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BULETINUL

INSTITUTULUI
POLITEHNIC
DIN IAI

Tomul LVIII (LXII)


Fasc. 1

MATEMATIC. MECANIC TEORETIC. FIZIC

2012

Editura POLITEHNIUM

BULETINUL INSTITUTULUI POLITEHNIC DIN IAI


PUBLISHED BY

GHEORGHE ASACHI TECHNICAL UNIVERSITY OF IAI


Editorial Office: Bd. D. Mangeron 63, 700050, Iai, ROMANIA
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Editorial Board
President: Prof. dr. eng. Ion Giurma, Member of the Academy of Agricultural
Sciences and Forest, Rector of the Gheorghe Asachi Technical University of Iai
Editor-in-Chief: Prof. dr. eng. Carmen Teodosiu, Vice-Rector of the
Gheorghe Asachi Technical University of Iai
Honorary Editors of the Bulletin: Prof. dr. eng. Alfred Braier,
Prof. dr. eng. Hugo Rosman,
Prof. dr. eng. Mihail Voicu Corresponding Member of the Romanian Academy,
President of the Gheorghe Asachi Technical University of Iai
Editors in Chief of the MATHEMATICS. THEORETICHAL MECHANICS.
PHYSICS Section
Prof. dr. phys. Maricel Agop, Prof. dr. math. Narcisa Apreutesei-Dumitriu,
Prof. dr. eng. Radu Ibnescu
Honorary Editors: Prof. dr. eng. Ioan Bogdan, Prof. dr. eng. Gheorghe Nag
Associated Editor: Associate Prof. dr. phys. Petru Edward Nica

Editorial Advisory Board


Prof.dr.math. Sergiu Aizicovici, University Ohio,
U.S.A.
Assoc. prof. mat. Constantin Bcu, Unversity
Delaware, Newark, Delaware, U.S.A.
Prof.dr.phys. Masud Caichian, University of Helsinki,
Finland
Prof.dr.eng. Daniel Condurache, Gheorghe Asachi
Technical University of Iai
Assoc.prof.dr.phys. Dorin Condurache, Gheorghe
Asachi Technical University of Iai
Prof.dr.math. Adrian Cordunenu, Gheorghe Asachi
Technical University of Iai
Prof.em.dr.math. Constantin Corduneanu, University of
Texas, Arlington, USA.
Prof.dr.math. Piergiulio Corsini, University of Udine,
Italy
Prof.dr.math. Sever Dragomir, University Victoria, of
Melbourne, Australia
Prof.dr.math. Constantin Fetecu, Gheorghe Asachi
Technical University of Iai
Assoc.prof.dr.phys. Cristi Foca, University of Lille,
France
Acad.prof.dr.math. Tasawar Hayat, University Quaid-iAzam of Islamabad, Pakistan
Prof.dr.phys. Pavlos Ioannou, University of Athens,
Greece
Prof.dr.eng. Nicolae Irimiciuc, Gheorghe Asachi
Technical University of Iai
Assoc.prof.dr.math. Bogdan Kazmierczak, Inst. of
Fundamental Research, Warshaw, Poland

Assoc.prof.dr.phys. Liviu Leontie, Al. I. Cuza


University, Iai
Prof.dr.mat. Rodica Luca-Tudorache, Gheorghe
Asachi Technical University of Iai
Acad.prof.dr.math. Radu Miron, Al. I. Cuza
University of Iai
Prof.dr.phys. Viorel-Puiu Pun, University
Politehnica of Bucureti
Assoc.prof.dr.mat. Lucia Pletea, Gheorghe Asachi
Technical University of Iai
Assoc.prof.dr.mat.Constantin Popovici,Gheorghe
Asachi Technical University of Iai
Prof.dr.phys.Themistocles Rassias, University of
Athens, Greece
Prof.dr.mat. Behzad Djafari Rouhani, University of
Texas at El Paso, USA
Assoc.prof.dr. Phys. Cristina Stan, University
Politehnica of Bucureti
Prof.dr.mat. Wenchang Tan, University Peking
Beijing, China
Acad.prof.dr.eng. Petre P. Teodorescu, University of
Bucureti
Prof.dr.mat. Anca Tureanu, University of Helsinki,
Finland
Prof.dr.phys. Dodu Ursu, Gheorghe Asachi
Technical University of Iai
Dr.mat. Vitaly Volpert, CNRS, University Claude
Bernard, Lyon, France
Prof.dr.phys. Gheorghe Zet, Gheorghe Asachi
Technical University of Iai

BULETINUL INSTITUTULUI POLITEHNIC DIN IAI


BULLETIN OF THE POLYTECHNIC INSTITUTE OF IAI
Tomul LVIII (LXII), Fasc. 1

2012

MATEMATIC. MECANIC TEORETIC. FIZIC

SUMAR

Pag.

MUGUR B. RU, Asupra unei teorii newtoniene alternative la teoria MOND


(engl., rez. rom.). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

CLIN GHEORGHE BUZEA, MARICEL AGOP i SIMONA RUXANDRA


VOLOV, Un nou model al carcinogenezei i progresiei tumorale n
cadrul dinamicii neliniare (I) (engl., rez. rom.). . . . . . . . . . . . . . .. . . . . .

DRAGO IANCU, CLIN GHEORGHE BUZEA i MARICEL AGOP, Un


nou model al carcinogenezei i progresiei tumorale n cadrul dinamicii
neliniare (II) (engl., rez. rom.). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33
MARICEL AGOP i CLIN GHEORGHE BUZEA, Un nou model al
carcinogenezei i progresiei tumorale n cadrul dinamicii neliniare (III)
(engl., rez. rom.). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 59
CRISTINA-DELIA NECHIFOR i SEBASTIAN POPESCU, Studiul
energeticii suprafeei (engl., rez. rom.). . . . . . . . . . . . . . . . . . . . . . . . . . . 79
IRINA RADINSCHI, CRISTIAN DAMOC i BOGDAN AIGNTOAIE, Test
de fizic online n Adobe flash CS4 pentru mbuntirea
performanelor studenilor (engl., rez. rom.) . . . . . . . . . . . . . . . . . . . . . . 89
MIHAI AVRAM, CONSTANTIN BUCAN, SILVIA MIU i MARIAN
TNASE, Grup de generare a energiei hidraulice n concepie
mecatronic (engl., rez. rom.) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 99

BULETINUL INSTITUTULUI POLITEHNIC DIN IAI


BULLETIN OF THE POLYTECHNIC INSTITUTE OF IAI
Tomul LVIII (LXI), Fasc. 1

2012

MATHEMATICS. THEORETICAL MECHANICS. PHYSICS

CONTENTS

Pp.

MUGUR B. RU, On a Newtonian Alternative Theory of MOND (English,


Romanian summary). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

CLIN GHEORGHE BUZEA, MARICEL AGOP and SIMONA RUXANDRA


VOLOV, A New Carcinogenesis and Tumor Progression Model in
the Framework of Non-linear Dynemics (I) (English, Romanian
summary). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

DRAGO IANCU, CLIN GHEORGHE BUZEA and MARICEL AGOP, A


New Carcinogenesis and Tumor Progression Model in the Framework
of Non-linear Dynemics (II) (English, Romanian summary). . . . . . . . . . . 33
MARICEL AGOP and CLIN GHEORGHE BUZEA, A New Carcinogenesis
and Tumor Progression Model in the Framework of Non-linear
Dynemics (III) (English, Romanian summary). . . . . . . . . . . . . . . . . . . . . 59
CRISTINA-DELIA NECHIFOR and SEBASTIAN POPESCU, Study on
Surface Energy of Polypropilene UV-Photo-Grafted with Glucose
(English, Romanian summary) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 79
IRINA RADINSCHI, CRISTIAN DAMOC and BOGDAN AIGNTOAIE,
Online Physics Test Developed in Adobe flash CS4 to Improve Students
Knowledge (English, Romanian summary) . . . . . . . . . . . . . . . . . . . . . . . 89
MIHAI AVRAM, CONSTANTIN BUCAN, SILVIA MIU and MARIAN
TNASE, Mechatronic Design of a Hydraulic Power-Supply Unit
(English, Romanian summary) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 99

BULETINUL INSTITUTULUI POLITEHNIC DIN IAI


Publicat de
Universitatea Tehnic Gheorghe Asachi din Iai
Tomul LVIII (LXII), Fasc. 1, 2012
Secia
MATEMATIC. MECANIC TEORETIC. FIZIC

ON A NEWTONIAN ALTERNATIVE THEORY FOR MOND


BY

MUGUR B. RU
Al. I. Cuza University of Iai,
Department of Physics
Received: November 28, 2011
Accepted for publication: December 5, 2011

Abstract. This paper is an attempt to find an alternative physical theory for


MOND. The basis of this physical theory was found to be a gravitational
potential generated by a repulsive energy. The influence of this energy appears
as an additional term to Newtons gravity law. This term plays an important role
under the condition that the asymptotic rotational speed of the galaxy is
independent from its radius. The found results are surprising because there are
also specific for MOND theory, but this time under ordinary Newtonian theory
assumptions.
Key words: dark energy; MOND; gravitational potential; galaxy rotation
curves; critical radius; asymptotic rotational speed.

1. Introduction
The Modified Newtonian Dynamics theory, MOND, was proposed by
(Milgrom 1983) as an alternative manner to explain the form of the galaxy
rotation curves. When the uniform velocity of galaxies was first observed it was
unexpected because this fact came in conflict with Newtonian theory of gravity
predictions. The farther out are the moving objects the lower velocities they
had. Later in the 70s the theory of dark matter seemed to solve this mystery.
According to this theory each galaxy contains an exterior halo, like a
contracting shell, of a special type of matter, dark matter. Consequently the
normal matter rotates more as a rigid body than as a fluid, as the Newtonian
theory suggests.

e-mail: m_b_raut@yahoo.com

Mugur B. Ru

Milgrom (1983) has tried to solve this problem in a different way. He


pointed out that Newtons law of gravity is valid when the gravitational
acceleration is large, but it may have not held at low accelerations.
Consequently he proposed a new form for Newtons law of gravity. A particle
at a distance r from a large mass M is amenable to an acceleration given by
a
GM
a = 2 .
r
a0

(1)

The right term is the Newtonian gravitational acceleration, the left term is
an interpolating function which is 1 for large accelerations and a/a0 for low
accelerations ( a 0 been a constant).
One immediate consequence of Eq. (1) is that the asymptotic rotational
speed of a galaxy becomes independent of radius

v = (GMa0

1
)4

(2)

This is the general case and it has an axiomatic validity, especially for flat
galaxies. Certainly, the goal of this theory is very easy to accomplish if there is
only one interpolating function. In reality there are many effective interpolating
functions, been dependent on the type of galaxy rotation curve we study. For
instance the spiral-type rotational galaxies curves can be explained with

( x) =

x
1 + x2

(3)

This fact makes MOND theory a little peculiar, but there is nothing
peculiar in a phenomenological theory, except only its lack of physical basis. If
we observe that Eq. (3) tends to x for law values of x, maybe we get used to its
peculiarity. The most significant tests of MOND are provided by disc-galaxy
rotation curves (Begeman et al., 1991; Sanders & Verheijen, 1998; Sanders,
1996 ; de Blok & McGaugh, 1998). However, the dark matter theory seems to
be the favorite regarding the galaxy rotation problem. The scientific community
prefers it instead MOND, although the correct in many aspects predictions of no
matter each of it is the comparison basis for the other, (McGaugh, 2004;
Famaey et al., 2007).
This paper is an attempt to find an alternative to MOND theory, in order
to explain the form of the galaxies rotation curves.

Bul. Inst. Polit. Iai, t. LVIII (LXII), f. 1, 2012

2. Repulsive Forces and the Dynamics of the Galaxies


In the following we show that one can obtain a theory to explain the
rotation curves of discoid galaxies, a theory based on an unknown form of
energy. It is certainly a new situation in this regard; so far responsible for the
above mentioned curves was the dark matter or in MOND theory acceptance the
law (1). Therefore we have a gravitational potential of the form

GM
A +1
+
r ,
r
+1

(4)

which is the result of solving Poisson's equation

= 4G ( + ue ) .

(5)

The second term on the right side of Eq. (4) is an empirical term attached
to the Newtonian gravitational potential, a term that describes the action of an
unknown repulsive energy. We have therefore A> 0.
With this potential (4) we try to show that this undefined energy may
cause the radial movement of the discoid galaxies observed in reality. From (4)
we find the expression of the first derivative of this equation

g =

GM
r

+ Ar ,

(6)

which has a great importance in the development of reasoning in the following.


Eq. (4) can not accept local maxima or minima only if the potential would
be as follows

l ( r ) = Al r l + Bl r l 1 ,

(7)

in which case it would be the result of Laplace's equation

= 0 .

(8)

Note that the potential (4) does not satisfy the condition (7), because
l 0, 1 , so there may be local configurations of potentials (4) where there
may be maxima or minima. Hence g = 0 in (6). From this condition we can
determine the critical radius whence equality occurs

GM
rc2

= Arc .

Therefore the expression of this critical radius will be

(9)

Mugur B. Ru
1

GM + 2
rc =
.

(10)

From (9) by expressing the constant A as a function of the critical radius


we can determine in a more synthetic way the accelerations expression
r + 2
g = g N 1 + 2 ,
r

GM
with g N = 2 and forces expression
r
r + 2
F = FN 1 + 2
r

GMm
deriving from the potential (4). Note that for distances
with FN = 2
r
smaller than the critical radius there will be attractive accelerations and forces,
after the critical radius the accelerations and forces become repulsive.
On reaching the critical radius the equilibrium of the galaxy will be the
result of the galaxy accelerations balance

a=

v 2 GM
= 2
rc
rc

whence we can determine the radial velocity of the galaxy as

v = ( GM )

1
1

2 2( + 2)

1
2( + 2)

(11)

From observations made on the motion of galaxies and taking into


account the Tully-Fisher empirical expression it results

v L M ,
1

where L represent the luminosity and = 3 ... 4 .


So, in our view we can determine the proper in two cases
corresponding to the two expressions of the potential (4), supplemented with the
condition (7). Therefore we have
1
3

vM ,
corresponding to =1 and the case in which we have a particular interest

(12)

Bul. Inst. Polit. Iai, t. LVIII (LXII), f. 1, 2012

v M 4,

(13)

corresponding to =0. Note that both potentials obtained from (4) with
expressions (12) and (13) provides the shape of the rotation curves of discoid
galaxies close to observations. But the form (4) with (13) it leads us
unexpectedly closer to the MOND theory. Indeed if we take A = a 0 we obtain
from (10) exactly

GM
rc =
a0

2
,

(14)

the critical radius from which the small accelerations approximation occurs in
the MOND theory. From (11) and (14) it results

v 4 = GMa0 ,

(15)

which is the well-known expression obtained in the MOND theory for the radial
velocities independent from the galaxies radius. What is important here is that
we got this result in the approximation

g = g N + a0 ,
and not in the approximation

g = ( g N a0 )1/2 ,
like in MOND theory. The difference lies in the fact that our theory has not
worked out with an expression of a modified inertia like in MOND theory,
Newton's Second Law remaining unchanged. So with (4) and (13) MOND
theory results can be obtained without the need to change the law of inertia like
in (1). We just need to change the definition of constant a 0 as an artifact of
galaxies.
3. Dark Energy and the Dynamics of the Galaxies
We might ask now what is the nature of this unknown energy responsible
for the observed shapes of rotation curves of galaxies. In (4), condition (12)
leads to = 1. Although this form of the potential (4) may explain the dynamics
of discoid galaxies, we still do not accidentally deflect the discussion on this
path. It shows that in (4), with = 1, the additional part of the gravitational
potential can be conceived as a Newtonian equivalent to the cosmological
constant

Mugur B. Ru

A=

c 2
.
3

From this we can infer only that Ar would express a repulsive force due
to expansion of the universe. It can be either dark energy or vacuum energy.
Assuming that the expansion of the universe would somehow influence the
dynamics of galaxies we reach the role of dark matter in this regard. So we can
think of a galaxy as being surrounded by a halo composed of dark matter.
c 2
r tends to divide
Expansion of the universe expressed by the force
3
galaxies but the dark matter they are "wrapped" opposes with a reactive force
which is opposite to the force of expansion. In this way the galaxies keep their
c 2
r leads to
form and their dynamics is the observed one. The force
3
observations of the form v M 1 / 3 but the form v M 1 / 4 can not be
explained by the same reactive force. Things get more complicated if we
consider A = a 0 . The acceleration a 0 is four orders of magnitude higher than

c 2
r (for example, our galaxy have r = 1020 m ). So dark energy,
3
that causes the expansion of the universe, is almost four orders of magnitude
smaller than the energy that causes the galaxy dynamics. The acceleration a 0
can not be attributed to expansion of the universe but it can be related to an
internal expansion force of the galaxy. Let us admit that this force would be due
to the generation of new matter in the galaxy (exploding stars, matter that tends
to be extended in the galaxy). In such conditions the expansion force of the
galaxy will find its reaction in the blanket of dark matter that surrounds it. This
will "push" the galaxy with a constant force, equal and opposite, of value a 0 .
This might explain the anomaly of Pioneer 10 spacecraft. There is an attractive
constant force in our galaxy, supplementary to the Newtonian one, which is
indirectly due to expansion trend of the galaxy and directly due to the blanket of
dark matter that surrounds it. Eq. (15) is valid because dark matter is opposing
to the trend of the dispersion caused by the rotation of the galaxy.
Under these conditions Eqs. (14) and (15) are valid without the need to
consider MOND theory. If we admit that a 0 have not the same meaning as in
the MOND theory but totally due to other causes, having no connection with the
expansion of the universe but only with internal dynamics of galaxies, is a
constant specific to each galaxy in part, then all we have talked so far is valid.
Otherwise the place of a 0 may be taken by the general value A which can be
determined from experimental curves. Amazingly, if we do this we get to the
the force

Bul. Inst. Polit. Iai, t. LVIII (LXII), f. 1, 2012

result A = a 0 (which was also determined from experimental curves, as a mean


value). In this case a 0 can not be conceived as in MOND theory but as a
galactic characteristic without any connection with the universe.
4. Conclusions
1. In this paper we propose an alternative Newtonian theory for MOND.
2. Under the hypothesis that for the shape of the radial velocity curves of
galaxies is responsible an unknown form of energy, this influence is found to be
expressed by a supplementary potential which it must be added to the
Newtonian gravitational potential.
3. Somewhat surprising, we found the results specific to MOND theory,
but this time with an ordinary Newtonian dynamics.
REFERENCES
Begeman K. G. , Broeils A. H., Sanders R. H., Mon. Not. of the Ro. Astron. Soc., 249,
523 (1991).
de Blok W. J. G., McGaugh S. S., Astrophys. J., 508, 132 (1998).
Famaey B. , Gentile G. , Bruneton J.-P., Zhao H. S., Phys. Rev. D, 75, 063002 (2007).
McGaugh S. S., Astrophys. J., 609, 65 (2004).
Milgrom M., Astrophys. J., 270, 371 (1983).
Ru M. B., Time Invariance of the Fundamental Physical Constants. Bul. Inst. Polit.
Iai, LIV(LX), 2, s. Matematic. Mecanic teoretic. Fizic, 33-38 (2010).
Sanders R. H., Astrophys. J., 473, 117 (1996).
Sanders R. H., Verheijen M. T. W., Astrophys. J., 503, 97 (1998).
Zwicky F., Helvetica Physica Acta, 6, 110-127 (1933).
Zwicky F., Astrophys. J., 86, 217 (1937).

ASUPRA UNEI TEORII NEWTONIENE ALTERNATIVE LA TEORIA MOND


(Rezumat)
Aceast lucrare este o ncercare de a gsi o teorie fizic alternativ pentru teoria
MOND. La baza acestei teorii st un potenial gravitaional generat de o energie
repulsiv. Influena acestei energii apare ca un termen adiional la legea gravitaiei
newtoniene. Acest termen joac un rol important n condiiile n care viteza asimptotic
de rotaie a unei galaxii este independent de raza sa. Rezultatele gsite sunt
surprinztoare deoarece ele sunt de asemenea specifice teoriei MOND, ns de ast dat
n cadrul unei teorii newtoniene obinuite.

