two pressure reservoirs, labeled
as Reservoir 1 and Reservoir 2 (Figure 1.2), are used to store compressed
air. A miniature DC diaphragm pump is used to pump air into Reservoir 1
to generate the primary pressure source for actuating on-chip elastomeric
valves (Grover et al. 2003, Hansson et al. 1994, Hosokawa and Maeda 2000,
Unger et al. 2000). A secondary pressure source, stored in Reservoir 2, is
derived from Reservoir 1 and stabilized by a feedback control system with a
precision of ±0.05 psi for driving liquid reagents through microfluidic chan-
nels. The system can be easily extended to have multiple secondary pressure
sources of different pressures if needed.
Each pressure reservoir is made of four segments of 1/8″ ID Tygon tubing
connected with a four-way barbed cross-connector, leaving four open ports.
Each open port of a reservoir is connected to a functional part of the pneu-
matic subsystem (such as a pump, a solenoid valve, or a pressure sensor,
as shown in Figure 1.2 and described in more detail in the following) via a
barbed connector. The volume of each reservoir is determined by the total
length of tubing used. In this work, the volumes of Reservoirs 1 and 2 are 6.2
and 16.2 mL, respectively.
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*** START OF THE PROJECT GUTENBERG EBOOK MR. JERVIS,

VOL. 1 (OF 3) ***
MR. JERVIS
NEW NOVELS AT
ALL LIBRARIES.
AT MARKET VALUE. By
Grant Allen. 2 vols.
RACHEL DENE. By
Robert Buchanan. 2 vols.
A COUNTRY
SWEETHEART. By Dora
Russell. 3 vols.
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EXPERIMENT. By Adeline
Sergeant. 2 vols.
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vol.
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1 vol.
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By T. W. Speight. 1 vol.
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Romance of Spain. By E. A.
Vizetelly. 1 vol.
London: CHATTO & WINDUS,
Piccadilly.
 MR. JERVIS
BY
B. M. CROKER
AUTHOR OF
“PRETTY MISS NEVILLE,” “DIANA BARRINGTON,” “A BIRD OF PASSAGE,”
“A FAMILY LIKENESS,” ETC.

IN THREE VOLUMES
VOL. I.

London
CHATTO & WINDUS, PICCADILLY
1894
“Lord of himself, though not of lands;
And having nothing, yet hath all.”

Sir H. Wotton.
 CONTENTS OF VOL. I.
CHAPTER PAGE
I. A Girl in a Thousand 1
II. “Tell me all the News” 18
III. “Other People has Nieces too” 27
IV. The Three Young Maids of Hoyle 44
V. An Indian Letter 58
VI. “Rowena”—Full Life Size 71
VII. Fairy relents 91
VIII. Daniel Pollitt, Esq., and Family 103
IX. Permission to Travel 118
X. Major Byng’s Suggestion 144
XI. A Reserved Lady 158
XII. Two Good Samaritans 176
XIII. Toby Joy 191
XIV. Stealing a March 208
XV. A Proud Moment 221
XVI. A Message from Miss Paske 242
MR. JERVIS.
 CHAPTER I.
A GIRL IN A THOUSAND.

