Proceeding of the 2006 IEEE

International Conference on Automation Science and Engineering

Shanghai, China, October 7-10, 2006

A Simulation Framework for Cell Manipulation

L. Zhang J. Cecil, Associate Professor
Research Associate, Center for Information Based Department of Industrial Engineering, Center for
Manufacturing (CINBM) Information Based Manufacturing (CINBM)
New Mexico State University New Mexico State University
Las Cruces USA Las Cruces USA
lwzhang@nmsu.edu jcecil@nmsu.edu

.Abstract –The focus of discussion in this paper is on cell modeling, simulation / visualization and exchange in a
manipulation activities and the creation of a simulation test product / process design context across a variety of
bed for cell manipulation. This paper delineates the design domains. The three major facets of INBM include (a)
of a simulation framework in the context of virtual reality modeling of information related to process design and
technologies and IT interfaces. A discussion of the role of planning (among others), (b) visualization and simulation
van der Waals forces coming into play is also provided of information as it pertains to process design issues
along with an overview of the modules in the simulation (including the use of virtual reality based prototyping
framework. techniques to support analysis, visualization and
simulation) and (c) the exchange of information across IT
Index Terms –Cell manipulation, Virtual Reality, infrastructures to support collaborative activities within
Simulation process domains [16, 17].

I. INTRODUCTION II. THE MANIPULATION RESEARCH TEST BED

Bio micro and nano technologies are among the most The simulation framework revolves around the design of
important of the recently emerging domains in science and the MRT and has several core components; one of them is
engineering. The focus of this paper is on biological cell the Virtual Reality based simulation / analysis module.
manipulation and the creation of a simulation framework Another key component are the physical cell manipulation
to assist in such activities. The field of biology presents resources (which can include probes, force measuring
interesting challenges especially in the context of using devices, and other mechanisms); an example of such a
micro / nano technological tools and approaches. One of physical environment can be a probe based manipulator, a
the recent areas of interest is the exploration of methods to micro robotic device capable of moving cells, etc.
manipulate (pull, push, move, etc) individual cells; Depending on the manipulation scenario, the information
NASA, the Department of Defense and other agencies model attributes will be used as a basis to simulate and
have underscored the importance of research in this area. understand the target task prior to accomplishing the cell
NASA’s interest stems from a need to address the loss of manipulation activity. Using an IT based collaborative
tissue (among others) when astronauts embark on space framework, geographically distributed resources can be
missions. Understanding issues related to cell used to address various segments of the cell manipulation
manipulation holds the potential to provide a basis to tasks. For example, a class of software agents in the MRT
developing methods to maintain required tissue and bone may interact with agents at other partner sites ; these can be
density which may be required to enable astronauts to stay visualization agents (which can capture images of cells) as
in space for longer periods of time. Cell manipulation also well as analysis agents (which perform a variety of
has potential in the early detection and treatment of cancer; analysis tasks such as the impact of inter atomic forces,
in bio robotics as well as other bio engineering etc). Such agents can be mobile and migrate from one
applications. computer to another using the Internet; they can also be
part of a semantic web based framework which would
The creation of a simulation framework delineated in allow a rapid collaborative response to a diverse set of cell
this paper is part of a long term initiative to create a manipulation needs.
Manipulation Research Test bed (MRT) for cell
manipulation activities. The idea for a MRT was proposed In the proposed design, an ‘information oriented’ or
by Cecil in [17 ]. The MRT is being designed with an ‘information intensive’ model for a target set of cell-
info rmation based manufacturing (INBM) foundation to manipulation activities is used to propel various target
support cell manipulation activities. A brief note on INBM activities; the various attributes of relevance are captured
is relevant. The term ‘INBM’ was proposed originally by in this information model as driving inputs, constraints,
Cecil in [17] and refers to the study of information performing mechanisms and decision outcomes; a
model ing language called eEML is used to build these
models; an information model can represent the core

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attributes influencing the target process [1]. Influencing model driven approach emphasizing the use of a virtual
criteria including constraints, information inputs, and environment prior to use of physical equipment to test and
physical inputs can be modeled explicitly and used to drive evaluate cell manipulation approaches. Since the test-bed
a target analysis or simulation activity.