BULETINUL INSTITUTULUI POLITEHNIC DIN IAI


Publicat de
Universitatea Tehnic Gheorghe Asachi din Iai
Tomul LVIII (LXII), Fasc. 1, 2012
Secia
MATEMATIC. MECANIC TEORETIC. FIZIC

A NEW CARCINOGENESIS AND TUMOR


PROGRESSION MODEL IN THE FRAMEWORK
OF NON-LINEAR DYNAMICS (I)
BY
CLIN GHEORGHE BUZEA1, MARICEL AGOP2
and SIMONA RUXANDRA VOLOV3
1

National Institute of Research and Development for Technical Physics, Iai


2
Gheorghe AsachiTechnical University of Iai
3
University of Medicine and Pharmacy Gr. T. Popa, Iai

Received: December 28, 2011


Accepted for publication: January 15, 2011

Abstract.We propose a new physical concept of carcinogenesis and tumor


progression by the use of a natural environment where malignant tumors grow,
space(-time) with non-integer fractal dimension, in quest for further applications
of the newly discovered phenomenon of tumor self-seeding by circulating
cancer cells (CTC). We assume that metastasic tumor cells move (through the
systemic circulation) as a coherent wave, a chemically pumped travelling wave
laser with oxygen. The extracellular matrix (ECM) and the tumor
microenvironment (TME) are assumed as non-differential media endowed with
holographic properties. As a result, the tumor self-seeding by CTC may prove
mathematically, the fact that the CTC returning to the initial tumor site,
assembling a new tumor or fueling the primary tumor growth is a particular case
of complete holography (a characteristic of the living organisms). Moreover, we
believe cancer hypoxia and tumor self-seeding by circulating cancer cells are in
vivo proofs of this phenomenon. In this paper some general notions about
cancer, mathematics of cancer (connections between cancer, nondifferentiability and chaos) and information about holography are revealed.
Keywords: carcinogenesis, tumor, fractal, travelling wave, holography.

Corresponding author: e-mail: calinb2003@yahoo.com

10

Clin Gheorghe Buzea et al.

1. Introduction
During the past quarter century, tremendous steps have been made in the
diagnosis and treatment of cancer. Technology now allows the diagnosis and
treatment of tumors of ever-diminishing size, as with breast cancers; ductal
carcinoma in situ now comprises 2530% of all newly diagnosed breast
cancers at most medical centers (Armstrong et al., 2000). With earlier detection,
an understanding of growth patterns reflective of the natural biological
characteristics of these tumors must also evolve. Surgeons have always led the
fields of technological and basic scientific medical advances. Current concepts,
be they either the physiological characteristics of shock, organ transplantation,
antisepsis, wound healing, or gene therapy, have been forged by surgical
investigators.
The field of mathematics has undergone a similar evolution. Topology,
fractals, chaos theory, and development of nonlinear descriptive methods have
provided mathematicians new creative tools that permit the development of
models of tumor growth and behavior at the microenvironmental level
(Friedman & Reitich, 1999; Waliszewski et al.,1998). Specific formulas have
been described for growth, angiogenesis (Orme & Chaplain, 1997), cell-to-cell
adhesion (Perumpanani et al, 1997) and even pH regulation and drug delivery
(Secomb et al, 2001). From a clinical viewpoint many of these formulas may
seem oversimplified, but they collectively form an important foundation for
descriptive insight.
What has been lacking is the linkage of these two naturally and mutually
beneficial research endeavors. For oncologic surgeons, the ability to
mathematically describe (or, even better, predict) patterns of tumor behavior
provides an exciting, new, and precise method that may benefit both current and
future therapies. For the mathematician, an understanding of the clinical factors
essential for tumor development and metastasis provides realistic insight into
these complex biological processes, in turn permitting the development of
accurate, clinically relevant mathematical formulas.
In most medical centers, surgeons lead the team that provides
comprehensive cancer care. Oncologic mathematics provides surgeons another
opportunity to expand their leadership role and to better understand tumor
behavior and optimize cancer treatment.
In this paper we aim to envisage a new concept of carcinogenesis and
tumor progression. Consequently, we use the natural environment where
malignant tumors grow, space(-time) with non-integer fractal dimension, in
quest for further applications of the newly discovered and intriguing
phenomenon of tumor self-seeding by circulating cancer cells (CTC). More
precisely, we assume that the metastasic tumor cells move (through the systemic
circulation, yet not necessarily only there) as a coherent wave, or even more
precisely, a chemically pumped travelling wave laser with oxygen. The

Bul. Inst. Polit. Iai, t. LVIII (LXII), f. 1, 2012

11

extracellular matrix (ECM) and in particular, the tumor microenvironment


(TME) are assumed as non-differential media endowed with holographic
properties and may be good candidates for recording materials. As a result,
the tumor self-seeding by CTC may prove mathematically, the fact that the CTC
returning to the initial tumor site and fueling the primary tumor growth or even
grow a new tumor is a particular case of complete holography (i.e. a hologram
which does not represent only the virtual objects image, but it becomes the
very object - which we believe, is a characteristic of the living organisms). We
believe our findings may provide new opportunities to set up new targeted
therapies that may slow down or even prevent tumor progression.
The work is structured as follows. After a short introduction, in Sec. 2 we
provide some general notions about cancer, which will be addressed in the rest
of the paper. In Sec. 3, the mathematics of cancer as it is today is reviewed
shortly, and also a few words about the connections between cancer, nondifferentiability and chaos are provided. Further, in Sec. 4, some information
about holography: how it works and recording materials are revealed. This will
be important for what will follow.
2. The Biology of Cancer
2.1 Cancer, What Should be Noticed

Cancer or malignant neoplasm is a class of diseases that rises from the


anomalous behavior of normal tissue. Cancer cells are aberrant cells which have
acquired malignant traits such as uncontrolled growth (cells continuously
proliferate), tissue invasion (they intrude into normal tissue and they destroy it)
and metastasis (they spread outside the location of the body where they were
originally generated). Additionally, the term tumour or neoplasm is used to
indicate an abnormal swelling of tissue caused by an excessive cell
proliferation.
A tumour can be of benign or malignant nature, while benign tumours are
self-limiting, do not express patterns of invasion, and they do not metastasize,
malignant tumours do possess all these characteristics. The term malignant
tumour is also used as synonym for cancer, although some cancers, such as
leukemia, do not form tumours.
Cancer cells develop these malignant features because of genetic
mutations, accumulated during the organism lifetime. Cancer is in fact a multistep chance process that transforms a normal cell into a tumour cell, after
having collected a set of 58 crucial genetic alterations (Fodde et al., 2001;
Hahn et. al., 1999; Kinzler et al., 1996) as schematically shown in Fig. 1.
A newborn malignant cell, expressing aberrant traits, can lead to the
formation of cancer and, in most of the cases, of a tumour. Without treatment,
the destructive behavior of such colony of cells is usually lethal for the patient.
The probabilistic nature of this disease and the increase in life expectancy had

12

Clin Gheorghe Buzea et al.

made cancer the second cause of death in the industrialised countries (see any
cancer statistics). Nevertheless, cancer it is not a modern disease and it was
known since the antiquity: Egyptians of the New Kingdom (Olson et al., 2002),
Greeks (Porter, 1997) and Romans (Hajdu, 2004) accurately described medical
treatments for tumour removal. It is only within the last two centuries however,
that due to the higher standards of living, cancer has become one of the main
life-threatening diseases.

Fig. 1 Acquisition of the tumourigenic phenotype by a population of normal cells


through multiple genetic mutations.
2.2. Distinguishing Traits of Cancer

The tumourigenic properties, generically discussed in the previous


section, have shown to be common to almost all cancers. They have been
studied since the dawn of cancer research and they can be enumerated and
defined with a relatively high accuracy. These hallmarks are a set of
characteristic traits typical of cancer cells that are essential for the formation of
a macroscopic malignant neoplasm (Hanahan & Weinberg, 2000):
Self-Sufficiency in Growth Signals. All cells communicate through
signals. A biological signal is, in most of the cases, a protein able to deliver a
particular piece of information by binding uniquely to specific receptors on the
cell surface. Normal cells need mitogenic growth signals to proliferate (signals
that allow and stimulate cell proliferation). Those signals are regulated by the
homeostasis of the tissue and they guarantee a correct balance between cell
proliferation and death, according to the needs of the organism. In order to lead
to cancer, tumour cells may develop the ability of self-generating such signals
in one way or another. One possible way is a genetic aberration in one of the
fundamental genes responsible for the building of the signaling pathway, for
instance the RAS oncogene (Kinzler et al., 1996; Medema et al., 1993). As
consequence, the associated component of the signaling system would become
constitutively active and hence, independent by the signal molecule. A second
option is the self-production of growth factors that would stimulate growth by
paracrine signaling, where a cells stimulates the neighbours and vice-versa or
even autocrine signaling, when the cell stimulates its own receptors as shown in
Fig. 2.

Bul. Inst. Polit. Iai, t. LVIII (LXII), f. 1, 2012

13

Fig. 2 Example of self-signaling (autocrine): the cell produces its own growth factors
which stimulate the growth receptors on the surface (Dr. W.H. Moolenaar, Netherlands
Cancer Institute).

Insensitivity to Antigrowth Signals. As counterparts of growth factors,


homeostasis employs growth inhibiting signals as well. These signals act
similarly to their antagonists but they promote cell cycle arrest or cell
quiescence, rather than proliferation. An example of a crucial gene involved in
anti-growth pathways is the retinoblastoma protein (pRb). The retinoblastoma
protein is capable of altering the function of the E2F transcription factors and
control the expression of the bank of genes essential for the transition from
GAP-1 phase to DNA Synthesis phase of the cell cycle (Weinberg, 1995). The
disruption of such pathway results in the insensitivity of the cell to anti-growth
signals.
Evading Apoptosis. Apoptosis is a mechanism of controlled cell death.
Through special signals, a cell has the capacity of terminating itself in a highly
regulated way. A normal cell dying by apoptosis undergoes a sequence of
events such as condensation, fragmentation and phagocytosis. This avoids the
cell to free potentially dangerous enzymes and proteins stored inside its
cytoplasm and its nucleus. During apoptosis the cell membrane is kept intact
while, in 30120 minutes the cell is fragmented in small parts or apoptotic
bodies, still protected by pieces of membrane. Those cell leftovers are
successively phagocytated by macrophages within the next 24 hours (Wyllie et
al., 1980). Apoptosis is a common mechanism of cell death and takes part in the
homeostasis of a healthy organism as well as in its embryogenesis and in its
morphogenesis. When any cell violates such homeostasis, an apoptotic signal is
delivered to it. Therefore, in order for cancer cells to develop into a malignant
lesion, it is necessary to deactivate apoptotic signal pathways. A mutation in the
p53 tumour suppressor gene (TSG) is one of the most common ways to acquire
resistance to apoptosis because p53 regulates the whole signaling process of
programmed cell death. Indeed, more than 50% of human cancers carry a
mutation in the p53 tumour suppressor gene (Harris, 1996).
Limitless Replicative Potential. Even with all the anti-growth and antiapoptosis pathways triggered off, a cell could not generate a vast population

14

Clin Gheorghe Buzea et al.

able to form a tumour. That is because of the intrinsic proliferation limit of all
mammalian cells. All chromosomes have an ending cap called telomere, a Tloop non-coding DNA sequence (2...50 Kb) that prevents the end of the
chromosomes from attaching to other genetic material. At every mithosis the
cell loses a small part of its telomeres because of the impossibility for DNA
duplication enzymes, for instance DNA-polymerase, to continue working until
the very end of the genome (Fig. 3). This limitation is due to the fact that
enzymes like DNA-polymerase always move in the 53 direction of the
DNA sequence, so when the side of the replication is opposite, a small part of
the genome is lost. The shortening of the telomeres induces cell senescence, a
state of cellular elderly where division no longer occurs. This avoids genetically
unstable cells to replicate. Senescence starts after the so called Hayflick limit
(Hayflick, 1997) of about 50 cell divisions. In cancer cells instead, the disabling
of the pRb and the p53 pathways allows unlimited replication, until the point
when the telomeres are completely absent. Once having entirely consumed the
telomeres, the cell population is believed to undergo a phase of massive
genomic instability, causing extended cell death. The high selective pressure
induced by this crisis may permit specific resistant clones to emerge (Fig. 4).
Those survivor cells would be immortalised (unlimited proliferative potential)
by finding ways to maintain their telomeres long enough. A possible way is the
overexpression of the telomerase gene (Shay & Bacchetti, 1997) which appears
to take place in 8590 % of cancers. Telomerase is a telomere-rebuilding
enzyme normally expressed in germline cells and stem cells, in which
immortalisation is an essential feature. Once immortalised, malignant cells have
made a further step towards the formation of cancer.

Fig. 3 Illustration of the end replication problem: at both sides of the copying, the
leading DNA strand has lost part of the telomeric sequence, which stops at the 5 end of
the parental strand, whereas the lagging strand results completed until the very end
(Dr. R. Beijersbergen, Netherlands Cancer Institute).

Sustained Angiogenesis. In order for a cell to survive normally, it must


rely within 100 m from a capillary blood vessel (Hanahan & Weinberg, 2000).

Bul. Inst. Polit. Iai, t. LVIII (LXII), f. 1, 2012

15

For this reason, the initial exponential growth of a newborn malignant neoplasm
causes a shortage of nutrients among cancer cells. Local pre-existent
vascularisation is never enough to sustain growth for more than 108 cells. The
colony must therefore develop angiogenesis-triggering capabilities (Bouck et
al., 1996; Hanahan & Folkman, 1996). Angiogenesis is the process of formation
of new blood vessels in response to a stimulus secreted by poor vascularised
tissues. Angiogenesis is important for the organism morphogenesis and even
later maintains the correct supply of nutrients for all tissues. Fast growing cells,
such as cancer cells, start soon to starve, and have the need of additional blood
supply in order to keep expanding. A possible solution is the production by
cancer cells of vascular endothelial growth factors (VEGF) and fibroblast
growth factors (FGF1/2) which bind to the transmembrane receptors of
endothelial cells (cells covering the interior surface of blood vessels)
stimulating their growth towards the signal concentration gradient (Veikkola &
Alitalo, 1999). Angiogenesis is the principal mechanism that transforms a
microscopic malignancy into a macroscopic tumour and, also in the later stages,
it is necessary for a lesion to grow and sustain itself. This implies that
angiogenesis is an important target for anti-cancer drugs like thrombospondin-1
(Bull et al., 1994) and bevacizumab (Shih & Lindley, 2006), also known as
avastin.

Fig. 4 The progressive shortening of the telomeres leads to a massive cell death due to
the induced genomic instability (death by genomic catastrophe while duplicating). From
such process of intense genetic mutation and selection an immortalised clone could
emerge (Dr. R. Beijersbergen, Netherlands Cancer Institute).

Tissue Invasion and Metastasis. The most dangerous and destructive


features of cancer are tissue invasion and the consequent metastasis. Its ability
of forming distant colonies or metastases all over the body represents the cause
of 90% of all cancer related deaths (Sporn, 1996). Normal cells are usually

16

Clin Gheorghe Buzea et al.

unable to travel outside their own tissue due to their necessity to be anchored
and reside among similar cells. An eventual detachment from the extracellular
matrix or ECM (a complex structure of proteins and specific cells forming the
tissue scaffold and microenvironment see Sec. 6.1) would occur in a form of
apoptosis called anoikis (Frisch & Screaton, 2001). Contrary to their normal
counterparts, cancer cells are able to survive the loss of anchorage, to travel
through the vascular system and form distant tumours elsewhere (Fig. 5). The
traits expressed by invasive and metastatic cancer cells are principally loss of
cell-to-cell adhesion, anchorage-independence, chemotaxis (migration towards a
diffusible substance gradient), haptotaxis (migration towards a non-diffusible
substance gradient) and production of matrix degrading enzymes (e.g. Matrix
metalloproteinase) which cleave the extracellular matrix (Fidler, 2003;
Matrisian, 1992; Mignatti & Rifkin, 1993) making space for invasion and
freeing growth and angiogenic factors trapped inside.

Fig. 5 Tissue invasion is a multi-step process that requires the cancer cell to have
developed many malignant traits, necessary for the formation of new distant colonies
called metastases (Fidler, 2003).

3. Mathematics of Cancer
In comparison to molecular biology, cell biology, and drug delivery
research, mathematics has so far contributed relatively little to the area. A
search in the PubMed bibliographic database (http://www.ncbi.nlm.

Bul. Inst. Polit. Iai, t. LVIII (LXII), f. 1, 2012

17

nih.gov/PubMed/) shows that out of 1.5 million papers in the area of cancer
research, approximately 5% are related to mathematical modeling. However, it
is clear that mathematics could make a huge contribution to many areas of
experimental cancer investigation since there is now a wealth of experimental
data which requires systematic analysis.
Nevertheless, over the last decade, the activity in mathematical modeling
and computational simulation of cancer has increased dramatically (e.g.,
reviews such as (Araujo et al., 2004; Byrne et al., 2006; Adam, 1996; Bellomo
et al., 2003; Quaranta et al., 2005; Sanga et al., 2006). A variety of modeling
strategies have been developed, each focusing on one or more aspects of cancer.
Cellular automata and agent-based modeling, where individual cells are
simulated and updated based upon a set of biophysical rules, have been
developed to study genetic instability, natural selection, carcinogenesis, and
interactions of individual cells with each other and the microenvironment.
Because these methods are based on a series of rules for each cell, it is simple to
translate biological processes (e.g., mutation pathways) into rules for the model.
However, these models can be difficult to study analytically, and computational
costs can increase rapidly with the number of cells. Because a 1-mm tumor
spheroid may have several hundred thousand cells, these methods could become
unwieldy when studying tumors of any significant size. See (Alarcn et al.,
2005; Anderson, 2003; Mallett et al., 2006) for examples of cellular automata
modeling and (Abbott et al., 2006; Mansury et al., 2002) for examples of agentbased modeling. In larger-scale systems where the cancer cell population is on
the order of 106 or more, continuum methods may provide a more suitable
modeling technique. Early work, including (Byrne et al., 1996; Byrne et al.,
1996; Greenspan et al., 1976), used ordinary differential equations to model
cancer as a homogeneous population, as well as partial differential equation
models restricted to spherical geometries. Linear and weakly nonlinear analyses
have been performed to assess the stability of spherical tumors to asymmetric
perturbations (Araujo et al., 2004; Byrne et al., 2006), (Byrne et al., 2002;
Chaplain et al., 2001; Cristini et al., 2003; Li et al., 2007) in order to
characterize the degree of aggression. Various interactions of a tumor with the
microenvironment, such as stress-induced limitations to growth, have also been
studied (Ambrosi et al., 2002; Ambrosi et al., 2002; Ambrosi et al., 2002;
Araujo et al., 2004; Araujo et al., 2005; Jones et al., 2000; Roose et al., 2003).
Most of the modeling has considered single-phase (e.g., single cell species)
tumors, although multiphase mixture models have also been developed to
provide a more detailed account of tumor heterogeneity (Ambrosi et al., 2002;
Byrne et al., 2003; Chaplain et al., 2006).
Recently, nonlinear modeling has been performed to study the effects of
morphology instabilities on both avascular and vascular solid tumor growth.
(Cristini et al., 2003) used boundary integral methods to perform the first fully
nonlinear simulations of a continuum model of tumor growth in the avascular

18

Clin Gheorghe Buzea et al.

and vascular growth stages with arbitrary boundaries. These investigations of


the nonlinear regime of shape instabilities predicted encapsulation of external,
non-cancerous tissue by morphologically unstable tumors. (Li et al., 2007)
extended the model from (Cristini et al., 2003) in 3-D via an adaptive boundary
integral method. (Zheng et al., 2005) built upon the model in (Cristini et al.,
2003) to include angiogenesis and an extratumoral microenvironment by
developing and coupling a level set implementation with a hybrid continuumdiscrete angiogenesis model originally developed by (Anderson & Chaplain,
1998). As in (Cristini et al., 2003), (Zheng et al., 2005) found that low-nutrient
(e.g., hypoxic) conditions could lead to morphological instability. Their work
served as a building block for recent studies of the effect of chemotherapy on
tumor growth (Sinek et al., 2004) and for studies of morphological instability
and invasion (Cristini et al., 2005; Frieboes et al., 2006; Hogea et al., 2006)
have also begun exploring tumor growth and angiogenesis using a level set
method coupled with a continuum model of angiogenesis. Macklin &
Lowengrub used a ghost cell/level set method for evolving interfaces to study
tumor growth in heterogeneous tissue and further studied tumor growth as a
function of the microenvironment (Macklin & Lowengrub, 2007). Finally,
(Wise et al.; Frieboes et al., 2007) have developed a diffuse interface
implementation of solid tumor growth to study the evolution of multiple tumor
cell species, which was employed in (Frieboes et al., 2007) to model the 3-D
vascularized growth of malignant gliomas (brain tumors).
In the case of biological systems, the fractal structure of space in which
cells interact and differentiate is essential for their self-organization and
emergence of the hierarchical network of multiple cross-interacting cells,
sensitive to external and internal conditions. Hence, the biological phenomena
take place in the space whose dimensions are not represented only by integer
numbers (1, 2, 3, etc.) of Euclidean space. In particular, malignant tumors
(Jones et al., 2000; Roose et al., 2003; Byrne et al., 2003; Chaplain et al., 2006)
grow in a space with non-integer fractal dimension. More precisely, it was
proved that the analytical formulae describing the time-dependence of the
temporal fractal dimension and scaling factor very well reproduce the growth of
the FlexnerJobling rats tumor in particular and growth of other rats tumors in
general. The results of some test calculations indicated that the formula derived
for the time-dependent temporal fractal dimension and the scaling factor
satisfactory describe the experimental data obtained by Schrek for the BrownPearce rabbits tumor growth in the fractal space-time (Waliszewski et al.,
1998; Waliszewski et al., 1999; Waliszewski et al., 2000; Waliszewski et al.,
2001).
In our assertion fractal space(-time) consists in developing the
consequences of the withdrawal of space(-time) differentiabilitys hypothesis
and acquiring a fractal geometry, namely, space(-time) becomes explicitly
dependent on the observation scale (Nottale, 1993).