“I suppose I must write, and say she may come. Personally, I shall
be delighted to have her; but I’m afraid Granby will think a girl in the
house rather a bore. Three is such an awkward number in India!”
“And sometimes in other places,” added a lady who sat on the
fender-stool, blowing a great wood fire, with a preposterously small
pair of bellows.
“You know what I mean, Milly,” retorted her companion, a
handsome, indolent-looking woman, who reclined in an easy-chair,
with an open letter in her lap. “Houses out here are only built for two,
as a rule—especially in cantonments. A victoria or pony-cart holds
but two, and two is a much more manageable number for dinners
and tiffins. Still, I shall be glad to have a girl to chaperon; it will give
me an object in life, and more interest in going out.”
“Could you take more?” asked the lady with the bellows, casting a
sly smile over her shoulder.
“To be sure I could, you disagreeable little creature! When a
woman is no longer quite young, and her days of romance are at an
end, the hopes and prospects of a pretty companion give her
another chance in the matrimonial lucky-bag—a chance at second-
hand, but still sufficiently exciting. Alas! life after a certain age is like
a bottle of flat soda-water.”
“I do not think so,” rejoined the lady with the bellows, stoutly.
“No; I should be surprised if you did. You are so sympathetic and
energetic. You throw yourself heart and soul into Dorcas meetings,
bazaars, nurse-tending, and other people’s joys or afflictions. Now,
my sympathies and energies rarely extend beyond Granby and
myself. I am becoming torpid. I can scarcely get up the steam for a
ball; even the prospect of cutting out old Mother Brande fails to rouse
me. However, when I have a charming niece to marry—and to marry
well—things will assume a different aspect. How amusing it will be to
eclipse the other girls and their scheming mothers; how gratifying to
see all the best partis in the place grovelling at her feet! Her triumphs
will be mine.” And Mrs. Langrishe slowly closed her heavy eyelids,
and appeared—judging from her expression—to be wrapped in
some beatific vision. From this delicious contemplation she was
abruptly recalled by the prosaic question—
“How old is she?”
“Let me see—dear, dear me! Yes,” sitting erect and opening her
fine eyes to their widest extent, “why, strictly between ourselves, she
must be twenty-six. How time flies! She is my eldest brother’s
daughter, one of a large family. Fanny, my sister in Calcutta, had her
out eighteen months ago, and now she is obliged to go home, and
wants to hand Lalla over to me.”
“I understand,” assented her listener, with a sagacious nod.
“Can you also understand, that, simply because Fanny and I have
no children of our own, our people seem to expect us to provide for
their olive-branches? I don’t quite see it myself, though I do send
them my old dresses. Now let me read you my letter,” unfolding it as
she spoke.
“450, Chowringhee, Feb. 22nd.
“Dearest Ida,
“The doctors here say that Richard must positively go home
at once. He has been out too long, and it is quite time that
another member of the firm took a turn in the East. He has
been working hard, and it is essential for him to have a
complete holiday; and I must accompany him—a step for
which I was quite unprepared. I have taken a house at Simla
for the season—that I can easily relet and get off my hands;
but what am I to do with dear little Lalla?
“The poor child only came out last cold weather year, and
cannot endure the idea of leaving India—and no wonder, with
 any number of admirers, and a box of new dresses just
landed by the mail steamer! I had intended giving her such a
gay season, and sending Dick home alone; but now all my
nice little schemes have been knocked on the head—how
soon a few days, even a few hours, out here alters all one’s
plans! And now to come to the gist of my letter—will you take
Lalla? I would not trust her with any one but her own aunt,
though I know that Mrs. Monty-Kute is dying to have her. You
will find her a most amusing companion; no one could be dull
with Lalla in the house. She is a pretty girl, and will do you
credit, and is certain to be the belle of the place. She has
rather a nice little voice, plays the banjo and guitar, and
dances like a professional. As to her disposition, nothing in
this world is capable of ruffling her serene temper—I cannot
think who she takes after, for it is not a family trait—I have
never once seen her put out, and that is more than can be
said for a girl in a thousand. In fact, she is a girl in a thousand.
I can send her to you with a lovely outfit, a new habit and
saddle, and her pony, if you wish. I am sure, dear, you will
receive her if you can possibly manage it; and do your best to
get her well settled, for you know poor Eustace has Charlotte
and Sophy now quite grown up; even May is eighteen. You
are so clever, so popular, so full of sense, dearest Ida—so
superior to my stupid self—that if you do consent to take Lalla
under your wing, her fortune is practically made. We have
engaged passages in the Paramatta, which sails on the
twelfth, so write by return of post to
“Your loving sister,
“Fanny Crauford.”
“Fanny is quite right,” said Mrs. Langrishe, with a slight tinge of
contempt in her tone. “She is by no means clever—just an impulsive,
good-natured goose, without a scrap of tact, and is taken in and
imposed on on all sides. I won’t have the pony, that is positive, and
gram ten seers for the rupee.”
“Then you have quite decided to take the young lady?” exclaimed
her companion incredulously.
 “Yes;” now leaning back and clasping two long white hands behind
her head. “Pretty, amusing, accomplished, good-tempered—I don’t
see how I can possibly say no this time, though hitherto I have
steadily set my face against having out one of my nieces. I have
always said it was so dreadfully unfair to Granby. However, this
niece is actually stranded in the country, and it would look so odd if I
declined; besides, I shall like to have her; we shall mutually benefit
one another. She will amuse me—rejuvenate me; be useful in the
house—arrange flowers, write notes, read to me, dust the
ornaments, make coffee and salad, and do all sorts of little odd jobs,
and ultimately cover me with glory by making the match of the
season!”
“And on your part—what is to be your rôle?”
“I will give her a charming home; I will have all the best men here,
and I will take her everywhere; give her, if necessary, a couple of
smart new ball-dresses, and that too delicious opera-mantle that has
grown too small for me.”
“Or you too large for it—which?” inquired Mrs. Sladen, with a slight
elevation of her eyebrows.
“Milly, how odious you can be!”
“And about Major Langrishe?” continued Milly, unabashed.
“Oh, Granby will be all right; but I must write to Fanny by this post,
and say that I shall be delighted to have Lalla. Pour out the tea like a
good little creature, whilst I scribble a line; the dâk goes down at six.”
The other lady, who had kindled the fire and was now making tea,
was not, as might be supposed, the mistress of the house, but
merely an old friend who had dropped in for a chat this cold March
afternoon. She was a slight, delicate-looking woman, with dark hair,
dark eyes, and numerous lines on her thin, careworn face, though
she was barely thirty. No one ever dreamt of calling Mrs. Sladen
pretty, but most women voted her “a darling,” and all men “a little
brick.” Married in her teens, before she knew her own mind (but
when her relations had thoroughly made up theirs), to an elderly
eligible, she had become, from the hour she left the altar, the slave