Fig 1 The Manipulation Research Test Bed

Physical cell manipulation using external probes is a will be driven by information models, alternate
complex domain; at the micro / nanolevel, applications manipulation strategies proposed from various sources and
dependent on cell manipulation have yet to be realized locations can be embedded effectively in the test bed and
because of problems and limitations associated with micro controlled by remote or distributed users and collaborators.
/ nano manipulation [2]. These fields are in their infancy Over a period of time, the MRT will evolve into an
and related physical and chemical phenomena are not information-rich environment that would allow users to
completely understood; in this context, there is a need to test and combine different cell manipulation strategies.
develop innovative methods to help understand issues
relating to cell manipulation. The initial design of the MRT includes the following
components:
The proposed research lays the foundation for the 1) the simulation / analysis module
creation of a Manipulation Research Test-bed (MRT), 2) the interfaces to the simulation module
which would help study bio-manipulation techniques in a 3) the virtual reality sensors (motion trackers,
virtual environment before physical experiments need to immersive wands and haptic devices).
be conducted. A simple example of this test would be to
determine virtually if a specific kind of probe tip can be The simulation / analysis module seeks to support the
used to ‘pull’ or ‘push’ a cell from one location to another. study of the inter atomic forces which come into play
By interacting with this virtual (simulation) model, users during nano assembly. Currently, the focus is on
can compare alternate manipulation strategies, understanding Van der Waals forces (VDW) in the context
effectiveness of various grippers / tools, etc before of nano assembly. The typical modeling scenarios
physically completing a given manipulation task. considered are discussed in the next section

To achieve the goals of the MRT, an important activity The immersion module’s function is to enable users to
involves obtaining a fundamental understanding of the interact with the virtual environment; these devices include
inter atomic forces that play an important role in cell a work wand and a haptic device along with motion
manipulation activities. T his is discussed in section III of trackers and eye wear. In a typical interaction session, a
this paper. In the context of previous efforts, while other user would be able to evaluate a manipulation strategy
researchers have attempted to study physical cell using the simulation environment; subsequently, based on
manipulation activities, there has been a lack of focus on obtaining an improved understanding of the targeted task,
the creation of simulation models or environments for cell the physical cell manipulation tasks are completed.
manipulation . Our research seeks to explore an information

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 The overall simulation framework is under For bio cell manipulation, the use of various methods for
implementation. Currently, the preliminary gripping is discussed in [7, 8, 9, 10, and 11]. In [7], the
implementation of the VR based visualization / simulation developm ent of a novel polymer-based micro robotic
module has been completed. Other activities under gripper (that can be actuated in a liquid medium) to
progress include the design of the interface between the manipulate cells is presented. The basic structure for this
information model (figure 1) wit h the simulation module gripper is a trimorph thermal actuator with a platinum
and conducting experiments related to obtaining a better metal heater encapsu lated by poly-para-xylylene C
understanding of probe based manipulation and related (parylene C) polymer layers. Due to the large difference of
issues. The remaining sections of this paper focus on the thermal expansion coefficients of the different layers, the
development of quantitative models related to cell actuator can be controlled with much larger deflection than
manipulation, which will serve as the basis for the creation conventional MEMS actuators.
of the simulation module.
T he functioning of a SU-8-based electrothermally
activated micro gripper which can operate in physiological
III. MODELS FOR UNDERSTANDING CELL ionic solutions is described in [8, 9]. This gripper consists
MANIPULATION of two “hot-and-cold-arm” actuators that are fabricated in a
two-mask surface micromachining process. It can be used
A. Background for the manipulation of single cells in solution with
The field of biology presents interesting challenges minimal undesired interactions; such a micro gripper can
especially in the context of using micro/nano technological be used in biological applications where manipulation of
samples is needed.
tools and approaches. As mentioned earlier, understanding
issues related to cell manipulation holds the potential to
In [10], the design of a monolithic Shape Memory
develop methods and procedures to maintain required
Alloy (SMA) micro gripper is discussed which can be used
tissue and bone density which is necessary to enable
to assemble microscopic building blocks (of 60mm width)
astronauts to stay in space for longer periods of time. The
into tissue engineering scaffolds. The gripper consists of
design of devices to facilitate such manipulation and
two small fingers for grasping, an actuator (which changes
growth of cells and the study of the role of interactive
its shape upon heating by Joule effect) and a parallel
forces will eventually enable the creation of bio technology
elastic structure to provide a pullback force on cooling as
oriented robotic devices which would enable doctors and
well as to control finger movement. The material used has
scientists develop break through technologies.
nonlinear mechanics and the actuator undergoes larger
deflections. A computational model is introduced to
In this emerging area, some of the research includes
determine some design parameters for the gripper to
modeling of interactive forces which come into play and
optimize the design.
gripper design for the manipulation of cells in biological
contexts. A brief literature review follows.
A silicon micro gripper with a large gripping force, and
Studies related to autonomous manipulation of single relatively rigid structure body and flexibility in functional
cells and the characterization of biomembrane mechanical design is proposed in [11]. The gripper is 1000 x 200 x 380
properties using microrobotic systems with integrated μm3 in dimension and a SMA (Ni-Ti-Cu) film is used as
vision and force sensing modules has been reported by actuator. This design functions in an out -of-plane bending
several researchers [3, 4, 5, and 6]. I n [4], Fluckiger mode, with two integrated SMA/Si cantilevers in opposite
describes the development of a point -load model for a cell. actuation directions. When the electrodes are electrically
The modelling process of a cell point-load situation is heated, the cantilever bends up due to the shape memory
studied and improved by analyzing the stress in the cell effects of SMA films, thus generating the needed gripping
force; a total gripping motion of 110 μm can be realized
membrane. With the use of Mathematica ® software,
along with a gripping force of 0.04 N on the tip of the
geometric parameters are obtained to describe the shape of
gripper.
the membrane. The three equations create a nonlinear
system of equations that are solved by using the Least-
Diop et al proposed a microbubble at the tip of optical
Squares and the analytical Jacobian method. The research
fiber probe etched by a low power continuous wave laser
also established that this developed point-load model is
radiation [12]. The research proposed and validated the
quite close to physical reality. In [5], the design of a
concept of using this microbubble as a nanoliter
microrobotic system capable of conducting automatic
biochamber to benignly trap and manipulate single cells in
embryo pronuclei DNA injection is discussed. Both
fluids under controlled environmental conditions. One very
embryo pronuclei injection and intracytoplasmic injection
exciting long-term line of research is the study of a single
(cell injection) are used to introduce foreign genetic
living cell and it’s response to mechanical, electrical,
material into cells. In [6], nanoscale linear servomotors
chemical and biological stimuli.
with integrated position sensing are investigated from
experimental, theoretical, and design perspectives.