Bul. Inst. Polit. Iai, t. LVIII (LXII), f. 1, 2012

19

On the other hand, of great use in our further reasonings, will be the fact
that in many biological systems it is possible to empirically demonstrate the
presence of attractors that operate starting from different initial conditions
(Ivancevic). Some of these attractors are points, some are closed curves, while
the others have noninteger, fractal dimension and are termed strange
attractors (Guarini et al., 1993). It has been proposed that a prerequisite for
proper simulating tumor growth by computer is to establish whether typical
tumor growth patterns are fractal. The fractal dimension of tumor outlines was
empirically determined using the box-counting method (Sedivy, 1996). In
particular, fractal analysis of a breast carcinoma was performed using a
morphometric method, which is the box-counting method applied to the
mammogram as well as to the histologic section of a breast carcinoma (Sedivy
& Windischberger, 1998).
If tumor growth is chaotic, this could explain the unreliability of
treatment and prediction of tumor evolution. More importantly, if chaos is
established, this could be used to adjust strategies for fighting cancer. Treatment
could include some form of chaos control and/or anti-control.
4. A Few Words about Holography
A hologram is usually recorded on a photographic plate or a flat piece of
film, but produces a three-dimensional image. In addition, making a hologram
does not involve recording an image in the conventional sense. To resolve this
apparent paradox and understand how holography works, we have to start from
first principles.
In conventional imaging techniques, such as photography, what is
recorded is merely the intensity distribution in the original scene. As a result, all
information about the optical paths to different parts of the scene is lost.
The unique characteristic of holography is the idea of recording both the
phase and the amplitude of the light waves from an object. Since all recording
materials respond only to the intensity in the image, it is necessary to convert
the phase information into variations of intensity. Holography does this by
using coherent illumination and introducing, as shown in Fig. 6, a reference
beam derived from the same source. The photographic film records the
interference pattern produced by this reference beam and the light waves
scattered by the object.
Since the intensity at any point in this interference pattern also depends
on the phase of the object wave, the resulting recording (the hologram) contains
information on the phase as well as the amplitude of the object wave. If the
hologram is illuminated once again with the original reference wave, as shown
in Fig. 7, it reconstructs the original object wave.
An observer looking through the hologram sees a perfect threedimensional image. This image exhibits all the effects of perspective, and depth
of focus when photographed, that characterized the original object.

20

Clin Gheorghe Buzea et al.

Fig. 6 Hologram recording: the interference pattern produced by the reference wave
and the object wave is recorded.

Fig. 7 Image reconstruction: light diffracted by the hologram reconstructs


the object wave.
4.1. Early Development

In Gabors historical demonstration of holographic imaging (Gabor,


1948), a transparency consisting of opaque lines on a clear background was
illuminated with a collimated beam of monochromatic light, and the
interference pattern produced by the directly transmitted beam (the reference
wave) and the light scattered by the lines on the transparency was recorded on a
photographic plate. When the hologram (a positive transparency made from this
photographic negative) was illuminated with the original collimated beam, it
produced two diffracted waves, one reconstructing an image of the object in its
original location, and the other, with the same amplitude but the opposite phase,
forming a second, conjugate image.
A major drawback of this technique was the poor quality of the
reconstructed image, because it was degraded by the conjugate image, which

Bul. Inst. Polit. Iai, t. LVIII (LXII), f. 1, 2012

21

was superimposed on it, as well as by scattered light from the directly


transmitted beam.
The twin-image problem was finally solved when Leith and Upatnieks
(Leith & Upatnieks, 1962; Leith & Upatnieks, 1963; Leith & Upatnieks, 1964)
developed the off-axis reference beam technique shown schematically in Figs. 6
and 7. They used a separate reference wave incident on the photographic plate
at an appreciable angle to the object wave. As a result, when the hologram was
illuminated with the original reference beam, the two images were separated by
large enough angles from the directly transmitted beam, and from each other, to
ensure that they did not overlap.
The development of the off-axis technique, followed by the invention of
the laser, which provided a powerful source of coherent light, resulted in a surge
of activity in holography that led to several important applications.
4.2. The In-line Hologram

We consider the optical system shown in Fig. 8 in which the object (a


transparency containing small opaque details on a clear background) is
illuminated by a collimated beam of monochromatic light along an axis normal
to the photographic plate.

Fig. 8 Optical system used to record an in-line hologram.

The light incident on the photographic plate then contains two


components. The first is the directly transmitted wave, which is a plane wave
whose amplitude and phase do not vary across the photographic plate. Its
complex amplitude can, therefore, be written as a real constant r. The second is
a weak scattered wave whose complex amplitude at any point (x, y) on the
photographic plate can be written as o(x, y), where |o(x, y)| << r.
Since the resultant complex amplitude is the sum of these two complex
amplitudes, the intensity at this point is

22

Clin Gheorghe Buzea et al.

I ( x, y ) = r + o( x, y ) = r 2 + o( x, y ) + ro( x, y ) + ro ( x, y ),
2

(1)

where o*(x, y) is the complex conjugate of o(x, y).


A positive transparency (the hologram) is then made by contact printing
from this recording. If we assume that this transparency is processed so that its
amplitude transmittance (the ratio of the transmitted amplitude to that incident
on it) can be written as

t = t 0 + TI ,

(2)

where t0 is a constant background transmittance, T is the exposure time and is


a parameter determined by the photographic material used and the processing
conditions, the amplitude transmittance of the hologram is
t( x, y ) = t 0 + T [ r 2 + o( x, y ) + ro( x, y ) + ro ( x, y )].
2

(3)

Finally, the hologram is illuminated, as shown in Fig. 9, with the same


collimated beam of monochromatic light used to make the original recording.
Since the complex amplitude at any point in this beam is, apart from a constant
factor, the same as that in the original reference beam, the complex amplitude
transmitted by the hologram can be written as
2

u ( x, y ) = rt( x, y ) = r (t 0 + Tr 2 ) + Tr o( x, y ) +
+ Tr 2 o( x, y ) + Tr 2 o ( x, y ).

(4)

The right-hand side of (4) contains four terms. The first of these,
r(t0+Tr2), which represents a uniformly attenuated plane wave, corresponds to
the directly transmitted beam.
The second term, Tr |o(x, y)|2, is extremely small, compared to the other
terms, and can be neglected.
The third term, Tr2o(x, y), is, except for a constant factor, identical with
the complex amplitude of the scattered wave from the object and reconstructs an
image of the object in its original position. Since this image is formed behind
the hologram, and the reconstructed wave appears to diverge from it, it is a
virtual image.
The fourth term, Tr2o*(x, y), represents a wave similar to the object
wave, but with the opposite curvature. This wave converges to form a real
image (the conjugate image) at the same distance in front of the hologram.
With an in-line hologram, an observer viewing one image sees it
superimposed on the out-of-focus twin image as well as a strong coherent
background. Another drawback is that the object must have a high average
transmittance for the second term on the right-hand side of (4) to be negligible.

Bul. Inst. Polit. Iai, t. LVIII (LXII), f. 1, 2012

23

As a result, it is possible to form images of fine opaque lines on a transparent


background, but not vice versa. Finally, the hologram must be a positive
transparency. If the initial recording is used directly, in (2) is negative, and the
reconstructed image resembles a photographic negative of the object.

Fig. 9 Optical system used to reconstruct the image with an in-line hologram,
showing the formation of the twin images.
4.3. Off-axis Holograms

To understand the formation of an image by an off-axis hologram, we


consider the recording arrangement shown in Fig. 10, in which (for simplicity)
the reference beam is a collimated beam of uniform intensity, derived from the
same source as that used to illuminate the object.

Fig. 10 The off-axis hologram: recording.

The complex amplitude at any point (x, y) on the photographic plate due to
the reference beam can then be written as
r ( x, y ) = r exp(i2x ),

(5)

where =(sin)/, since only the phase of the reference beam varies across the
photographic plate, while that due to the object beam, for which both the
amplitude and phase vary, can be written as

24

Clin Gheorghe Buzea et al.

o( x, y ) = o( x, y ) exp[i( x, y )].

(6)

The resultant intensity is, therefore,


2

I ( x , y ) = r ( x , y ) + o ( x, y ) = r ( x , y ) + o ( x, y ) +
+ r o( x, y ) exp[i( x, y )]exp(i2x ) + r o( x, y ) exp[i( x, y )]exp(i2x ) = (7)
2

= r 2 + o( x, y ) + 2r o( x, y ) cos[2x + ( x, y )].

The amplitude and phase of the object wave are encoded as amplitude and
phase modulation, respectively, of a set of interference fringes equivalent to a
carrier with a spatial frequency of .
If, as in (2), we assume that the amplitude transmittance of the processed
photographic plate is a linear function of the intensity, the resultant amplitude
transmittance of the hologram is
t( x, y ) = t '0 + T o( x, y ) 2 + Tr o( x, y ) exp[i( x, y )]exp(i2x ) +
+ Tr o( x, y ) exp[i( x, y )]exp(i2x ),

(8)

where t`0 = t0 +Tr2 is a constant background transmittance.


When the hologram is illuminated once again with the original reference
beam, as shown in Fig. 11, the complex amplitude of the transmitted wave can
be written as
2

u ( x, y ) = r ( x, y )t( x, y ) = t '0 r exp(i2x) + Tr o( x, y ) exp(i2x ) +


+ Tr 2 o( x, y ) + Tr 2 o ( x, y )exp(i4x).

(9)

The first term on the right-hand side of (9) corresponds to the directly
transmitted beam, while the second term yields a halo surrounding it, with
approximately twice the angular spread of the object. The third term is identical
to the original object wave, except for a constant factor Tr2, and produces a
virtual image of the object in its original position. The fourth term corresponds
to the conjugate image which, in this case, is a real image. If the offset angle of
the reference beam is made large enough, the virtual image can be separated
from the directly transmitted beam and the conjugate image.
In this arrangement, corresponding points on the real and virtual images
are located at equal distances from the hologram, but on opposite sides of it.
Since the depth of the real image is inverted, it is called a pseudoscopic image,
as opposed to the normal, or orthoscopic, virtual image. It should also be noted
that the sign of only affects the phase of the reconstructed image, so that a
positive image is always obtained, even if the hologram recording is a
photographic negative.

Bul. Inst. Polit. Iai, t. LVIII (LXII), f. 1, 2012

25

Fig. 11 The off-axis hologram: image reconstruction.


4.4. Recording Materials

Several recording materials have been used for holography (Smith,


1977). Table 1 lists the principal characteristics of those that have been found
most useful.

Material

Table 1
Recording materials for holography
Exposure Resolution
mm-1
Processing
J/m2

10000

Normal
Bleach
Wet

Amplitude
Phase
Phase

(diffraction
efficiency)
0.06
0.60
0.90

102
10-104
10-1

3000
5000
500-1200

Wet
Dry
Dry

Phase
Phase
Phase

0.30
0.90
0.30

10

10000

None

Phase

0.20

Photographic

1.5

5000

DCG
(dichromated gelatin)
Photoresists
Photopolymers
PTP
(photothermoplastics)

102

BSO
( Bi12SiO20
photorefractive
crystals)

max
Type

High-resolution photographic plates and films were the first materials


used to record holograms. They are still used widely because of their relatively
high sensitivity when compared to other hologram recording materials
(Bjelkhagen, 1993). In addition, they can be dye sensitized so that their spectral
sensitivity matches the most commonly used laser wavelengths.

26

Clin Gheorghe Buzea et al.

The silver-halide sensitized gelatin technique makes it possible to


combine the high sensitivity of photographic materials with the high diffraction
efficiency, low scattering and high light-stability of DCG (dichromated gelatin)
(Pennington et al., 1971).
In positive photoresists, such as Shipley AZ-1350, the areas exposed to
light become soluble and are washed away during development to produce a
relief image (Bartolini, 1977).
Several organic materials can be activated by a photosensitizer to produce
refractive index changes, due to photopolymerization, when exposed to light
(Booth, 1977). A commercial photopolymer is also available coated on a
polyester film base (DuPont OmniDex) that can be used to produce volume
phase holograms with high diffraction efficiency (Smothers et al., 1990).
Photothermoplastics (PTP) - a hologram can be recorded in a multilayer
structure consisting of a glass or Mylar substrate coated with a thin, transparent,
conducting layer of indium oxide, a photoconductor, and a thermoplastic (Lin &
Beauchamp, 1970; Urbach, 1977).
When a photorefractive crystal is exposed to a spatially varying light
pattern, electrons are liberated in the illuminated areas. These electrons migrate
to adjacent dark regions and are trapped there. The spatially varying electric
field produced by this space-charge pattern modulates the refractive index
through the electro-optic effect, producing the equivalent of a phase grating.
The spacecharge pattern can be erased by uniformly illuminating the crystal,
after which another recording can be made (Huignard & Micheron, 1976;
Huignard, 1981).
In order to maximize the visibility of the interference fringes formed by
the object and reference beams, while recording a hologram, it is essential to
use coherent illumination. In addition to being spatially coherent, the coherence
length of the light must be much greater than the maximum value of the optical
path difference between the object and the reference beams in the recording
system. Lasers are therefore employed almost universally as light sources for
recording holograms.
Consequently, to get a hologram, one needs a laser, which provides a
powerful source of coherent light, and a recording material which records the
interference pattern produced by a reference beam and the light waves scattered
by the object.
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UN NOU MODEL AL CARCINOGENEZEI I PROGRESIEI TUMORALE


N CADRUL DINAMICII NELINIARE (I)
(Rezumat)
Se propune un nou concept fizic al carcinogenezei i progresiei tumorale prin
utilizarea unui mediu natural n care tumorile maligne se pot dezvolta, adic spaiultimp fractal, cu scopul de a gsi aplicaii ulterioare ale noului fenomen descoperit,
autonsmnarea tumoral prin celule canceroase circulante. n prezenta lucrare sunt
preezentate noiuni generale despre cancer, matematica cancerului (conexiunea ntre
cancer, nedifereniabilitate i haos) i holografie.

BULETINUL INSTITUTULUI POLITEHNIC DIN IAI


Publicat de
Universitatea Tehnic Gheorghe Asachi din Iai
Tomul LVIII (LXII), Fasc. 1, 2012
Secia
MATEMATIC. MECANIC TEORETIC. FIZIC

A NEW CARCINOGENESIS AND TUMOR


PROGRESSION MODEL IN THE FRAMEWORK
OF NON-LINEAR DYNAMICS (II)
BY

DRAGO IANCU1, CLIN GHEORGHE BUZEA2 and MARICEL AGOP3


University of Medicine and Pharmacy Gr. T. Popa, Iai
National Institute of Research and Development for Technical Physics, Iai
Gheorghe Asachi Technical University of Iai
Received: December 28, 2011
Accepted for publication: January 15, 2011

Abstract. Starting from a basic model for solid tumors growth, a chaotic
multi-scale cancer-invasion model is manufactured, which embeds a Lorenz
attractor in its solutions. Furthermore we show how a laser can be expressed in
terms of a Lorenz system and correspondences between the laser and the above
mentioned chaotic multi-scale cancer-invasion model are proposed. Also, we
show that the basic model for solid tumors growth admits a travelling wave
solution and we suggest that metastatic tumor cells which move through the
systemic circulation, and not necessarily there, are similar to a coherent wave,
i.e. a travelling wave, chemically pumped oxygen type laser.
Keywords: carcinogenesis, tumor, fractal, travelling wave, holography.

1. Basic Model
1.1. The PDE Cancer-invasion Model

We consider and present in what follows in extenso, the basic


mathematical model of growth of a generic solid tumour, which is assumed just
been vascularised, i.e. a blood supply has been established. Let us focus on four
key variables involved in tumour cell invasion, in order to produce a minimal

Corresponding author: e-mail: calinb2003@yahoo.com

34

Drago Iancu et al.

model, namely tumour cell density (denoted by n), matrix-degradative enzymes


(MDE) concentration (denoted by m), the complex mixture of macromolecules
from the extracellular materials (MM) concentration (denoted by f ) and the
oxygen concentration (denoted by c). Each of the four variables (n, m, f, c) is a
function of the spatial variable x and time t. Initially, we define a system of
coupled non-linear partial differential equations to model tumour invasion of
surrounding tissue.
We will assume that the ECM consists of a mixture of MM (e.g. collagen,
fibronectin, laminin and vitronectin) only and not any other cells. Most of the
MM of the ECM which are important for cell adhesion, spreading and motility
are fixed or bound to the surrounding tissue. MDEs are important at many
stages of tumour growth, invasion and metastasis, and the manner in which they
interact with inhibitors, growth factors and tumour cells is very complex.
However, it is well known that the tumour cells produce MDEs which degrade
the ECM locally. As well as making space into which tumour cells may move
by simple diffusion (random motility), we assume that this also results in a
gradient of these bound cell-adhesion molecules, such as fibronectin. Therefore,
while the ECM may constitute a barrier to normal cell movement, it also
provides a substrate to which cells may adhere and upon which they may move.
Most mammalian cell types require at least some elements of the ECM to be
present for growth and survival and will indeed migrate up a gradient of bound
(i.e. non-diffusible) cell-adhesion molecules in culture in vitro (Carter, 1965;
Quigley et al., 1983; Lacovara et al., 1984; McCarthy et al., 1984; Klominek et
al., 1993; Lawrence et al., 1996).
By definition, haptotaxis is the directed migratory response of cells to
gradients of fixed or bound chemicals (i.e. non-diffusible chemicals). While it
has not yet been explicitly demonstrated that haptotaxis occurs in an in vivo
situation, given the structure of human tissue, it is not unreasonable to assume
that haptotaxis is a major component of directed movement in tumour cell
invasion. Indeed, there has been much recent effort to characterise such directed
movement (Klominek et al., 1993; Lawrence et al., 1996; Debruyne et al.,
2002). We therefore refer to this directed movement of tumour cells in this
model as haptotaxis, i.e. a response to gradients of bound MM such as
fibronectin. To incorporate this response in the mathematical model, we take the
haptotactic flux to be Jhapto = n f , where > 0 is the (constant) haptotactic
coefficient.
As mentioned above, the only other contribution to tumour cell motility
in the model is assumed to be random motion. To describe the random motility
of the tumour cells, we assume a flux of the form Jrand = Dnn, where Dn is the
constant random motility coefficient.
We only model the tumour cell migration at this level, as all other tumour
cell processes, such as proliferation, adhesion and death will be considered at

Bul. Inst. Polit. Iai, t. LVIII (LXII), f. 1, 2012

35

the single cell level within the hybrid discrete-continuum model. The
conservation equation for the tumour cell density n is therefore given by
n
+ J rand + J hapto = 0,
t

and hence the partial differential equation governing tumour cell motion (in the
absence of cell proliferation) is
n
= Dn 2 n ( nf ) .
t

(1)

The ECM is known to contain many MM, including fibronectin, laminin


and collagen, which can be degraded by MDEs (Stetler-Stevenson et al., 1996;
Chambers et al., 1997). We assume that the MDEs degrade ECM upon contact
and hence the degradation process is modelled by the following simple equation
f
= mf ,
t

(2)

where is a positive constant.