of a selfish, irascible husband, whose mental horizon was bordered
by two tables—the dinner-table and the card-table—and whose
affections were entirely centred in his own portly person. Milly
Fraser’s people were on the eve of quitting India; they were poor;
they had a large and expensive family at home; otherwise they might
have hesitated before giving their pretty Milly (she was pretty in
those days) to a man more than double her age, notwithstanding that
he was drawing good pay, and his widow would enjoy a pension.
They would have discovered—had they made inquiries—that he was
heavily in debt to the banks; that he could not keep a friend or a
servant; and that, after all, poor young Hastings, of the staff-corps,
whom they had so ruthlessly snubbed, would have made a more
satisfactory son-in-law.
Mrs. Sladen had two little girls in England, whom her heart
yearned over—little girls being brought up among strangers at a
cheap suburban school. How often had her husband solemnly
promised that “next year she should go home and see the children;”
but, when the time came, he invariably hardened his heart, like
Pharaoh, King of Egypt, and would not let her go. If she went, who
was to manage the house and servants, and see after his dinner and
his comforts? He was not going to be left in the hands of a
khansamah! And, moreover, where was the money for her passage
to come from? He had not a rupee to spare (for her).
Colonel Sladen was a shrewd man when his own interests were
concerned. He was alive to the fact that he was not popular, but that
things were made pleasant to him all round for the sake of the
unfortunate lady whom he harried, and bullied, and drove with a
tongue like the lash of a slaver’s whip. Yes; if she went home, it
would make a vast difference in his comfort, socially and physically.
Many a rude rebuff she had saved him; many a kindness was done
to him for her sake; and many a woman fervently thanked her good
genius that she was not his wife. In spite of her uncongenial partner,
Mrs. Sladen managed to be cheerful, and generally bright and
smiling, ready to nurse the sick, to decorate the club for dances, to
help girls to compose ball-dresses, to open her heart to all their
troubles, and to give them sympathy and sound advice. “Oh, do not
marry a man simply because your people wish it,” she might have
said (but she never did), “and merely because he is considered a
good match; far better to go home and earn your bread as a shop-
assistant, or even a slavey. Take a lesson from my fate.”
Mrs. Langrishe, on the other hand, ruled her dear Granby with a
firm but gracious sway. Their match had been made in England, and
had proved in one respect a severe and mutual disappointment.
Well, “disappointment” is an ugly word; shall we say “surprise”?
Captain Langrishe had been attracted by Ida Paske’s handsome
face, stately deportment, and magnificent toilettes. He was
impressed by her superb indifference to money—rumour endowed
her with a large income, and rumour had no real grounds for this
agreeable assertion. Ida was one of a numerous family, was good-
looking, self-reliant, ambitious, and eight and twenty. Her dresses
were unpaid for, and her face was her fortune. She, on her part,
believed the insignificant-looking little officer—whose pale profile
looked exactly as if it were cut out of a deal board—to be
enormously rich. He, too, affected to despise outlay, and kept
hunters, and talked of his yacht. He was going to India, immediately,
and the wedding was hurried on; but long ere the happy pair had
reached Bombay, they had discovered the real state of affairs. He
knew that his bride was penniless; and she was aware that the
hunters had been hired, the yacht had been a loan, and that three
hundred a year, besides his pay, was the utmost limit of her
husband’s purse. They were a wise couple, and made the best of
circumstances; and by-and-by Captain Langrishe came to the
conclusion that he had got hold of a treasure, after all! His Ida was
full of tact and worldly wisdom, and possessed administrative powers
of the highest order. She understood the art of keeping up
appearances, and laid to her heart that scriptural text which says,
“As long as thou doest well unto thyself, men will speak well of thee.”
She ensured her husband a comfortable home, studied his tastes,
flattered his weaknesses, was always serene, affectionate, and well-
dressed. Her dinners were small but celebrated; her entrées and
savouries, a secret between her cook and herself. She did not
dispense indiscriminate hospitalities—no, she merely entertained a
few important officials, smart women, and popular men, who would
be disposed to noise abroad the fame of her dainty feasts, and to
pay her back again with interest. Shabby people, and insignificant
acquaintances, never saw the interior of her abode, which was the
embodiment of comfort and taste. Her dresses were well chosen and
costly; diamonds sparkled on her fingers and on her neck; and
though but till recently a captain’s wife, her air and manner of calm
self-approval was such, that the wives of higher officials meekly
accepted her at her own valuation, and frequently suffered her to
thrust them into the background and usurp their place. Such was her
ability, that people took the cue from her, and valued an invitation to
afternoon tea with Mrs. Langrishe far above an elaborate dinner with
less exclusive hostesses.
Neither the furious attacks of her enemies (and she had not a
few), nor the occasional indiscretions of her friends, ever ruffled the
even temperament of this would-be “grande dame.” It was an
astonishing but patent fact that she invariably occupied, so to speak,
a chief seat; that she was always heralded on her arrival at a station
—met, entertained, and regretfully sped. Whilst ladies as worthy
languished in the dâk bungalow, and drove in rickety ticca gharries,
she had the carriages of rajahs at her disposal, and was
overwhelmed with attentions and invitations. Surely all this was
amply sufficient to make these women “talk her over” and hold her at
arms’ length. Men who knew Captain Langrishe’s resources
marvelled amongst themselves, and said, “Gran has very little
besides his pay; how the deuce does he do it? Look at his wife’s
dresses! And they give the best dinners in the place. There will be a
fine smash there some day!” But years rolled on, and there was no
sign of any such crisis. The truth was that Granby Langrishe had
married an exceedingly able woman—a woman who thoroughly
understood the art of genteel pushing and personal advertisement.
She had persistently edged—yea, driven her husband to the front,
and he now enjoyed an excellent appointment at the price of the two
dewy tears that stood in his Ida’s expressive eyes when bemoaning
his bad luck to an influential personage. The Langrishes were
drawing two thousand rupees a month,—and were held in
corresponding esteem.
 Mrs. Langrishe does not look forty—far from it. She has taken
excellent care of herself—no early rising, no midday visiting, for this
wise matron. She is tall, with a fine figure, alas! getting somewhat
stout; her brows are straight and pencilled; beneath them shine a
pair of effective grey eyes; her features are delicately cut; if her face
has a fault, it is that her jaw is a little too square. Whatever people
may say of Ida Langrishe, they cannot deny that she is remarkably
handsome, and as clever as she is handsome. As a spinster, she
had not been entirely successful in her own aims; but it would go
hard, if, with her brains, her circle of acquaintances, and her valuable
experience, she did not marry her niece brilliantly.
 CHAPTER II.
“TELL ME ALL THE NEWS.”