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 gripper
In [13], the creation of a collaborative framework to
support robust information exchange across heterogeneous
engineering domains is discussed. The application context
relates to nano particles and (bio) cell manipulation tasks;
the initial findings relating to distributed accomplishment
of target activities in this identified context. In the scenario
considered, the potential project partners who possess
skills and resources related to nano tube design, synthesis,
manipulation plan generation, and simulation form a Bio particle
Virtual Enterprise, whose objective is to accomplish target
set of nano manipulation tasks. The proposed framework is Pick up adhesion
composed of an enterprise level Planning Manager (which
generates a detailed top level plan based on given user
specification), a Design Coordinator (that identifies and Fig.2 Adhesion between particle and a two pronged manipulator
evaluates the candidate design companies to find a Other researchers have studied the use of innovative
potential design that can be used for a target bio or nano grippers to manipulate cells [14, 15]; the VDW forces
manipulation task), a Synthesis/Manufacturing between the gripper and the bio particles varies when the
Coordinator (which focuses on identifying partners and shape of gripper change. Our research has considered the
resources capable of manufacturing a specified design of a gripping surface similar to that of a saw-tooth
manipulator for a given manipulation task); in the modeled manipulator as shown in figure 3.
context, the manipulators considered are carbon nano tubes
attached to the tip of Atomic Force Microscope (AFM)
probe; a Manipulation Plan Coordinator focuses on
gripper
identifying candidate manipulation plan generators, and a
Simulation coordinator deals with identifying candidate
simulation tool vendors who provide services to evaluate
nano tube and nano manipulation plan. The framework is
proposed based on the 3APL (An Abstract Agent
Programming Language) architecture with scalability in
mind so that new modules can be support a ‘plug and play’
type of integration depending on the customer
requirements.
In the next sub -section, a discussion of an analysis
Bio particle
Model for the interaction of a virtual probe tip with a cell Saw tooth like surface
release
particle is provided. The context assumes that a probe will
Fig.3 Using a saw tooth shaped gripping surface
be used to push/manipulate a biological cell.
The interaction potential between a saw tooth shaped
B. The Probe and Cell Interaction Model gripping surface to a bio cell can be calculated (see figure
The release of any bio cell particle compared to its 4). The shape of the gripping surface can be segmented
‘gripping’ or ‘picking’ is considered to be more difficult. into several parts, including part 1, part 2, part 3, part 4 and
At the micron scale (most cells are several microns in part 5. E 1 is the interaction potential between the one
size), the effect of gravity at the micron scale can be gripper surface and a bio cell model; E2 , E3, E4, and E5 are
ignored; instead adhesive forces come into play, which the corresponding interaction potential between the bio cell
makes it difficult to release a bio particle (figure 2). These and each part of the gripper shape respectively. The
interactive (adhesive) forces include several components relationship of E1, E2, E3, E4, and E5 can be established
including van der Waals forces (VDW). The first segment using equations (1), (2) and (3). E 4 can be determined using
of our research aims at modeling the interactive forces an approach outlined in [3]. The calculation of E3 and E5
while attempting to minimize these VDW forces by can be accomplished using the steps summarized in the
changing the shape of the gripping surface. following sections .