Active MDEs are produced (or activated) by the tumour cells, diffuse
throughout the tissue and undergo some form of decay (either passive or active).
The equation governing the evolution of MDE concentration is therefore given
by
m
= Dm 2 m + g (n, m) h(n, m, f ),
t

(3)

where Dm is a positive constant, the MDE diffusion coefficient, g is a function


modelling the production of active MDEs by the tumour cells and h is a
function modelling the MDE decay. For simplicity we assume that there is a
linear relationship between the density of tumour cells and the level of active
MDEs in the surrounding tissues (regardless of the amount of enzyme
precursors secreted and the presence of endogenous inhibitors) and so these
functions are taken to be g = n (MDE production by the tumour cells) and h =
=m (natural decay), respectively.
It is well known that solid tumours need oxygen to grow and invade.
Oxygen is assumed to diffuse into the MM, decay naturally and be consumed
by the tumour. For simplicity oxygen production is proportional to the MM
density. This is a crude way of modelling an angiogenic oxygen supply for a
more appropriate way of modelling the angiogenic network. The oxygen
equation therefore has the form,

36

Drago Iancu et al.

c
= Dc 2 c + f n c,
t

(4)

where Dc, , , are positive constants representing the oxygen diffusion


coefficient, production, uptake and natural decay rates, respectively.
The complete system of equations describing the interactions of the
tumour cells, MM, MDEs and oxygen as detailed above, is
random motility

n
=
t


Dn 2 n

haptotaxis



( nf ) ,

degradation

f
= mf ,
t

diffusion
decay


 production


m
2
= Dm m + n m ,
t

(5)

diffusion
uptake decay
 production



c
2
= Dc c + f n c,
t

where Dn, Dm and Dc are the tumour cell, MDE and oxygen diffusion
coefficients, respectively, is the haptotaxis coefficient and , , , , and
are positive constants. We should also note that cellmatrix adhesion is
modelled here by the use of haptotaxis in the cell equation, i.e. directed
movement up gradients of MM. Therefore, maybe considered as relating to
the strength of the cellmatrix adhesion.
2. Non-dimensionalisation and Parameterisation
In order to use realistic parameter values, one must first of all nondimensionalise the equations in the standard way. We rescale distance with an
appropriate length scale L (e.g. the maximum invasion distance of the cancer
cells at this early stage of invasion, approximately 1 cm), time with (e.g. the
average time taken for mitosis to occur, approximately 824 h (Calabresi et
al., 1993)), tumour cell density with n0, ECM density with f0, MDE
concentration with m0 and oxygen concentration with c0 (where n0, f0, m0 and c0
are appropriate reference variables). Therefore, setting
n =

n
f
m
c
x
t
=
, f = , m
, c = , x = , t = ,

n0
f0
m0
c0
L

in (5) and dropping the tildes for notational convenience, we obtain the scaled
system of equations

Bul. Inst. Polit. Iai, t. LVIII (LXII), f. 1, 2012


random motility

n
=
t


dn2 n

f
=
t

37

haptotaxis



( nf ) ,

deg radation


mf

diffusion
decay


 production


m
= d m 2 m + n m ,
t

(6)

diffusion
uptake decay
 production



c
= d c 2 c + f
n c ,
t

where dn=Dn/L2, = f0/L2, =m0, dm=Dm/L2, =n0/m0, =, dc =Dc/L2,


= f0/c0, =n0/c0, =.
The cell cycle time can be highly variable (particularly the G1 phase) and
really depends on the specific tumour under consideration. As a rough guide we
take = 16 h, halfway between 824 h (Calabresi et al., 1993). The cell
motility parameter Dn ~ 109 cm2 s1 was estimated from available experimental
evidence (Bray, 1992). Tumour cell diameters again will vary depending on the
type of tumour being considered but are in the range 10100 m (Melicow,
1982) with an approximate volume of 109 to 3 108 cm3 (Folkman et al.,
1973; Casciari et al., 1992). We will assume that a tumour cell has the volume
1.5 108 cm3 and therefore take n0 = 6.7 107 cells cm3. The haptotactic
parameter ~ 2600 cm2 s1 M1 was estimated to be in line with that calculated
in (Anderson et al., 2000) and the parameter f0 ~ 108 to 1011 M was taken from
the experiments of (Terranova et al., 1985). We took Dm to be 109 cm2 s1,
which is perhaps small for a diffusing chemical, but recent experimental
evidence implies that it is in fact a combination of the MDE and MM, which
results in degradation of the MM and that this bound chemical diffuses very
little (Hotary et al., 2000). An in vivo estimate for the MDE concentration m0 is
somewhat difficult to obtain since there is currently no published value (that we
are aware of) and we also know that certain inhibitors (e.g. tissue inhibiting
metalloproteases) are produced within the ECM which will affect the MDE
concentration. Plasma levels of specific MDEs have been measured (e.g. MMP2 (Zervoudaki et al., 2004)) and are approximately 130 ng ml1 with further
increases observed in patients with cancer (Johansson et al., 2000). How this
relates to the MDE concentration within the ECM is not clear, we have
therefore left this parameter undefined. Estimates for the kinetic parameters ,
and were not available since these are very difficult to obtain experimentally we therefore use the values of (Anderson et al., 2000). Oxygen is known to

38

Drago Iancu et al.

diffuse through water at a rate of Dc = 105 cm2 s1 and cells consume oxygen at
a rate of 6.25 1017 M cells1 s1 (Casciari et al., 1992). The background
oxygen concentration within the tissue was somewhat difficult to estimate as
this depends on how well the tissue is vascularised. If we take the concentration
of oxygen in the blood supplying the tumour/tissue to be 0.15 ml O2 per ml of
blood and since we know that 1 M of oxygen occupies 22400 ml then there is
0.15/22400 M O2 ml1 = 6.7 x 106 M O2 ml1, and since 1 ml = 1 cm3 then we
calculate c0 = 6.7 x 106 M O2 cm3 (Sherwood, 2001). Clearly, this would be an
overestimate, since not all of the domain will be fully vascularised but this at
least gives us a reference value. The values of the non-dimensional parameters
were given as

d n = 0.0005, r = 0.01, h = 50, d m =0.0005,


k = 1, s = 0, d c = 0.5, n = 0.5, w = 0.57,

f = 0.025.

(7)

3. Laser Beam in a Multiscale Diffusion Cancer-invasion Model


3.1. Laser as a Lorenz System

A laser system is the result of an interaction between the electromagnetic


field and the substance, under certain circumstances. The Lorenz form of laser
equations may be obtained using a semi-classical reasoning where the
environment is analysed quantically, using the formalism of density matrix, and
the electromagnetic field is treated clasically, by means of Maxwells equations
(Loudon, 1983; Sargent III et al., 1977). Here we consider only two energy
levels of the involved microscopic systems (atoms, molecules, ions).
The first treatment of a two levels system was made by Bloch who
analysed the interaction of electrons with an oscillatory magnetic field
superposed over a static magnetic field, in the framework of a magnetic
resonance phenomenon. Due to the similarity of treatments and form of the
obtained equations for the laser system, one can say that it forms the MaxwellBloch system.
Note that the density matrix method is applied in the treatment of laser
systems, no matter how many energy levels, or number of oscillating modes are
considered, as well as, in the consequent quantum treatment, where the
electromagnetic field is quantized (Pantel & Puthoff, 1969; Nussenzveig, 1973).
We start by discussing the effect of the electromagnetic field on the atoms
of the environment. In the simplest situation, the electric field will induce in
each atom an electric dipole whose moment is proportional to the field and is
oriented along its direction. Neglecting the vectorial character, we have
(8)
= E ,
where is a constant characteristic to the type of the atom considered. If the
concentration of (identical) atoms in the considered environment is Na, then the

Bul. Inst. Polit. Iai, t. LVIII (LXII), f. 1, 2012

39

polarization vector of the environment, equals the vectorial sum of all the dipole
moments from the unit volume, and will be given by

P = N a = 0 E ,

(9)

where 0 is the empty space permitivity and represents the electric


susceptibility of the environment.
The problem of the induced dipole moment must be solved quantically
using Schrdingers equation
i

= H,
t

(10)

where H is the Hamiltonian operator and the wave function of the atom.
Since a monochromatic field of frequency 0, not very intense, interacts
with the atom inducing transitions between two of its energetic levels, E1 and E2
i.e. E2 - E1 = 0, it is usual to neglect the other levels and to approximate the
atom as a system with two energy levels. If the wave functions of the atom in
the two states are 1 and 2, respectively, then we have

= C11 + C22 ,

(11)

where C1, C2 are the time dependent complex amplitude probabilities for the
atom to find itself on the energy levels E1 and E2, respectively. In other words
11 = C1C1 C1 represents the probability of the atom to find itself in the state
2

1, and 22 = C2C2 C2 the probability of the atom to find itself in the state
2

2. The combinations 12 = C1C2 and 21 = C2C1 are transition probabilities


between the two states. The four numbers ij (i, j = 1, 2) forms the so called
density matrix for the 2-levels system. The asterisc attached to a parameter
means the complex conjugate of the respective parameter. Obviously, 21 = *12.
The Hamiltonian operator of the system will consist of a sum between the
Hamiltonian of the nonperturbed atom H 0 and a term which describes the
interaction of the atom with the field, H ' ,

H = H 0 + H ' .

(12)

The functions 1 and 2 are eigenfunctions of the nonperturbed


Hamiltonian, i.e.

H 01 = E11 , H 02 = E22 ,

(13)

Replacing (11), (12) and (13) into the Schrdinger equation, and after
some standard calculus, we get the equations

40

Drago Iancu et al.

C2 ,
iC1 = E1C1 + H12

C1 ,
iC 2 = E2C2 + H 21

(14)

where we introduced the notations


= 1 H 2 dV ,
H12

= 2 H 1dV .
H 21

(15)

It has been taken into account the orthonormal property of the wave
functions 1 and 2

i j dV = ij

(i, j = 1, 2),

(16)

where ij is Kroenekers symbol, and the fact that the interaction matrix H`ij has
no diagonal elements.
It is common to introduce the following simplification: if one chooses the
zero energy value at the center of the interval between the two energies, then
they become
E2 =

0
,
2

E1 =

0
,
2

(17)

and the Eqs. (14) rewrite


iC1 =

0C1
C2 ,
+ H12
2

0C2
C1.
+ H 21
2

iC 2 =

(18)

In quantum mechanics, the electric dipole momentum is calculated as the


expectation value of the classical electric dipole momentum = ex, where e is
the electron charge, and x is its displacement along the direction of the electric
field.
For an atom in the state , this is given by

= exdV = C1C2 + C1C2

1 ex 2 dV .

(19)

The integral 12 = 1ex 2 dV represents the electric dipole momentum


of the interaction. In the considered approximation, the interaction Hamiltonian
is identic to the classical expression of the interaction energy between an
electric field and the induced electric dipole: U = -E, but with 12 (the
dipole momentum of the interaction), i.e.

= 12 E.
H12

(20)

By choosing a convenient phase relation between the wave functions, we


can make 12 real so H`12, H`21 to be also real.
Eq. (19) suggests considering the expression

Bul. Inst. Polit. Iai, t. LVIII (LXII), f. 1, 2012

X = C1C2 + C1C2 12 + 21.

41

(21)

We remark that the polarization (9) is expressed as a function of X


through the equation

P = N a 12 X = N a 12 12 + c.c.,

(22)

where by c.c. we denote the complex conjugate of the previous expression.


We further consider the combinations

Y = i(C1C2 C1C2 ) i( 12 21 ),
2

Z = C2 C1 22 11.

(23)
(24)

For Z we also have a simple interpretation. If we multiply (24) by Na we


get the expressions Na22 and Na11, which represents the populations from the
unit volume of the two levels, in other words, Na Z N represents the difference
of population between the levels (inversion of population) from the unit
volume.
All the three expressions X, Y, Z are functions depending only on time.
Their time derivatives are easily calculated using Eqs. (18) and their complex
conjugates. The following relations result:
i
H 21
) Z = 0Y ,
X = 0Y ( H12

(25)

2
Y = 0 X + 12 EZ ,

(26)

2
Z = 12 EY ,

(27)

where in Eq. (25) the second form was obtained taking into account H`12 = H`21.
By multiplication of Eq. (25) with Na12, it transforms into an equation

for P , namely
P = N a 12 X = N a 12 ( 12 + 21 ) = N a 12 12 + c.c.

(28)

The equation for 12 is obtained from Eqs. (25) and (26), taking into
account Eqs. (21) and (23). It results
12 = i0 12 + i

12
EZ .

(29)

42

Drago Iancu et al.

Another equation for polarization is obtained by deriving Eq. (25) once


again and using (26). It results
+ 2 P = 20 2 EN .
P
0
12

(30)

It is interesting to note that, in the absence of the electromagnetic field,


i.e. for E = 0, Eq. (30) describes a harmonic oscillator. This is unacceptable,
since polarization is induced by the field, so it must attenuate after the field
cancels. Physically, it occurs both because of the internal dynamics of the
atomic (molecular) systems and of the dephasing between the oscillations of
different dipoles by means of their self-interaction or their interaction with the
crystal lattice (for a solid environment). This phenomenon is taken into
consideration through phenomenological reasonings by introducing an
amortization term of the form P T2 in the equation. Eq. (30) transforms into the
equation of a forced dumped oscillator:

+ P + 2 P = 20 2 EN .
P
0
12
T2

(31)

Usually, the time T2 is named transversal relaxation time. It is


characteristic to the non-diagonal elements of the density matrix, so Eq. (29)
must be rewritten
12 + ( 12 i0 ) 12 = i

12
EZ ,

(32)

where 12 =1/T2.
By multiplication of Eq. (27) with Na the left side becomes N . Replacing
Y from (25) in (27), we get
N
2
=
EP .
t 0

(33)

Eq. (33) shows that, at the disappearance of the electromagnetic field, the
inversion of population must remain constant. However, an electromagnetic
field resonant with the considered transition ( 0) is composed of quanta
which can be absorbed by atoms, so may have the effect of a transfer of
population between the two levels. It is obvious that, at the canceling of the
field, the inversion of population must evolve towards an equilibrium value Ne
which is obtained by a process of pumping and by spontaneous relaxation
processes. They imply the presence of other energetic levels besides those
already considered. We proceed again by phenomenological reasonings. We
suppose that this evolution is again exponentially, thus we add a term of the

Bul. Inst. Polit. Iai, t. LVIII (LXII), f. 1, 2012

43

form ( N N e ) T1 11 ( N N e ) , where T1 is named longitudinal relaxation


time (it is characteristic to the diagonal elements of the density matrix). The
equation for the inversion of population becomes
N
2
+ 11 ( N N e ) =
EP
t
0

(34)

Eq. (34), together with (28) coupled with (32), or with (31) represents the
substance equations. They must be associated with the electromagnetic field
equation which we transcribe here

2E

2 2 E
c 2 t 2

= 0

2P
t 2

(35)

where c 2 = 1/0 0 , = /0 is the refraction index of the environment (without


the contribution of the transition between the two levels), P is the resonant part
of the induced polarization and two non-conductive and non-magnetic laser
environments were considered. In this case also, the energy losses produced by
different mechanisms will be considered phenomenologically by means of an
attenuation term introduced in the final form of the equation.
If we have a laser oscillator, the laser medium is placed between two
mirrors which form an open cavity, and the oscillations may be triggered only
by modes of oscillation characteristic to the cavity. They must satisfy the
Helmholtz equation
2U + k 2U = 0,

(36)

where k = c/c, c being the frequency of the considered mode (index c from
cavity). For simplification, in what follows, we consider =1 (gaseous
environment).
We suppose the oscillation is produced on a single mode described by a
spatial dependence of the form W(x, y, z). This dependence will characterize
both the field and polarization, so we can write

(t )W ( x, y, z )exp(i t ) + c.c.
E=E
c

(37)

P = P (t )W ( x, y, z )exp(ic t ) + c.c.