The French windows of Mrs. Langrishe’s drawing-room opened

into a deep stone verandah embowered in honeysuckle and passion
flowers, and commanded a matchless view, irrespective of the
foreground, in which Mrs. Sladen’s rickshaw is the chief feature, or
the gravel sweep, grass garden, and beds of pale wintry roses; but
beyond the pineclad hills, among which red roofs are peeping,
beyond the valley of rhododendrons, and a bold purple range,
behold the snows! a long, long barrier of the everlasting hills, to such
as the eyes of the psalmist had never been lifted. People may
whisper that they were disappointed in the Taj, that Delhi was a
delusion, and the marble rocks a snare; but who can declare that the
snows were beneath his expectations? And if he were to say so, who
would be found to believe him? The evening breeze is raw and chill,
it has travelled sixty miles from those icy slopes, it creeps up the
khud, and warns the shivering roses that the sun has set—it stirs the
solemn deodars as they stand in dark outline against the sky.
Mrs. Langrishe, rising from her writing-table, letter in hand, sweeps
back to her friend, who is again sitting on the fender-stool, staring
into the fire, thinking, perchance, of those bygone days when she
was a girl whose friends were anxious to get her settled.
“Milly,” said her hostess, “you are passing the post-office, and you
can post this for me; you had better go now, dear, as you know you
have had a sore throat, and it is getting late.”
Mrs. Sladen rose at once; she was accustomed to being sent on
errands and to being made use of by her intimates. She pulled on
her cheap gloves, twisted her stringy boa round her neck, and held
out her hand for the letter that was to bring Miss Paske to Shirani. As