E1 = E2 + E3 (1)
E2 = E4 − E5 (2)
E1 = E4 − E5 + E3 (3)

30
 b−x
w b
C12 ρ dz
2 3
Ep − st = ∫ dy ∫dx ∫ [( x − x ) (6)
+ ( y − y0 ) + ( z − z0 ) ]
2 2 2 3
1 0 0 x− b 0

= F ( x0 , y0 , z0 )
E1 =
=E 2+
+E3 Step 2: Modeling the interaction potential between bio
cell and part 3.
z
w

(1)
(x,y,z)
2 4 5
b y
R
b
E2=E4-E5

(x0 ,y0 ,z 0)
x

(2) Fig.6 interaction between a sawtooth shaped gripper and a spherical

Fig.4 Segments of the manipulator (or gripper) cell model

E 3 can be determined using the proposed 3 step Using the relative orientation between a sphere body and
approach, which can be summarized as follows: the saw-tooth like body, the scope of the value s of x, y, z
can be determined:
Step 1: Determine the interaction potential between a
molecule in bio cell and part 3. x0 ∈ [ x1 , x2 ]

z y 0 ∈ [ y1 , y2 ]
w z 0 ∈ [ z1, z2 ]

(x,y,z) The interaction potential between the two bodies can be

represented as
b y
b x2 y2 z2
(x0 ,y0 ,z0 )
E3 = ∫ dx ∫ dy ∫A ×F (x ,y ,z ) dz (7)
x1 y1 z1
x

E 3 subsequently can be determined as a function of the

Fig. 5 Interaction between a sawtooth shaped body and a particle distance between the bio cell and the part3, which is D and
As s hown in figure 5, part 3 is a saw tooth shaped part can be found according to the relative orientation between
of the gripper surface; the particle in a bio cell can be a sphere body and the saw-tooth shaped body .
assumed to be located in an arbitrary point (x0,y 0,z 0). .To
simply the calculation, in figure 5, b is the length of the Step 3: Modeling VDW force between bio cell and the
gripper in x direction. The half length in z direction is also gripper.
supposed b. w is the width of the gripper part, the shape Using a similar approach, E5 can be calculated.
scope of part3 can be assumed as: Subsequently, using equation (3), E1 can be expressed as a
x ∈[0, b] function of the distance between the bio cell and the
y ∈ [0, w ] gripping surface, using the following relationship:
z ∈ [ x − b ,x + b ]
∂E1 (8)
Then the interaction distance between arbitrary point in Fvdw =
∂D
part3 and a point in bio cell can be found by equation (4)
C. Other components of the framework
r2 = ( x − x0 )2 + ( y − y0 )2 + ( z − z0 )2 (4)
The volume element can be found in equation (5) Apart from the simulation / analysis module, a
representation module has also been designed primarily to
dV = dxdydz (5) allow study of virtual reality based representation of
The interaction potential between the particle and the objects and particles that are of direct relevance to the
saw-tooth like body can be expressed by equation (6) research topics outlined in this paper. The graphical
model ing of various probes within a VR environment is

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under way; another representation issue being studied is O. Khatib, Springer-Verlag London Ltd., 2005, pp.
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A CKNOWLEDGMENT Biophysics Journal. 90(10):3813-22, 2006
Funding for this research was obtained through grants [13] Gobinath, N., and Cecil, J., Investigation of a
from the National Science Foundation (NSF Grant No. framework for collaborative activities across
0423907) and New Mexico State University (through a heterogeneous engineering domains, Proceedings of
research cluster mini grant in the biosciences area). Their IMECE 2005 , the ASME Mechanical Engineering
assistance is gratefully acknowledged. Congress and R&D Expo, November 5-11 2005,
Orlando, FL
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