(38)

and

respectively, where E (t ) and P (t ) are slowly time-varying (complex)


amplitudes.
Since the vectors E and P have the same directions, we can neglect the
vectorial aspect. Introducing (37) and (38) in (35), applying the slowly varying

44

Drago Iancu et al.

amplitude approximation, i.e. taking d 2 E dt 2 0 , d 2 P dt 2 c P and having


in view that W(x, y, z) satisfies Eq. (36), we get

dE ic
=
P.
dt 2 0

(39)

It is necessary to include the loss by radiation which are due to, in the
first place, mirrors imperfections. We do that by introducing a term E in the
left hand side, so the field equation becomes

i
dE
+ E = c P .
dt
20

(40)

The equation for polarization is obtained comparing Eqs. (22) and (38).
It results

12 =

exp(i t )
PW
c
,
N a 12

12 =

1 dP
+ ic P W exp(ic t ),

N a 12 dt

(41)

which introduced in Eq. (32), and after multiplying both sides with W*exp(-ict)
and integrating over the entire volume (mode) of the cavity, leads to
i 2
dP
+ ( 12 + i(c 0 )) P = 12 EN
,
dt

(42)

where, in the left hand side, we introduced the first term from (37) and where N
represents the inversion of population from the volume occupied by the cavity
mode, defined by the relation

N=

N a ( 22 11 )W WdV

WdV

(43)

We then introduce the relations for the field and polarization (37) and
(38) into the equation for the inversion (34). Using the approximation P = ic P ,
neglecting the rapidly varying terms (which contain exp (2ict)), multiplying
by WW* and integrating over the volume of the cavity, we get
2iA0
N
+ 11 ( N N e ) =
( E P EP ),
t

(44)

Bul. Inst. Polit. Iai, t. LVIII (LXII), f. 1, 2012

45

where N is given by Eq. (43). We consider c/0 = 1, and note

A0 =

N a (W W )2 dV

WdV

(45)

Eqs. (40), (42) and (44) form the Bloch-Maxwell system and describe a
unimodal laser oscillator. If we make the change of variables

t=

i12
1
t , E =
A,
12
2 A0 12
(46)

212 0
12 0
P =
R, N N e =
n,
c 122
c A0 12
the Bloch-Maxwell equations gets the form of the Lorenz system. They become

dA
= A + R,
dt
dR
= rA R(1 + i) An,
dt

(47)

dn
1
= bn + 2 ( AR + A R),
dt
where the following notations were used

0
2 N e

, = c
, b = 11 , r = c 12 .
12
12
12
20 12

(48)

In the form (47) the equations make up a complex Lorenz system. This
was discussed in detail in the paper (Fowler et al., 1982). The complex Lorenz
system transforms into the well known real Lorenz system if the resonance is
~
~
exact (c = 0 = 0) and the phases of the amplitudes E and P are
chosen so the functions A and R to be real

46

Drago Iancu et al.

dA
= ( R A),
dt
dR
= A(r n) R,
dt

(49)

dn
= AR bn.
dt
The fact that a unimodal laser oscillator is described by the Lorenz
system was remarked for the first time by Haken (Haken, 1975). Therefore, it
was demonstrated that the imense variety of dynamical behaviors, including the
chaotic ones, presented by a Lorenz system, must be expected to occur in a
laser. Among the first who reported Lorenz type chaotic behaviors in a laser,
were Weiss and Brock (Weiss & Brock, 1986).
Equations of the same form are obtained also when one consideres a
travelling wave laser, such as laser amplificators where the wave passes only
one time the environment, or a circular unidirectional laser (Milonni et al.,
1987; Newell et al., 1992).
3.2. A Chaotic Multi-scale Cancer-invasion Model

From the nondimensional spatio-temporal model (6), discretization was


performed by neglecting all the spatial derivatives resulting in the following
simple 4D temporal dynamical system
dn
= 0,
dt
df
= mf ,
dt
dm
= n m,
dt

(50)

dc
= f n c.
dt

When simulated, the temporal system (50) with the set of parameters (7)
exhibits a virtually linear temporal behavior with almost no coupling between

Bul. Inst. Polit. Iai, t. LVIII (LXII), f. 1, 2012

47

the four concentrations that have very different quantitative values (all phase
plots between the four concentrations, not shown here, are virtually onedimensional). To see if a modified version of the system (50) could lead to a
chaotic description of tumor growth, and following the method in (Ivancevic et
al., 2008), four new parameters, a1, a2, a3, and a4 are introduced. The resulting
model is
dn
= 0,
dt
df
= a1( m f ),
dt
dm
= f ( a3 c ) m + a2 n,
dt

(51)

dc
= fm a4 c n.
dt

The introduction of the parameters (a1, a2, a3, a4) was motivated by the
fact that tumor cell shape represents a visual manifestation of an underlying
balance of forces and chemical reactions (Olive & Durand, 1994). Specifically,
the parameters represent the following quantities: a1 = tumor cell volume
(proliferation/non-proliferation fraction), a2 = glucose level, a3 = number of
tumor cells, a4 = diffusion from the surface (saturation level).
A tumor is composed of proliferating (P) and quiescent (or nonproliferating) (Q) cells. Tumor cells shift from class P to class Q as the tumor
grows in size (Kozusko & Bourdeau, 2007). Model dependence on the ratio of
proliferation to non-proliferation is introduced via the first parameter, a1. The
discretization of Eq. (6a) leads to cell density being modelled as a constant in
Eq. (51a). Accordingly, cell density does not play a role in the dynamics. In
(51) the cell density is re-introduced into the dynamics via the cell number, a3.
The importance of introducing a3 also appears in connection with the cyclindependent kinase (Cdk) inhibitor p27, the level and activity of which increase in
response to cell density. Levels and activity of Cdk inhibitor p27 also increase
with differentiation following loss of adhesion to the ECM (Chu et al., 2008).
The ability to estimate the growth pattern of an individual tumor cell type
on the basis of morphological measurements should have general applicability
in cellular investigations, cellgrowth kinetics, cell transformation and
morphogenesis (Castro et al., 2003).
Cell spreading alone is conducive to proliferation and increases in DNA
synthesis, indicating that cell morphology is a critical determinant of cell

48

Drago Iancu et al.

function, at least in the presence of optimal growth factors and extracellular


matrix (ECM) binding (Ingber, 1990). In many cells, the changes in
morphology can stimulate cell proliferation through integrin-mediated
signaling, indicating that cell shape may govern how individual cells will
respond to chemical signals (Boudreau & Jones, 1999).
Parameters (a1, a2, a3, a4), introduced in connection with cancer cells
morphology and dynamics could also influence the very important factor
chromatin associated with aggressive tumor phenotype and shorter patient
survival time.
For computations, the parameters were set to a1=0.06, a2=0.05, a3=26.5
and a4=40. Small variation of these chosen values would not affect the
qualitative behavior of the new temporal model (51). Simulations of (51), using
the same initial conditions and the same non-dimensional parameters as before,
show chaotic behavior in the form of Lorenz-like strange attractor in the 3D
(fmc) subspace of the full 4D (nfmc) phase-space (Figs. 1-4).

Fig. 1 A 3D Lorenz-like chaotic attractor from the modified tumor growth model (59
b-d). The attractor effectively couples the MMconcentration f, the MDE
concentration m, and the oxygen concentration c in a masklike fashion.

Bul. Inst. Polit. Iai, t. LVIII (LXII), f. 1, 2012

Fig. 2 The m f phase plot of the 3D attractor.

Fig. 3 The m c phase plot of the 3D attractor.

Fig. 4 The f c phase plot of the 3D attractor.

49

50

Drago Iancu et al.

The spatio-temporal system of rate PDEs corresponding to the system in


(6) provides the following multi-scale cancer invasion model
n
= d n 2 n ( nf ) ,
t
f
= a1(m f ),
t

(52)
m
= d m 2 m + a2 kn + f ( a3 c ) m,
t

c
= d c 2 c + fm n a4 c.
t

The new tumorgrowth model (52) retains all the qualities of the original
model (6) plus includes the temporal chaotic butterflyattractor. This chaotic
behavior may be a more realistic view on the tumor growth, including
stochasticlike longterm unpredictability and uncontrollability, as well as
sensitive dependence of a tumor growth on its initial conditions.
Now, if we compare (51) with (49) and make a one-to-one
correspondence between these two systems of equations, we see that A which is
the electric field amplitude corresponds to f, the MM concentration, R which is
the polarization amplitude corresponds to m, the MDE concentration and n the
inversion of population corresponds to c, the oxigen concentration. Since both
systems, the laser and the tumor invasion can be written in the form of a Lorenz
system, we can suppose that the metastatic cancer cells moving through the
systemic circulation form a coherent wave, i.e. a particular type of chemically
pumped (since it may obtain its energy from chemical reactions) laser with
oxygen. In the following section we show moreover, that this coherent wave can
be identified with a travelling wave laser with oxygen.
4. Travelling Waves in the Multiscale Diffusion
Cancer-invasion Model
Let us write the system (6) again. We assume the model studies the
averaged behaviour of the tumor cells in the direction of invasion only and
ignores variations in a plane perpendicular to the direction of invasion.

Bul. Inst. Polit. Iai, t. LVIII (LXII), f. 1, 2012

51

Invasive cells. Since in their experiments (Aznavoorian et al., 1990)


reported minimal chemokinetic movement, a key feature of the following model
is the absence of the term for random cell motility. Also, we introduce a term of
increased proliferation of malignant cells relative to normal cells, F(n), which
will be initially modeled as a logistic type growth of the form k1 n ( k2 n)
which has been shown (Vaidya & Alexandro Jr., 1982) to describe adequately
the growth of human tumours grown (Schwartz, 1961).
Extracellular matrix. Since extracellular matrix elements are much longer
than cells, their motility is negligible compared to the movement of the
malignant cells and the oxigen. We hence model the dynamics of connective
tissue as a simple passive degradation by the activity of the tissue proteases; we
describe this proteolysis by G(f, m), since it depends on the amount of collagen
f still present as well as the protease m.
Proteases. The production of proteases is tightly confined to the interface
between an invading tumour and the receding connective tissue. In some
instances it is possible to localise the interstitial collagenase production to the
stromal fibroblasts immediately adjacent to the site of tumour invasion, which
suggests that invasive cells release a stimulus for induction of interstitial
collagenase by fibroblasts. (Nabeshima et al., 1991) have characterised and
sequenced a tumour cell derived collagenase stimulatory factor. However, there
are other explanations for the production of the protease only at the invading
front. (Xie et al., 1994) have shown the density dependent induction of 92-kd
type IV collagenase activity in cultures of A431 human epidermoid carcinoma
cells. They showed that only dividing cells stained positive when treated with
anti-MMP antibodies and hence that only noncontact-inhibited tumour cells
produce protease. Many proteases are predominantly membrane bound (e.g.
uroplasminogen activator), but even when the protease is secreted into the
extracellular space, activation has been shown to occur only on the cell surface,
so that the behaviour closely resembles that for membrane bound proteases
(Werb, 1997). Thus we do not include protease diffusion in the model. We
introduce the function H(n, f) to represent the dependence of this tightly
regulated protease production on the local concentrations of the melanoma cells
and collagen. In addition we assume that the protease decays linearly, with halflife K.
Oxygen. As in the original model, we presuppose it diffuses into the MM,
decays naturally, is consumed by the tumour and for simplicity, oxygen
production is proportional to the MM density. Therefore, we introduce the
function I(n, f) and c decays linearly, with half-life . The parameter c does not
appear anywhere else in the system, so this equation will be easily separated.
Combining all of the above, we are now ready to write the model as

52

Drago Iancu et al.


haptotactic cell movement

n
=
t




f
k3 n
x x

invasive cell proliferation


F ( n)

proteolysis



f
= G ( f , m),
t

(53)

m
=
t

protease production




H ( n, f )

natural decay


Km

diffusion

production and uptake decay


c
2c
= dc 2 +
I ( f , n)
c ,
t
x

where F, G, H and I are functions of n, f and m. Compared to previous work on


the modelling of cell movement, this model is unusual in that there is no cellular
diffusion. This case has been considered previously (Rascle & Ziti, 1995) in the
very different context of cellular aggregation, where they obtained conditions
for blow-up in the absence of cell kinetics.
Before continuing with the model analysis, we eliminate m from the
equations as follows. The time scales associated with protease production and
protease decay are much shorter than a typical timescale for the invading cells.
Hence writing H (n, f ) = KH (n, f ) , where we assume K>>1, and multiplying
through Eq. (53 c) by the small parameter K1, we deduce that to leading order
m = H (n, f ) . Henceforth no reference to m is needed: this expression may be
used to eliminate m from Eqs. (53 a) and (53 b). In the same way, writing
I ( f , n) = I ( f , n) , assuming >> 1 and multiplying through Eq. (53 d) by the
small parameter 1, we deduce that to leading order c = I ( f , n) . This type of
quasi-steady state assumption is a common one in enzyme kinetics (Murray,
1990), and numerical simulations of the three equations (53 a)(53 d) compare
well with the simplified system of two equations; the great advantage of the two
equation case is that it is amenable to detailed mathematical analysis.
We examine the model using the simple functional forms

F (n) = k1n(k2 n),

G ( f , m) = k4 mf ,
(54)

H (n, f ) = k5 nf , I ( f , n) = k6 f k7 n.

Bul. Inst. Polit. Iai, t. LVIII (LXII), f. 1, 2012

53

4.1. Nondimensionalisation

After making the substitutions for F, G, H and I from (54) into equations
(53 a)(53 d) and eliminating m using m = H(n, f) and c using c = I(f, n) we
nondimensionalise the resulting equations using
12

k
n
f
t
x
n = , f = , t = , x = , L = 3 ,
n
f
T
L
k 2 k 4 k5
T=

k
1
, n = k2 , f = 1 .
k1k2
k 4 k5

Dropping tildes for notational convenience then gives rise to the system

n
f
= n(1 n) n ,
t
x x
(55)

f
= nf 2 .
t
4.2. Spatially Homogeneous System

Setting /x = 0 in (55 a) we remark that the spatially homogeneous


system has two steady states:
i) n = 0, f arbitrary this is a continuum of (unstable) steady states
parametrised by the (variable) amount of connective tissue in different tissues;
ii) n = 1, f = 0 this (stable) steady state corresponds to complete
replacement of the normal tissue by invading malignant cells.
With /x = 0, (55 a) and (55 b) can be solved explicitly giving
n(t ) = [1 + exp(t + c2 )] ,
1

(56)
f (t ) = [t c1 + log[1 + exp( t + c2 )]]1 ,

where c1 and c2 are arbitrary constants. The behaviour as t shows that n1


and f0, hence justifying our classification of the steady state (n, f) = (1, 0) as
stable.
4.3. Travelling Wave Analysis

Intuitively one expects the invasion process to correspond to travelling


wave solutions of the model (55 a) and (55 b) with the normal tissue steady

54

Drago Iancu et al.

state n = 0 ahead of the wave and the fully malignant state n = 1, f = 0 behind
the wave. This is confirmed by numerical solutions of (55 a) and (55 b), which
are not discussed here. Such travelling wave solutions can be studied
analytically using the travelling wave differential equations. We look for
constant shape travelling wavefront solutions of (55 a) and (55 b) by setting
n( x, t ) = N ( z ),

f ( x, t ) = F ( z ), z = x t ,

(57)

where is the positive wavespeed which has to be determined. When solutions


of the type (57) exist, they represent travelling waves moving in the positive x direction. Substitution of (57) into (55 a) and (55 b) followed by simple
algebraic manipulation gives

dN
2 NF 2

dz

2N 3F 3

N
(1
N
)
,
=

(58)

dF NF
=
.
dz

The analysis of (58 a) and (58 b) involves the study of the (N, F) phase
plane. Since we are looking for travelling waves connecting (1, 0) and (0, F ) in
the (N, F) phase plane we look for solutions of (58 a) and (58 b) with boundary
conditions

N ( ) = 1, F ( ) = 0, N () = 0, F ( ) = F ,

(59)

which requires (1, 0) to have an unstable manifold while (0, F ) must have a
stable manifold. In order to study this we look at the stability of the system (58
a) and (58 b).
4.4. Stability Analysis

The steady states (N0, F0) of (58 a) and (58 b) are (0, F ) and (1, 0),
where F represents a continuum of steady states. We study their stability by
looking at the eigenvalues of the stability matrix linearised about the steady
states. The eigenvalues about (0, F ) are 1/ and 0. The corresponding
eigenvectors are (1, F ) and (0, 1). The negative eigenvalue indicates that there
is a stable manifold along (1, F ) . The zero eigenvalue represents translations
along the continuum of steady states.

Bul. Inst. Polit. Iai, t. LVIII (LXII), f. 1, 2012

55

The eigenvalues about (1, 0) are 1/ and 0. The eigenvector


corresponding to 1/ is (1, 0) and represents movement along the N axis. The
eigenvector corresponding to the zero eigenvalue is (0, 1) which is in the
direction perpendicular to the N axis. Numerical solutions of (58 a) and (58 b)
show that the trajectory leaving this steady state leaves along the eigenvector
corresponding to the zero eigenvalue of the linearised system. This zero
eigenvalue comes from (58 b). In order to get a clearer picture of the behaviour
close to (1, 0) we look at the nonlinear terms in (58 b). One method to do this is
to use the techniques of centre manifold theory which shows that as z - ,
N(z) approaches 1 exponentially while F(z) tends zero as z1.
The existence of an unstable manifold about (0, F ) as z and a stable
centre manifold about (1, 0) as z is consistent with the existence of a
travelling wave orbit connecting the two steady states.

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UN NOU MODEL AL CARCINOGENEZEI I PROGRESIEI TUMORALE N


CADRUL DINAMICII NELINIARE (II)
(Rezumat)
Utiliznd un model standard de cretere a tumorilor solide, se realizeaz modelul
haotic de dezvoltare a cancerului la scale multiple n care atractorul Lorentz se regsete
ntre soluiile lui. Mai mult, ntruct teoria laserului poate fi exprimat n termenii unui
sistem Lorentz, se gsete o coresponden ntre modelul haotic de dezvoltare a
cancerului la scale multiple i laser. n acest ultim context, se arat c modelul standard
de cretere a tumorilor solide admite o soluie de tip und cltoare i se sugereaz c
celulele tumorale de tip metastatic care se deplaseaz prin intermediul sistemului
circulator, simulnd soluia mai sus amintit, se comport ca un laser de tip special
(laserul cu oxigen).

BULETINUL INSTITUTULUI POLITEHNIC DIN IAI


Publicat de
Universitatea Tehnic Gheorghe Asachi din Iai
Tomul LVIII (LXII), Fasc. 1, 2012
Secia
MATEMATIC. MECANIC TEORETIC. FIZIC

A NEW CARCINOGENESIS AND TUMOR


PROGRESSION MODEL IN THE FRAMEWORK
OF NON-LINEAR DYNAMICS (III)
BY

MARICEL AGOP1 and CLIN GHEORGHE BUZEA2


1

Gheorghe AsachiTechnical University of Iai


National Institute of Research and Development for Technical Physics, Iai

Received: December 28, 2011


Accepted for publication: January 15, 2011

Abstract. We present the extracellular matrix (ECM) and in particular, the


tumor microenvironment (TME) as being non-differential media endowed with
holographic properties (capacity to memorize, interference abilities and a source
of forces through the informational energy etc.). Moreover, we illustrate two
well known phenomena: tumor self-seeding by CTC (circulating cancer cells)
and hypoxia which in our opinion both support the ideea of complete holography
(a hologram which becomes the very object).
Keywords: carcinogenesis, tumor, fractal, travelling wave, holography.

1. Tumor-associated ECM or Tumor Microenvironment, Nonlinear


Medium with Holographic Properties
1.1. Extracellular Matrix and Tumor Microenvironment

Within tissue, cells are surrounded by a meshwork of proteins and


proteoglycans collectively called the extracellular matrix (ECM), which
compartmentalizes tissues. The ECM is divided into two distinct layers:
i) the basement membrane, which is composed of sheet-like layers of
ECM and lies under epithelial cells segregating tissues into functionally distinct
regions;

Corresponding author: e-mail: calinb2003@yahoo.com

60

Maricel Agop and Clin Gheorghe Buzea

ii) the interstitial matrix, which exists within intercellular space. The
ECM serves multiple functions that are critical for embryonic development and
wound repair. These functions include providing tissues with shape and
flexibility and acting as a cushion to absorb external pressure. The ECM also
serves as a base for cell anchorage, which mediates cell polarity, intercellular
signaling, and assists in migration. The key to the ECM function lies in its
unique composition and structure. The ECM is constructed in a specific pattern
that is critical to its ability to carry out these functions and alterations in the
expression level or arrangement of proteins within the ECM can be used to
manipulate its function.
The most obvious function of the ECM is to provide structural support,
shape, and stability for tissues. It does this by functioning as a base for cell
anchorage. This base consists of three main structural components collagen,
fibronectin, and elastic fibres, which bind to one another building a protein
lattice upon which cells adhere.
Cell adherence to the ECM lattice provides cells support needed for cell
migration. This is particularly important during embryonic development when
cells are required to migrate into surrounding regions and differentiate into
specific tissues (Svoboda et al., 2008). A less obvious yet possibly more
important function of the ECM in regards to tissue homeostasis and disease is
its ability to mediate intracellular signaling. The ECM affects signaling through
three main mechanisms:
i) cell ECM interaction;
ii) regulation of the bioavailability of growth factors;
iii) the function of matricellular proteins. Cell attachement to the ECM via
integrins induces signaling cascades that promote survival. Loss of cell-ECM
contact can result in a form of apoptosis termed anoikis (Giannoni et al., 2008).
Anchorage-dependent survival is observed in most cells with the exception of
red blood cells and inflammatory cells. However, tumor cells are often resistant
to anoikis and can survive without a physical attachment to the ECM allowing
them to successfully metastasize to distant tissues (Chiarugi & Giannoni, 2008).
The ECM also affects cellular activity by serving as a reservoir for
proteins required for propper tissue function and repair. This includes a plethora
of growth factors and proteases. These pleiotropic molecules have been shown
to robustly affect proliferation, survival and migration in numerous cell types.
Once growth factors are secreted from cells, they often become embeded within
the ECM and require ECM degradation by proteases such as elastase to release
the active protein allowing it to interact with surrounding and transduce
downstream signaling. The ability of the ECM to control the bioavailability of
growth factors provides another means of regulating cellular activities and
further explains how alterations in the makeup of the ECM as observed in
diseases such as cancer affect cell response.

Bul. Inst. Polit. Iai, t. LVIII (LXII), f. 1, 2012

61

Matricellular proteins also reside in the ECM. They are a unique family
of proteins that do not function as structural proteins but rather orchestrate the
deposition of the ECM and mediate cell-cell and cell-ECM interactions. To do
this, matricellular proteins interact directly with cell surface receptors, structural
proteins, growth factors and proteases found within the ECM (Framson & Sage,
2004). Their expression is found in every tissue, begins early in development,
persist throughout adulthood and is increased durring tissue remodeling events.
Matricellular proteins are critical regulators of many aspects of cell function
including differentiation, survival, proliferation and migration making them
necessary for proper tissue function. Not surprisingly, given their affect on cellECM mediated signaling pathways, matricellular proteins have been shown to
strongly influence tumor growth.
For tumor cells to metastasize, the local ECM must be remodeled to
create an environment conducive to tumor survival and progression. This
includes altering the architecture and compozition of the tumor-associated ECM
or tumor microenvironment (TME) to facilitate tumor cell dissemination (Pupa
et al., 2002). Changes in ECM architecture are primarely carried out by enzimes
such as MMPs which assist in remodeling of the TME by degrading structural
proteins such as colagen and fibronectin allowing tumor cells to freely navigate
through the surrounding ECM. MMPs and other proteases assist in destruction
of the first barrier tumor cells face to successful metastasis, the basement
membrane. They degrade the underlying basement membrane allowing tumor
cells to escape the primary tumor and invade into surrounding non-neoplasic
tissues. MMPs continue to breakdown barriers in the surrounding ECM clearing
a path to blood vessels where tumor cells will intravasate into the circulatory
system and seed secondary tumors (Hofmann et al., 2005). Destruction of the
ECM by proteases also promotes tumor progression by facilitating the release of
angiogenic and mitogenic factors bound within the ECM (von Kempen et al.,
2003). In a surprising unexpected twist, studies revealed that the breakdown of
ECM proteins by MMPs was more complex than anticipated. In fact it is a
highly organized process which results in the generation of both protumor and
antitumor cleavage products (Lopez-Otin et al., 2009).
Presence of the ECM is required for cellular survival therefore increased
degradation of the ECM within the TME must be balanced by an increase in
ECM synthesis. The development of a tumor, much like a wound, provokes a
robust inflammatory response causing an influx of mast cells, macrophages and
neutrophils into the TME (Wu & Zhou, 2009).
We may summarize that the extracellular matrix provides signalling cues
that regulate cell behaviour and orchestrate functions of cells in tissue formation
and homeostasis. The composition of the ECM, its three-dimensional
organization and proteolytic remodelling are major determinants of the
microenvironmental signalling context that controls cell shape, motility, growth,
survival and differentiation. In recent years, the importance of ECM signalling

62

Maricel Agop and Clin Gheorghe Buzea

has been underscored by the evidence that misregulation of cellECM


interactions can contribute to many diseases, including developmental, immune,
haemostasis, degenerative and malignant disorders.
Consequently, the structure and the behavior of the tumor-associated
ECM allows us to think of it as a non-differential medium, and as will be shown
in what follows, a medium which holds the properties of a hologram (capacity
to memorize, interference abilities) and may become a source of forces. In other
words, ECM and TME are very suitable candidates for a recording material.
2. Tumor-associated ECM as a Non-differential Medium has the
Capacity to Memorize
Let us assume that motion on TME takes place on continuous but nondifferentiable curves, i.e. fractal curves of fractal dimension D F . The dynamics
of such system is described by the complex operator (Agop et al., 2008; Agop
et al., 2010; Agop et al., 2010),


( 2 ) 1
= +V
iD (dt ) D ,
t t
F

(1)

where

= V iU.
V

(2)

The real part V of the complex speed field V represents the standard classical
speed, which is differentiable and independent of the resolution, dt , while the
imaginary part U is a new quantity arising from fractality, which is nondifferentiable and resolution-dependent. The quantity D is the Nottales
coefficient and corresponds to the transition fractal non-fractal (Agop et al.,
2008; Agop et al., 2010; Agop et al., 2010).
We are now able to write the equation of geodesics (a generalization of
the first Newtons principle) in the form,
V

V
)V
iD (dt )( 2 D ) 1 V
= 0.
=
+ (V
t
t
F

(3)

This means that the global complex acceleration field, V t , depends on the
, on the non-linearity (convective) term,
local complex acceleration field, t V
)V
, and on the dissipative one, V . Moreover, the behavior of a fractal
(V
fluid is of viscoelastic or of hysteretic type which means that the fractal fluid
has memory. Such a result is in agreement with the opinion given in (Agop et
al., 2010; Agop et al., 2008): the fractal fluid can be described by Kelvin-

Bul. Inst. Polit. Iai, t. LVIII (LXII), f. 1, 2012

63

Voight or Maxwell rheological model with the aid of complex quantities e.g. the
complex speed field, the complex acceleration field etc.
3. Tumor-associated ECM as a Non-differential Medium has
Interference Abilities
The Eq. (1) is a Navier-Stokes type equation with an imaginary viscosity
coefficient

0 = iD(dt )( 2/ D

) 1

(4)

= 0 , we can choose
If the motions of the fractal fluid are irrotational, i.e. V
of the form
V
= 2iD (dt )
V
ln ,
(5)
( 2/ DF ) 1

with the scalar potential of the complex speed.


For = eiS , with the amplitude and S the phase of , the
complex speed field (2), using (5) takes the explicit form

= 2 D(dt )(2/ DF ) 1 S iD(dt ) ( 2/ DF )1 ln ,


V
V = 2 D(dt )(2/ DF ) 1 S ,
(6)

U = D(dt )(2/ DF ) 1 ln .

By substituting (6) in (3) and separating the real and the imaginary parts, up to
an arbitrary phase factor which may be set zero by a suitable choice of the phase
of , we obtain

m0
+ (V )V = -Q,
t

(7)

+ ( V) = 0,
t
with Q the fractal potential,
Q = 2m0 D 2 (dt ) ( 4/ D

)2

m0 U
m0 D (dt ) ( 2/ D
2

) 1

(8)

64

Maricel Agop and Clin Gheorghe Buzea

and m 0 the rest mass of the fractal fluid particle. Eq.(7a) is the momentum
conservation law, Eq. (7b) is the density conservation law, and they define
together a fractal hydrodynamics (FHD).
In the one-dimensional case, using the substitutions
t = , kx = ,

v
=V,
v0

k 3D2
= N , 2 =
(dt ) D
0
v0

(9)
,

the equation system (7) takes the form


V
V
2 2 2
+V
=
t
N 2

N ,

(10)
N ( NV )
+
= 0.
t

Using the method from (Agop et al., 2010) with the initial conditions

V ( 0 , = 0) = c,
N ( 0 , = 0) =

0 2
exp
= N 0 ( 0 ),

(11)

and the boundary conditions

V ( 0 = c , ) = c,
N ( 0 = , ) = N ( 0 = +, ) = 0,

(12)

the solution of the system (10) takes the form


2

2
c + ( 0 )

V ( 0 , ) =
,
2
2 2
2
+

2

2
( 0 c )
1
exp
,
N ( 0 , ) =
2 2 2 2
2 2 2 2
+

+

(13)

Bul. Inst. Polit. Iai, t. LVIII (LXII), f. 1, 2012

65

where is the distribution parameter. These solutions induce the complex


speed field
2

2
c 2 +
( 0 )
0 c

,
2i
V ( 0 , ) =
2
2
2 2
2 2
2
2
+
+



(14)

the complex current density speed field


2

2
c 2 + ( 0 )

2
( 0 c )

j ( 0 , ) =
exp
,
3/
2
2 2 2 2
2 2 2 2
+
+

2
( 0 c )
0 c
2i
exp
,
3/ 2
2
2 2 2 2
2 2 2
+
+

(15)

the complex specific potential

Q ( 0 , ) = 0 2i 2

( 0 , c ) 2
2 2 2 2
+

+ 2i 2

1
2

2
+ 2

(16)

and the complex force field


2

2 2
F ( 0 , ) = 0 + 4i ( 0 c ) 2 +
.

(17)

In Figs. (1 a-g) the dependencies of N ( 0 , ) - a), ReV ( 0 , ) - b),


ImV ( 0 , ) - c), Re j ( 0 , ) - d), Im j ( 0 , ) - e), Im Q ( 0 , ) - f)
and Im F ( , ) vs. ( ) and are given.
0

66

Maricel Agop and Clin Gheorghe Buzea


b)

a)

ReV

N
1
0.75
0.5
0.25
0
-10
10

10
5
0

-5

10
5

-10
10

-5

5
2.5
0
-2.5

-5

10 -10

c)

5
10 -10

d)

ImV

-5

Re J

10
5
0
-5
-10
-10
10

-5

1
100.75
0.5
5
0.25
0
-10
10

10
5
0
-5

5
10 -10

e)

-5

-5

5
10 -10

f)

Im J

0.4
0.2
0
-0.2
-0.4
-10
10

10 0
-25
5
-50
-75

10
5

-5
-5

-10
10
-5

g)

5
10

-10

-5

5
10

-10

10
5
0
-5
-10
-10
10

10
5
0
-5
-5

5
10 -10

Fig.1 The dependencies of N ( 0 , ) -a), Re V ( 0 , ) -b), Im V ( 0 , ) -c),

Re j ( 0 , ) - d), Im j ( 0 , ) - e), ImQ ( 0 , ) -f) and Im F ( 0 , ) -g) vs.


( 0 ) and .

These specify the followings:

Bul. Inst. Polit. Iai, t. LVIII (LXII), f. 1, 2012

67

i) the force field, F ( 0 , ) , imposes fractal characteristics to the global


dynamics of the system. Consequently, the complex speed and the complex
current density fields are non-homogenous in the coordinates 0 and ;
ii) the predictable (observable) global dynamics, for example of linear
uniform motion form, are obtained by making zero the force field, F ( 0 , ) .
In this case, the complex speed field takes the simple form
V ( = c , ) c + i0.
(18)
0

This means that the particle of fluid in free motion polarizes the fractal
medium behind himself, 0 c , and ahead of itself, 0 c , in such a
form that the resulting forces are symmetrically distributed with respect to the
plane through the observable particle position, 0 = c at any time - see
the symmetry of the curves in Figs. (1 a-g). In such context, the presence of a
perturbation e.g. one given by a laser beam, induces an asymmetry of the
force field, having as an effect the excitation of a specific mode of structuring
matter.
The solution (13 b) corresponds to the density of time-dependent Gaussian
scalar potential speed packet associated to a free particle, having the scalar
potential speed function,

[ ( ) c ]2
1
0

exp
( 0 , ) =

2 2 1 + i 2
1/ 4

+i

(19)

c2
c ( 0 )
exp i
+i
.
2
4
Moreover, through Eq. (13b), the phase, S, of this scalar potential speed
function is connected with the real part (observable ) of complex velocity field.
Now, let us assume the particle interaction with an external potential
(which can be approximately modeled, for example, by an infinite square-well
potential), resulting in a discontinuous change in momentum. Localized timedependent solutions for this problem, i.e. bouncing scalar potential speed
packets, can be constructed in a very straightforward way from solutions of the
free-particle problem (Agop et al., 2010). With 0 = 0 the wall position, the
simple difference solutions of the form ( 0 , ) (( 0 ), ) not only
satisfy the free-particle Schrdinger equation or the equivalent form (given by
the system of Eq. (7) of the fractal hydrodynamics) for all ( 0 ) values (if
( 0 , ) does), but also accommodate the new boundary condition at the
wall, namely that (0, ) = 0 . Then, the probability density is

68

Maricel Agop and Clin Gheorghe Buzea


2

N R ( 0 , ) = ( 0 , ) (( 0 ), ) =
= N + ( 0 , ) + N ( 0 , )

2 N + ( 0 , ) N ( 0 , ) cos

N + ( 0 , ) = N ( 0 , ) ,

where

(20)

2 2

2
0 c

,

2
2
2

N ( 0 , ) = N (( 0 ), )

and

N ( 0 , ) are given by Eq. (13b). The result (20) is equivalent with the
interference of a progressive scalar potential speed packet (for > 0 ) with a
regressive one (for < 0 ) see Figs. (2 a-c).
~
b) c = 7
a) c = 5
1

1
0.5
0.75
0.5
0.4
0.25
0
0.3

0.75
0.5
0.25
0
-4

0.5
0.4
0.3
-4

0.2
-2

0.2
-2

0.1

0.1

Regressive scalar
potential speed packet
4

c) c = 9

N ( 0 , )

Progressive scalar
potential speed
-0

0.5

0.75
0.5
0.25
0

0.4
0.3
-4

0.2
-2
0

0.1
2
4

Fig. 2 Progressive scalar potential speed packet ( > 0 ), and a regressive one ( < 0 )
for various values of normalized speed, c.

The interference term from Eq. (20) gives local maxima and minima see
Figs. (3 a-c) and Figs. (4 a-c). Their space-time positions depend on the initial
velocity c . From Figs. (3 a-c) and (4 a-c) it results that the multi-peak structure
can be observed both for the spatial component and for the temporal one, but in
the last case only for << 2 Figs. (4 a-c).

Bul. Inst. Polit. Iai, t. LVIII (LXII), f. 1, 2012

a)

c~ = 5

b)

1.5

69

c~ = 7

1.5
0.5

0.4

0.5
0

0.5

0.4

0.5
0

0.3
-4

0.3
-4

0.2

0.2

-2

-2
0

0.1
2

2
4

N R ( 0 , )

0.1
4

c)

c~ = 9

2
1.5

0.5

1
0.4
0.5
0

0.3
-4

0.2
-2

-0

0.1
2
4

Fig. 3 Spatial interference of a progressive scalar potential speed packet with a


regressive one for various values of normalized speed, c.

4. Tumor-associated ECM as a Non-differential Medium Makes the


Fractal Medium to Become a Source of Forces
The informational energy of a distribution is defined through the known
relation (Mazilu et al., 1994),

E = ln dx,

(21)

where (x) is the density of distributions, and we note by x, on the whole, the
random variables of the problem, dx being the elementary measure of their field.
This functional represents a measure of the uncertainty degree, when
defining the probabilities, i.e. it is positive, it increases when uncertainty also
incresases taken in the sense of expanding distribution and it is additive for
sources that are independent as compared to uncertainity. If we admit the
maximum of informational energy in the inference against probabilities, having
at our disposal only a partial piece of information this is equivalent to frankly
admitting the fact that we cannot know more. Through this, the distributions
that we obtain must be at least displaced, as compared to the real ones, because
there is no restrictive hypothesis regarding the lack of information. In other

70

Maricel Agop and Clin Gheorghe Buzea

words, such a distribution can be accomplished in the highest number of


possible ways. The partial piece of information we have at our disposal, is
given, in most cases, in the form of the average of an f(x) function or of more
functions
f =
a)

( x) f ( x)dx.

c~ = 0.1

b)

0.5

(22)

c~ = 0.2

0.5
10
0.25
0
8
-0.25
6
-0.5
0

0
-0.5
0
4

0.2

10
8
6
4

0.2

0.4

0.4
2

0.6

0.6
0.8
1

N R ( 0 , )

0.8

c) c = 0.3

0.5
0.25
0
-0.25
-0.5
0

10
8
6
4

0.2
0.4

-0

0.6
0.8
1

Fig. 4 Temporal interference of a progressive scalar potential speed packet with a


regressive one for various values of normalized speed, c.

Relation (2), together with the standard relation of distribution density

( x)dx = 1,

(23)

are now constraints the variation of the functional (21) has to subject to, in order
to offer the distribution density corresponding to the maximum of informational
energy. In this concrete case, Lagranges non determined multipliers method
directly leads to the well known exponential distribution
( x ) = exp( x f ( x )).

(24)

Let us notice that through the fractal component of the complex scalar
potential of the speed field
= D ln .

(25)

Bul. Inst. Polit. Iai, t. LVIII (LXII), f. 1, 2012

71

Eq. (21), ignoring the scale factor D, is identical with the average mean of (25)

E=

= ln dx.
D

(26)

In the particular case of a radial symmetry, imposing the constraints

( r ) rdr ,

(27)

(r )dr 1,

(28)

r=

the distribution density (r) through the maximum of informational energy


implies the expression
( r ) = exp( r ), , = const.

(29)

or in notations

exp( ) 0 ,

2
,
a

2r
( r ) = 0 exp .
a

(30)

(31)

Then the fractal speed


u=D

d
2D
(ln ) =
= const.
dr
a

(32)

through the fractal potential

Q=
=

m0u 2
2 d
d2

m0 D 2 2 (ln ) +
(ln ) =
r dr
2
dr

2m0 D 2 1 2
,
a a r

(33)

implies the fractal field of central forces

4m D 2
dQ
(34)
= 02 .
dr
ar
Consequently, the fractal medium by maximization of the
informational energy becomes a source of central forces (Ibnescu et al., 2006;
Ibnescu et al., 2006).
F (r ) =

72

Maricel Agop and Clin Gheorghe Buzea

Moreover, the maximum informational energy principle may be put into


a one-to-one correspondence with the H theorem of Boltzmann which states
dH
=
dt

( x, t ) ln ( x, t )dx 0.

(35)

In other words, we know that real processes (and in particular the


biological ones) are ireversible as opposed to the ideal ones which are
reversible. In such a context, accepting the fact that maximum informational
energy principle is correlated to the time ireversibility, one allows a clear
difference between inert matter and biological or living matter: for inert matter
the activation of the hologram results in getting a virtual image, yet for the
biological matter the hologram becomes the very object.
5. Tumor Self-seeding by CTC and Hypoxia Support the Ideea of
Complete Holography
5.1. The Self-seeding Hypothesis of Tumor Growth

The spread of cancer cells from their original location to other sites in the
body, known as metastasis, has long been thought of as a one-way journey. But
some researchers also believe that metastatic cancer cells can fuel primary
tumor growth, with potentially important implications for the timing and nature
of cancer treatment.
The concept of tumor self-metastasis, or tumor self-seeding, originated
at Memorial Sloan-Kettering Cancer Center, based on a series of studies led by
Drs. Joan Massagu, head of the Metastasis Research Center, and Larry Norton,
deputy physician-in-chief of the centers breast cancer programs. In studies of
mice, Dr. Massagu observed that breast tumors expressing genes associated
with metastasis were growing faster than tumors that did not express these
genes, even though the genes had no apparent role in increased cell division or
decreased cell death (Fig. 5). These results did not fit in with the standard
theories of tumor growth. In 2006, the two researchers proposed that cells which
break free from a tumor and colonize distant tissues may also return home via
the circulatory system to the welcoming microenvironment in which they first
developed (Norton, 2006). The two researchers tested their hypothesis in a
mouse model of cancer and published their results in 2009 in Cell (Kim et al.,
2009).

Bul. Inst. Polit. Iai, t. LVIII (LXII), f. 1, 2012

73

Fig. 5 In the self-seeding concept of cancer growth and metastasis, a mobile tumor
cell can take one of five different pathways in the body. A evade and return to the
primary tumor, using only the close ECM and not the systemic circulation; B escape
into the systemic circulation and then return to the original tumor; C migrate through
the systemic circulation and grow a metastatic tumor elsewhere in the organism; D
evade and return to the metastatic tumor, not using the systemic circulation; E escape
and return to the metastatic tumor through the systemic circulation.

For one experiment, they chose a non-metastatic breast cancer cell line
and an isolated set of daughter cells from that line that had gained the ability
over time to metastasize to the lungs. When the researchers implanted the parent
cells in one mammary gland and the metastatic daughter cells in the opposite
gland to serve as donor tumors, the daughter cells migrated to the lungs and to
the tumors that were being formed by the parent cells in the opposite gland,
accounting for 5 to 30 percent of the eventual size of the parent tumors. Parent
tumors seeded by daughter cells grew faster than parent tumors that were
implanted alone without daughter cells in the opposite gland.
The researchers observed this same seeding behavior with daughter cells
that metastasize to the bones and brain, and with colon cancer and melanoma
cell lines, but they did not see the effect when they transplanted daughter cells
that were not metastatic.
In a set of follow-up experiments performed in the laboratory, the
researchers showed that cells from primary tumors can attract circulating
metastatic tumor cells, and they identified several proteins that likely encourage
this migration. They also found that the returning metastatic cells promoted
primary tumor growth by releasing proteins that change the tumor
microenvironment, including blood vessels and immune cells.

74

Maricel Agop and Clin Gheorghe Buzea

Their hypothesis began to get support from other researchers who were
testing it in their own laboratories. In 2009, Dr. Philip Hahnfeldt and his
colleagues published the results of computer modeling studies designed to look
at the intersection of two biological phenomena found in tumors (Enderling et
al., 2009). One of these phenomena is that a small population of cancer cells
may act like stem cells; they may have the ability to reproduce an infinite
number of times, creating more cells like themselves with the capability for
endless proliferation but also producing daughter cancer cells that eventually
lose the ability to divide. The second phenomenon is that tumor growth is
limited by the space available for expansion. Normally, healthy cells have an
amount of space between them that is not available in a tumor. Cancer cells
grow tightly together in a dense mass until all available space has been
occupied, at which point cell division stops. But at the edges of the tumor,
where the normal tissues are less dense, cancer cells continue to multiply and
push outward, expanding the tumor size.
Their models showed an important and counterintuitive relation
between cell migration, cell death, and tumor growth. When the progeny of a
cancer stem cell in the model did not migrate or die spontaneously, tumor
growth stagnated at around 110 cells. In contrast, a combination of high death
rate among the non-stem cell progeny and a high cell migration rate produced
the largest tumors in the shortest amount of time, to almost 100,000 cells in just
over 3 years.
This theoretical phenomenon accelerated tumor growth jump-started by
a high rate of tumor cell death has potential implications for the clinical
treatment of cancer. Traditional cytotoxic chemotherapy drugs kill large
numbers of rapidly dividing cancer cells, but may not affect cancer stem cells in
every tumor type. Currently, no anticancer drugs exist that specifically interfere
with the process of metastasis, though researchers are actively working on
understanding the genetic changes that drive a cancer cells ability to break
away from a tumor and survive in the blood stream, in the hopes of making
metastasis a valid therapeutic target.
In the light of the above, we think of the CTC returning to the initial
tumor site and fueling the primary tumor growth or even grow a new tumor as a
particular case of complete holography (i.e. a hologram which does not
represent only the virtual objects image, but becomes the very object - which
we believe, is a characteristic of the living organisms).
5.2. Hypoxia and Cancer

Hypoxia triggers a multitude of cellular processes, including an adaptive


response, and is defined as an oxygen level lower than the approximate 7%
observed in normal and well-vascularised tissues (Vaupel et al., 2001; Vaupel,
2004). When the oxygen supply is diminished, cells need to adapt to the harsh

Bul. Inst. Polit. Iai, t. LVIII (LXII), f. 1, 2012

75

environment as well as initiate the vascularisation process that will increase the
local oxygen supply. Central in the hypoxic response is the angiogenic shift,
with production of potent angiogenic factors such as vascular endothelial
growth factor (VEGF). Hypoxia is present in many solid malignancies, and the
mean oxygen level in tumours corresponds to approximately 1.5% (Vaupel et
al., 2001). This is partly due to the abnormal vascularisation in tumours, which
is insufficient in supplying oxygen to the sometimes rapidly expanding
malignant lesion. Besides the generally impaired oxygen supply, there are also
areas with an acute lack of oxygen, resulting in necroses and widespread cell
death. In breast cancer these types of necrotic processes are often associated
with clinically aggressive behaviour. Markers for hypoxia such as HIF-1a have
also been linked to highly malignant features and are potentially relevant
prognostic markers for identifying subgroups of breast cancer with certain
malignant properties (Harris, 2002; Kimbro & Simons, 2006). There is an
ongoing debate whether hypoxia contributes to more aggressive tumours or if
aggressive tumours have more widespread hypoxia, and seemingly one
explanation does not necessarily exclude the other. Recent research focusing on
hypoxic responses and delineation of important regulators of hypoxia has
clearly indicated that the hypoxia response in tumours can be used to define
novel treatment strategies (ODonnell et al., 2006). The future arsenal of novel
cancer therapies will most certainly include specific targeting of hypoxic
processes.
Human cancers are characterized by intratumoral hypoxia that results
from dysregulated cell proliferation. Physiological responses triggered by
hypoxia impact on all critical aspects of cancer progression, including
immortalization,
transformation,
differentiation,
genetic
instability,
angiogenesis, metabolic adaptation, autocrine growth factor signaling, invasion,
metastasis, and resistance to therapy.
We assume the relationship between hypoxia and aggressive tumors may
be due to the presence of the coherent wave laser with oxygen of metastatic
tumor cells in the area, where the produced oxygen gradients lead to oxygen
consumption. It has been already shown that laser photocoagulation is effective
in the treatment of diabetic retinopathy, in a series of major studies (Lovestam
et al., 2000; McCarty et al., 2000; Fong et al., 1999; Dogru et al., 1999). The
oxygen-consumption may be based on a multilayer solution to Ficks law of
diffusion, yet the essence is that the oxygen consumption is greatest where the
oxygen gradient changes most rapidly (Yu et al., 2005; Cringle et al., 2002;
Cringle et al., 2002).
All the above considerations and hypoxias impact on all critical aspects
of cancer progression support the ideea that, the metastatic tumor cells moving
through the systemic circulation (and not necessarily inthere), may be
considered a travelling wave chemically pumped type laser with oxygen.

76

Maricel Agop and Clin Gheorghe Buzea

6. General
1. Cancer does not conform to simple mathematical principles. Its
irregular mode of carcinogenesis, erratic tumor growth, variable response to
tumoricidal agents, and poorly understood metastatic patterns constitute highly
variable clinical behavior. Defining this process requires an accurate
understanding of the interactions between tumor cells and host tissues and
ultimately determines prognosis. Applying time-tested and evolving
mathematical methods to oncology may provide new tools with inherent
advantages for the description of tumor behavior, selection of therapeutic
modes, prediction of metastatic patterns, and providing an inclusive basis for
prognostication. Mathematicians describe equations that define tumor growth
and behavior, whereas surgeons actively deal with biological processes.
Mathematics in oncology applies these principles to clinical settings.
2. The main conclusions of this paper are as follows:
i) mathematics of cancer proves to be chaotic and highly non-linear,
justifying the use of space(-time) non-differentiability as a starting base model;
ii) a chaotic multi-scale cancer-invasion model is manufactured, which
embeds a Lorenz attractor in its solutions;
iii) since laser can be expressed as a Lorenz system, we may assume
some correspondences between the laser and the above mentioned chaotic
multi-scale cancer-invasion model;
iv) the basic model for solid tumor growth admits a travelling wave
solution;
v) we suggest that metastatic tumor cells which move through the
systemic circulation are similar to a coherent wave, i.e. a travelling wave
chemically pumped type laser with oxygen;
vi) we assume the extracellular matrix and in particular, the tumor
microenvironment are non-differential media endowed with holographic
properties (capacity to memorize, interference abilities and source of forces);
vii) the two well known phenomena: tumor self-seeding by CTC and
hypoxia, in our opinion, both support the ideea of complete holography (a
hologram which becomes the very object in the particular case of living
organisms).
3. Experimentally testable, mathematics applied in oncology may provide
a framework to determine clinical outcome on a patient-specific basis and
increase the growing awareness that mathematical models help simplify
seemingly complex and random tumor behavior.
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UN NOU MODEL AL CARCINOGENEZEI I PROGRESIEI TUMORALE N
CADRUL DINAMICII NELINIARE (III)
(Rezumat)
Se arat c matricea extracelular i n particular micromediul tumoral se
comport ca un mediu fractal ce prezint proprieti holografice, capacitate de
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trag concluziile generale asupra modelului.

BULETINUL INSTITUTULUI POLITEHNIC DIN IAI


Publicat de
Universitatea Tehnic Gheorghe Asachi din Iai
Tomul LVIII (LXII), Fasc. 1, 2012
Secia
MATEMATIC. MECANIC TEORETIC. FIZIC

STUDY ON SURFACE ENERGY OF POLYPROPILENE


UV-PHOTO-GRAFTED WITH GLUCOSE
BY

CRISTINA-DELIA NECHIFOR1,2 and SEBASTIAN POPESCU1


1

"AL. I. Cuza" University of Iai,


Gheorghe Asachi" Technical University of Iai,

2"

Received: November 28, 2011


Accepted for publication: December 5, 2011

Abstract. In this study we analyzed how the surface energy parameters of


polypropylene membranes are modified when different method for UV grafting
were applied. Commercial Polypropylene (PP) membranes with thickness = 80
m were UV-photo-grafted with Glucose using an Hg vapour lamp HBO-200, at
room temperature, in the presence of air. Three different preparation methods
were applied for PP surface photo-grafting. Method I: UV irradiation of the
membrane immersed in a homogeneous mixture of monomer/template solution,
for 15, 30 and 60 minutes. Method II: The PP membranes are UV irradiated for
15, 30 and 60 minutes, than immersed for 24 hours in monomer/template
solution. Method III: the polymeric films were first immersed in
monomer/template solution for 24 hours than UV irradiated for the same time.
The solution monomer/template consists in: 2mM Acrylamide (Aam), 80mM
N , N , -Methylenebisacrylamide (MBAAm), 2mM Glucose and water. All the
membranes were cleaned with distilled water and ethanol and dried at 40 oC
before the UV photo- grafting. Surface energy of the polymeric membranes was
evaluated and some important parameters were followed: contact angle for water
and ethanol, critical surface tension, surface polarity, work of adhesion, work of
spreading, wetting tension and contributions of non-polar and polar forces to the
surface free energy. All the parameters which characterize the surface energy of
UV- grafted PP membranes with glucose are strong dependent by the
preparation method. According to these experimental results we can say that the
best parameters are accomplished for the method I and III in order to use these
polymeric membranes in biomedical field.

Corresponding author: email: cristina.nechifor@tuiasi.ro

80

Cristina-Delia Nechifor and Sebastian Popescu

Key words: Surface energy, UV-photo grafting, monomer/template


solution, contact angle, critical surface tension, surface polarity.

1. Introduction
Modification of polymers has received greater attention in light of the
scarcity of starting materials required for the synthesis of new monomers to
deliver better polymeric materials (Bhattacharya et al., 2009). Modification is
essential to meet various challenges, as it is very difficult to get new polymers
(Gupta et al., 2003). Surface and bulk properties can be improved easily by
modifying conventional polymers (Kato et al., 2003). The grafting method is
extremely attractive as the modified biomaterial is obtained in the purest form
possible (Ulbricht, 2006). The grafting is applicable to almost all polymermonomer combinations with enormous possibilities of physico-chemical and
biological characteristics both on the surface and in the bulk matrix (Kato K. et
al. 2003). The degree of grafting may be easily controlled by the careful
variation of the radiation exposure (Gupta B. et al., 2003). Although there are
different ways to synthesize graft copolymers, radiation methods have become
the most versatile in terms of the physico-chemical behavior of the modified
materials (Ulbricht, 2006). These methods provide materials with high level of
purity; they are surface-selective or may lead to the bulk modification of the
matrix as well (Gao et al., 2005). The modification involves treatment of the
polymer surface with UV radiation to activate the surface or the bulk,
respectively. This activated surface is subsequently treated with a polymerizable
monomer under appropriate conditions so that the monomer is grafted on the
polymer (Praschak et al., 1998).
Grafting has several advantages: (1) the ability to modify the polymer
surface to have very distinct properties through the choice of different
monomers, (2) the ease and controllable introduction of graft chains with a high
density and exact localization of graft chains to the surface with the bulk
properties unchanged, and (3) covalent attachments of graft chains onto a
polymer surface assuring long-term chemical stability of introduced chains, in
contrast to physically coated polymer chains (Ulbricht, 2006; Praschak et al.,
1998; Gopal et al., 2007).
UV irradiation method: UV radiation interacts with the substance in the
primary stages by the mechanism of excitation of its atoms and molecules.
Exposure of polymers to ultraviolet radiation can lead to extensive physical and
chemical modification of polymeric materials (Jiangxi, 2008; Safrany, 2002).
These changes in properties may have both detrimental and beneficial
consequences in determining the end uses of polymer. It is beneficial in the
sense that it can cause cross-linking and grafting on the surface of the polymers
but on the other hand it may cause chain scission (breaking of bond) as well,
thus damaging the polymer (Gopal et al., 2007).

Bul. Inst. Polit. Iai, t. LVIII (LXII), f. 1, 2012

81

Absorption of energy radiation by polymers induces excitation and


ionization and these excited and ionized species are the initial chemical
reactants for graft polymerization. The ejected electron must lose energy until it
reaches thermal stability. The resulting species can further react to give free
radicals, which can cause monomers to polymerize and polymers to crosslink
and degrade and, in mixtures, monomers to graft to polymers (Ulbricht, 2006;
Praschak et al., 1998; Gopal et al., 2007; He et al., 2009 ). The primary reactive
species involved in the radiation chemistry of macromolecules is the free
radical. Free radicals are species having an unpaired electron, which results
from cleavage of a chemical bond (He et al., 2009 ). The electronic excitation or
removal of valence electrons can result in the formation of free radicals that
may readily cross-link the polymer chains thereby increasing the molecular
weight, hardness, and wear resistance (Gopal et al., 2007). The displacement of
target atoms by energetic collisions can cause permanent damage in the polymer
through chain scission by displacing atoms from polymer chains. This results in
a deduction of average molecular weight (Cao et al., 1998; Waldman et. al.,
2008 ).
Oxidizing and nonoxidizing conditions play a very important part in
surface modification. When oxygen is present it reacts very rapidly with
radicals produced by irradiation. As a result, the free-radical reaction pathways
and the molecular reaction products are dominated by oxidation chemistry and
these differences are reflected in the physical property changes (RomeroSancheza et. al., 2005; Lisboa et. al., 2006; Rou et al., 2009).
Fig. 1 illustrates the radiation-induced grafting on a polymer surface that
was later used to immobilize drugs for further application. The hydrophobic
polymer is made hydrophilic via radiation-induced grafting. This hydrophilic
surface has functional sites capable of binding chemically to enzymes or
bioactive compounds (Jiangxi, 2008, Safrany, 2002, Cao et al., 1998, Rou et.
al., 2009).

Fig. 1 The Radiation-induced grafting on polymer surface.

2. Experimental
Commercial Polypropylene (PP) membranes with thickness = 80 m
were purchase from SC CEPROINV SA. The monomer used was acrylamide

82

Cristina-Delia Nechifor and Sebastian Popescu

(AAm), the crosslinking agent was N , N , -Methylenebisacrylamide (MBAAm),


and the template was Glucose purchased from Aldrich Chemical Co. The
solvent was distilled water obtained from Chemical Company (Romania).
Samples were irradiated with an Hg vapor lamp HBO-200, at room temperature,
in the presence of air, and the distance between the sample and lamp was 20 cm.
Three different preparation methods were applied for PP surface photografting. Method I: UV irradiation of the membrane immersed in a
homogeneous mixture of monomer/template solution, for 15, 30 and 60
minutes. Method II: The PP membranes are UV irradiated for 15, 30 and 60
minutes, than immersed for 24 hours in monomer/template solution. Method III:
the polymeric films were first immersed in monomer/template solution for 24
hours than UV irradiated for 15, 30 and 60 minutes. The membranes were dried
in oven at 37 oC. The solution monomer/template consists in: 2mM AAm,
80mM MBAAm, 2mM Glucose and water. All the membranes were cleaned
with distilled water and ethanol and dried at 40 oC before the UV photografting. The contact angles of the samples were evaluated with KSV CAM 101
(Instruments Ltd., U.S.), using the sessile drop technique with water and
ethanol.
The Sessile Drop Technique is a method used for the characterization of
solid surface energies, and in some cases, aspects of liquid surface energies. The
main premise of the method is that by placing a droplet of liquid with a known
surface energy, the shape of the drop, specifically the contact angle, and the
known surface energy of the liquid are the parameters which can be used to
calculate the surface energy of the solid sample. The simplest way of measuring
the contact angle is with a goniometer, which allows the user to measure the
contact angle visually. The droplet is deposited by a syringe pointed vertically
down onto the sample surface, and a high resolution camera captures the image,
which can then be analyzed using image analysis software.
Contact angle, , is a quantitative measure of the wetting of a solid by a
liquid. It is defined geometrically as the angle formed by a liquid at the three
phase boundary where a liquid, gas and solid intersect. A low value of contact
angle () indicates that the liquid spreads, or wets well, while a high contact
angle indicates poor wetting. If the angle is less than 90 degrees the liquid is
said to wet the solid. If it is greater than 90 degrees it is said to be non-wetting.
3. Results and Discussion
The focus of this research is to demonstrate that utilizing UV irradiation
the polymeric substrate can be grafted and molecularly imprinted polymers
(MIP) will be obtain for the use in drug delivery systems. Advantages of these
MIPs for drug delivery applications include their low cost, ease of sample
preparation, surface uniformity of the device and the possibility to improve

Bul. Inst. Polit. Iai, t. LVIII (LXII), f. 1, 2012

83

kinetics of drug release into human body from DDS with different forms and
shapes.
In this paper we analyzed how the surface energy of polypropylene
membranes are modified when different method for UV grafting were applied.
The contact angle of water and ethanol for PP membranes was measured before
and after physical treatments, and some important parameters for surface energy
were evaluated:
1. Work of Adhesion. Defined as the work required separating the liquid
and solid phases, or the negative free energy associated with the adhesion of the
solid and liquid phases. It is used to express the strength of the interaction
between the two phases. It is given by the Young-Dupre equation as

Wa = LV (1 + cos ) ,

(1)

where LV refer to the interfacial energies of the liquid/vapor, and is liquid


contact angle.
2. Work of Spreading. The negative free energy associated with spreading
liquid over solid surface. Also referred to as Spreading Coefficient it is given as

WS = LV (cos 1) .

(2)

3. Wetting Tension. A measurement of force/length defined as

T = LV cos .

(3)

This value, the product of the cosine of the contact angle and the surface
tension, also represents the wetting force normalized for length. It allows for a
characterization of the strength of the wetting interaction without separate
measurement of surface tension.
4. Critical Surface Tension. Using a series of homologous liquids of
differing surface tensions a graph of cos versus LV is produced. It will be
found that the data form a line which approaches cos = 1 at a given value of
C .
5. Surface polarity represent the ratio of SP to S , where S is the surface
free energy, and SP and SD the contributions of non-polar and polar forces,
respectively.
In Figs. 2 and 3 are represented contact angle of water and ethanol, for all
three methods of grafting, versus UV exposure time.
From these representations we can se that the contact angles of water
decrease after UV grafting process. The UV-photo grafted membranes which
contain glucose as template are maintained hydrophobic but the contact angle

84

Cristina-Delia Nechifor and Sebastian Popescu

decrease from 113.32 degree to 108 but no more than 93.03. A decrease, for 15
minutes of UV irradiation, followed by an increase of water contact angle, for
30 minutes than can be seen for Method I and III. The reverse can be seen for
Method II. This phenomenon can be explained taking into account the
preparation methods. In Methods I and II the polymeric membranes were
irradiated in the same time or immediately after the immersion in
template/monomer solution, so this could explain why at the surface of the
polymeric films are more polar groups. This phenomenon is sustained by the
comportment of surface polarity, represented in Fig. 3. The ethanol contact
angle decrease with UV irradiation time, for all three methods used to graft
polypropylene membranes. A little increase of contact angle can be seen for
Method III.

Fig. 2 Water contact angle


versus UV exposure time.

Fig. 3 Ethanol contact angle versus


UV exposure time.

Critical surface tension which represents the maximal surface tension of


a liquid which may completely wet a solid was calculated for our membranes.
As we can observe in Fig. 5 the critical surface tension increase for all the
samples.

Fig. 4 Surface polarity versus UV


exposure time.

Fig. 5 Critical surface tension versus UV


exposure time.

In Figs. 6 and 7 are represented the negative free energy associated with
spreading liquid (water and ethanol respectively) over solid surface of
polypropylene membranes functionalized with Glucose.
As we can notice for water work of spreading decrease for 15 minutes
UV irradiation and than increase for 30 minutes, in cases of Method I and III.
The reverse can be observed for Method II. The ethanol work of spreading
increase for all protocol of UV grafting, but a slow decrease can be seen in case
II and III.

Bul. Inst. Polit. Iai, t. LVIII (LXII), f. 1, 2012

Fig. 6 Work of spreading for water


versus UV exposure time.

85

Fig. 7 Work of spreading for ethanol


versus UV exposure time.

As we can see the wetting tension for water and ethanol respectively,
from Figs. 7 and 9, have the same behavior like water and ethanol work of
spreading.

Fig. 8 Wetting tension for water versus Fig. 9 Wetting tension for ethanol versus
UV exposure time.
UV exposure time.
Table 1
Contributions of non-polar and polar forces to the surface free energy
of PP membranes
Sample

SP

SD

Ungrafted
SI_15
SI_30
SI_60
SII_15
SII_30
SII_60
SIII_15
SIII_30
SIII_60

28.6
32.38
71.9
22.96
66.41
37.78
51.55
30.88
45.12
32.52

12.05
4.15
65.17
0.003
50.1
5.65
24.32
2.71
22.97
4.18

40.65
36.53
137.07
22.963
116.51
43.43
75.87
33.59
68.09
36.7

In Table 1 are listed the contributions of non-polar and polar forces to the
surface free energy of PP membranes. The samples were noted: I, II, and III,
means the preparation methods, 15, 30 and 60 means UV irradiation time.

86

Cristina-Delia Nechifor and Sebastian Popescu

The behavior of polar component to the surface free energy is identical


with surface polarity. This can be explained if we consider that the polarity of
surface is dependent from the number of polar groups from surface.
4. Conclusions
1. In this study we analyzed how the surface energy parameters of
polypropylene membranes are modified when different method for UV grafting
were applied, the important parameters followed were: contact angle for water
and ethanol, critical surface tension, surface polarity, work of adhesion, work of
spreading, wetting tension and contributions of non-polar and polar forces to the
surface free energy.
2. The contact angle of water and ethanol decrees for UV-photo grafted
membranes, in all three preparation methods. The critical surface tension
increases for all the samples with UV irradiation time. The wetting tensions for
water and ethanol respectively have the same behavior like water and ethanol
work of spreading. The behavior of polar component to the surface free energy
is identical with surface polarity. This can be explained if we consider that the
polarity of surface is dependent from the number of polar groups from surface.
3. All the parameters which characterize the surface energy of UVgrafted PP membranes with glucose are really dependent by the preparation
method. According to these experimental results we can say that by the method
I and III the best parameters are accomplished or using these polymeric
membranes in biomedical field.
Acknowledgements. The authors are grateful the financial support of
(CommScie) POSDRU/89/1.5/S/63663 Project.
REFERENCES
Bhattacharya A., Rawlins J. W., Ray P., Polymer Grafting and Cross Linking. John
Wiley & Sons, Inc., New Jersey, 2009.
Cao H., Zhang R., Sundar C. S., Yuan J., He Y., Sandreczki T. C., Jean Y. C.,
Degradation of Polymer Coating Systems Studied by Positron Annihilation
Spectroscopy. (I) UV Irradiation Effect. Macromolecules. 31(19), 6627-6634
1998.
Gao S.L., Hler R., Mder E., Bahners T., Opwis K., Schollmeyer E., Photochemical
Surface Modification of PET by Excimer UV Lamp Irradiation. Appl. Phys. B ,
81, 681-690 (2005).
Gopal R., Zuwei M., Kaur S., Ramakrishna S., Surface Modification and Application of
Functionalized Polymer Nanofibers. In Molecular Building Blocks for
Nanotechnology: From Diamondoids to Nanoscale Materials and Applications,
109, 2007, pp. 72-91.
Gupta B., Anjum N., Plasma and Radiation-Induced Graft Modification of Polymers for
Biomedical Applications. Advances in Polymer Science, 162, 35-61 (2003).

Bul. Inst. Polit. Iai, t. LVIII (LXII), f. 1, 2012

87

He D., Susanto H., Ulbricht M., Photo-irradiation for Preparation, Modification and
Stimulation of Polymeric Membranes. Progress in Polymer Science, 34, 62-98
(2009).
Jiangxi D. H., Surface-selective and Controllable Photo-grafting for Synthesis of
Tailored Macroporous Membrane Adsorbers. Essen, 2008.
Kato K., Uchida E., Kang E., Uyama Y., Ikada Y., Polymer Surface with Graft Chains.
Prog. Polym. Sci., 28, 209-259 (2003).
Lisboa P., Gilliland D., Ceccone G., Valsesia A., Rossi F., Surface Functionalisation of
Polypyrrole Films Using UV Light Induced Radical Activation. Applied Surface
Science, 252(13), 4397-4406 (2006).
Praschak D., Bahners T., Schollmeyer E., PET Surface Modifications by Treatment with
Monochromatic Excimer UV Lamps. Appl. Phys. A, 66, 69-75 (1998).
Romero-Sancheza M. D., Pastor-Blasa M. M.,. Martn-Martneza J. M., Walzak M.J.,
Addition of Ozone in the UV Radiation Treatment of a Synthetic Styrenebutadiene-styrene (SBS) Rubber. International Journal of Adhesion & Adhesives,
25(44), 358-371 (2005).
Rou L., Cacaval C.N., Rou D., Effect of UV Radiation on Some Polymeric Networks
Based on Vinyl Ester Resin and Modified Lignin. Polymer Testing, 28(3), 296300 (2009).
Safrany A., Preparation of Patterned Surfaces and Microspheres Using Radiation
Processing Techniques, Radiation synthesis and modification of polymers for
Biomedical Applications. IAEA, Vienna, 2002, pp. 179-191.
Ulbricht M., Advanced Functional Polymer Membranes. Polymer, 47, 2217-2262
(2006).
Waldman W., De Paoli M., Photodegradation of Polypropylene/polystyrene Blends:
Styrenee Butadienee Styrene Compatibilisation Effect. Polymer Degradation and
Stability, 93(1), 273-284 (2008).
STUDIUL ENERGETICII SUPRAFEEI MEMBRANELOR DE POLYPROPILEN
FUNCIONALIZATE CU GLUCOZ OBINUTE PRIN GREFARE CU
AJUTORUL RADIAIILOR UV
(Rezumat)
n aceast lucrare s-a urmrit modul n care se modific principalii parametrii ce
caracterizeaz energia de suprafa a membranelor din polipropilen ca urmare a
funcionalizrii acestora cu ajutorul radiaiilor din domeniul UV. Membanele
comerciale din polipropilen (PP), cu grosime = 80 m au fost grefate cu glucoz
folosind radiaiile din domeniul UV emise de o lamp de vapori de mercur de tip HBO200, n aer, la temperatura camerei. n acest scop s-au aplicat trei metode diferite de
preparare. Metoda I: iradierea UV a membranei de PP imersat ntr-o soluie omogen
de monomer/template timp de 15, 30 i 60 minute. Metoda II: membranele de PP sunt
iradiate UV acelai timp, iar apoi au fost imersate timp de 24 de ore n soluia
monomer/template. Metoda III: filmele polimere au fost inute n soluia
monomer/template pentru 24 de ore, apoi iradiate UV timp de 15, 30 i 60 minute.
Soluia omogen monomer/template const din: 2mm Acrylamid (AAm), 80mm
N , N , -Methylen(bis) acrylamid MBAAm, 2mm Glucoz i ap. Toate membranele

88

Cristina-Delia Nechifor and Sebastian Popescu

au fost curate cu ap distilat i etanol i usucate la temperatura de 40 oC nainte de


procesul de grefare. Energia suprafeei membranelor polimere a fost evaluat
urmrindu-se o serie de parametri foarte importani i anume: unghiul de contact al apei
i etanolului, tensiunea superficial critic, polaritatea suprafeei, lucru de aderen,
lucru de mprtiere, tensiunea de umectare i contribuiile interaciunilor non-polare i
polare la energia liber a suprafeei. S-a putut observa din acest studiu c absolut toi
parametrii ce caracterizeaz suprafaa membranelor polimere de PP din punct de vedere
energetc sunt puternic dependeni de metoda de grefare utilizat. Conform rezultatelor
experimentale obinute putem spune c cei mai buni parametrii ce pot fi indeplinii n
scopul utilizrii acestor membrane polimere n domeniul biomedical, sunt obinui prin
metodele I i III.

BULETINUL INSTITUTULUI POLITEHNIC DIN IAI


Publicat de
Universitatea Tehnic Gheorghe Asachi din Iai
Tomul LVIII (LXII), Fasc. 1, 2012
Secia
MATEMATIC. MECANIC TEORETIC. FIZIC

ONLINE PHYSICS TEST DEVELOPED IN ADOBE FLASH CS4


TO IMPROVE STUDENTS KNOWLEDGE
BY

IRINA RADINSCHI1, CRISTIAN DAMOC2 and BOGDAN AIGNTOAIEI3


Gheorghe Asachi Technical University of Iai
1
Department of Physics,
2
Continental Automotive Romania SRL, Iai
3
Faculty of Automatic Control and Computer Science
Received: December 28, 2011
Accepted for publication: January 5, 2011

Abstract. An online Physics Test, which is actually a quiz elaborated in


Adobe Flash CS4 and designated to be used for the second-semester course in
Physics at the Faculty of Civil Engineering and Building Services of "Gheorghe
Asachi" Technical University of Iasi, has been developed. This is one of the elearning tools which are part of the Physics curriculum. This virtual online test
verifies the students knowledge in the following fields of Physics: Mechanics II,
Electricity and Magnetism, Electromagnetic Waves and Solid Body Physics. The
online Physics Test is a valuable tool for the teaching staff, as well as for
students. Students can resort to it for pre-seminar activities and in order to
prepare their exams. This tool enables students to improve their learning
progress and results, and this is why we use it together with lectures, seminars
and Virtual Physics Laboratory classes. This online test is a completion of the
Virtual Physics Test elaborated for the first-semester course in Physics at our
faculty. We also performed a qualitative case study that contains two statistics.
One of them shows an increasing in the number of students who prefer to use the
online Physics Test and the other indicates that the increasing in the number of
the male students who have worked with the online Physics Test is greater that
the number of the female students who have used this educational background.
Key words: Online Physics Test, Adobe Flash CS4, e-learning.

Corresponding author: e-mail: radinschi@yahoo.com

90

Irina Radinschi et al.

1. Introduction
In recent years there is an increasing in the elaboration of new tools for elearning to prepare students for a useful career. Concerning the development of
powerful tools for the students who study Physics we point out the elaboration
of physics simulations, Virtual Physics Laboratories, Virtual Physics Tests and
video presentations that are used for improving the students knowledge
(Escalada et al., 1996; Radinschi et al., 2008; Murariu & Toma; Murariu;
Radinschi et al., 2007; Radinschi et al., 2010; Macas-Daz & Puri, 2007). All
these e-learning tools play the important role of acquire and transmit
knowledge. They are very useful for all the students, and especially for the
students who are away from the universities and for the students from
campuses. With the aid of these tools a rapid interaction can be also established
between teacher and students and between students, through the attached chat
window or Forum. The teacher and the students themselves can also interact by
e-mail.
We consider that a good student has to be prepared for the demands of
college work, well informed and guided and participate in activities to enhance
knowledge of physics. For this purpose we have developed a useful physics
environment creating a Virtual Physics Laboratory (Radinschi & Aigntoaie,
2010), and making a completion of our Virtual Physics Test that was designated
to the first-semester course in Physics. The results obtained by our students who
participated in these online activities make us to elaborate the online Physics
Test for the second-semester course in Physics at our faculty. We have
elaborated the on-line material taking into account the discussions with our
students and their needs for improving the level of knowledge.
The online Physics Test is developed in Adobe Flash CS4 and can be
used in pre-seminar activities, in parallel or after these and the Physics course.
The test allows students to train themselves. Together with the Virtual Physics
Laboratory contributes at the improving of students knowledge and support
them to make a real progress in the learning process.
2. Online Physics Test Developed in Adobe Flash CS4
After the experience that we had with the implementation of the first part
of the Virtual Physics Test that was integrated in the Physics curriculum we
decided to develop the second part that is designated to our students who attend
the second-semester course in Physics at our faculty. The material of our
Physics course of the second semester was adapted for the elaboration of the
online Physics Test and in this way we improve the e-learning environment that
we created in the first semester. The online Physics Test is elaborated in Adobe
Flash CS4 and contains questions from the chapters Mechanics II, Electricity
and Magnetism, Electromagnetic Waves and Solid Body Physics. The online

Bul. Inst. Polit. Iai, t. LVIII (LXII), f. 1, 2012

91

test offers students a supportive environment for learning Physics and engages
them to test their knowledge without the direct guidance of the teacher. In this
way they can easy learn the content of the Physics course and prepare for the
seminars and exams. There is a continue communication with the teacher and
with the colleagues using e-mail, the chat window and Forum. Because this
activity is free of choice and we do not impose to our student the use of the
online Physics Test we are satisfied because most of them choose to use this elearning tool. For the students who choose to use the online Physics Test the
final grade will be an average between the grade obtained in the exam and the
grade obtained in the online Physics Test. The questionnaire can be taken as
follows: the students have to access each page and choose the answer to each
question by clicking on the button. Each question has five answers and only one
of them is correct. The students have to choose the answer within a specified
time period and then they can access the next page of the questionnaire. With
the help of this application the teacher has the opportunity of testing his
students; however, the students can also test themselves, without the guidance
of a teacher. After the quiz has been scored, an information page will appear,
comprising the description of the results for the scores. Thus, at the end of the
test the students will be provided with an overview of their answer s and they
will be able to see the points they have gained.
In Fig. 1 we present a page of the online Physics Test.

Fig. 1 An example page of the online Physics Test developed for


the second-semester course in Physics.

92

Irina Radinschi et al.

We present below the main part of the code developed in Adobe Flash
CS4 for the example page of the online Physics Test.
// The setup function removes the old question & answers and places current
questions & answers in qHolder.
function setup():void
// declare local useful variables
var j:int;
// remove all of qHolder's children to clear content of the previous question.
while (qHolder.numChildren > 0)
{
qHolder.removeChild(qHolder.getChildAt(0));
}
// update question counter
txtCounter.text = "[ " + String(index+1) + " / " + String(nrOfQuestions) + " ]";
//
clear
feedback
for
the
new
question
txtFeedback_txt.text="";
//
text
formatting
of
the
questions
var qFormat:TextFormat = new TextFormat('Arial', qSize, qColor);
//
text
formatting
of
the
answers
var aFormat:TextFormat = new TextFormat('Arial', aSize, aColor);
// We build the text field according to specified parameters and add it as a child of
qHolder.
var qField:TextField = new TextField();
displayWidth;
//qField.height=qHeight;
// question field properties: position, size, formationg and content
qField.x=10;
qField.y=5;
qField.multiline=true;
qField.wordWrap=true;
qField.defaultTextFormat=qFormat;
//
set
the
format
qField.text = String(index+1) + ". " + arrQuestionsText[index]; // content
//
add
question
text
field
to
qHolder
qHolder.addChild(qField);
mcChoice1_mc.x
=
qHolder.x
+
qField.x
+
50;
mcChoice1_mc.y = qHolder.y + qField.y + 50 + qSize + (aSize+60)*0;
mcChoice2_mc.x
=
qHolder.x
+
qField.x
+
50;
mcChoice2_mc.y = qHolder.y + qField.y + 50 + qSize + (aSize+60)*1;
mcChoice3_mc.x
=
qHolder.x
+
qField.x
+
50;
mcChoice3_mc.y = qHolder.y + qField.y + 50 + qSize + (aSize+60)*2;
mcChoice4_mc.x
=
qHolder.x
+
qField.x
+
50;
mcChoice4_mc.y = qHolder.y + qField.y + 50 + qSize + (aSize+60)*3;
mcChoice5_mc.x
=
qHolder.x
+
qField.x
+
50;
mcChoice5_mc.y = qHolder.y + qField.y + 50 + qSize + (aSize+60)*4;
// create array to hold radio buttons for all choices
if(arrQuestionsType[index] == 0) // text

Bul. Inst. Polit. Iai, t. LVIII (LXII), f. 1, 2012

{
arrChoicesRb = new Array(arrChoicesText[index].length);
// add choices to qHolder
for (j=0; j<arrChoicesText[index].length; j++)
{
// set up each radio button
arrChoicesRb[j] = new RadioButton();
arrChoicesRb[j].label = arrChoicesText[index][j];
arrChoicesRb[j].value = j;
arrChoicesRb[j].width = qField.width;
arrChoicesRb[j].x = qField.x + 20;
arrChoicesRb[j].y = qField.y + 40 + qSize + (aSize+20)*j;
arrChoicesRb[j].group = rbg;
// add each as a child of qHolder
qHolder.addChild(arrChoicesRb[j]);
mcChoice1_mc.visible = false;
mcChoice2_mc.visible = false;
mcChoice3_mc.visible = false;
mcChoice4_mc.visible = false;
mcChoice5_mc.visible = false;
}
}
else // formula, use the mc
{
arrChoicesRb = new Array(arrQuestionsType[index]);
for (j=0; j<arrQuestionsType[index]; j++)
{
// set up each radio button
arrChoicesRb[j] = new RadioButton();
arrChoicesRb[j].label = "";
arrChoicesRb[j].value = j;
arrChoicesRb[j].width = qField.width;
arrChoicesRb[j].x = qField.x + 20;
arrChoicesRb[j].y = qField.y + 40 + qSize + (aSize+60)*j;
arrChoicesRb[j].group = rbg;
// add each as a child of qHolder
qHolder.addChild(arrChoicesRb[j]);
mcChoice1_mc.visible = true;
mcChoice2_mc.visible = true;
mcChoice3_mc.visible = true;
mcChoice4_mc.visible = true;
mcChoice5_mc.visible = true;
mcChoice1_mc.gotoAndStop(index.toString());
mcChoice2_mc.gotoAndStop(index.toString());
mcChoice3_mc.gotoAndStop(index.toString());
mcChoice4_mc.gotoAndStop(index.toString());

93

94

Irina Radinschi et al.

mcChoice5_mc.gotoAndStop(index.toString());
switch(j)
{
case 0: { mcChoice1_mc.mcQ_mc.gotoAndStop(j+1); } break;
case 1: { mcChoice2_mc.mcQ_mc.gotoAndStop(j+1); } break;
case 2: { mcChoice3_mc.mcQ_mc.gotoAndStop(j+1); } break;
case 3: { mcChoice4_mc.mcQ_mc.gotoAndStop(j+1); } break;
case 4: { mcChoice5_mc.mcQ_mc.gotoAndStop(j+1); } break;
default: {} break;
}
}
}
arrChoicesRb[arrChoicesUser[index]].selected = true;
//trace("User choice: " + arrChoicesUser[index] );
// Set the initial selection for the radio button group.
//arrChoicesRb[arrChoicesUser[index]].selected = true;
// Move the check button (already on the stage) to an appropriate spot below qHolder.
if(0 == index){ // first question
btnPrevQ_btn.visible = false;
btnNextQ_btn.visible = true;
mcResults_mc.visible = false;
}
else if(nrOfQuestions-1 == index){ // last question
btnPrevQ_btn.visible = true;
btnNextQ_btn.visible = false;
mcResults_mc.visible = true;
}
else{ // intermediate question
btnPrevQ_btn.visible = true;
btnNextQ_btn.visible = true;
mcResults_mc.visible = false;
}

We have also performed a statistic and compared the percentage of


students who used the Virtual Physics Test in the first-semester and in the
second-semester, respectively.
In Fig. 2 these percentages are given by semester in 2010.
The undergraduate student body is about 270 students in the first year
and 200 in the second year. From the statistic we conclude that the number of
students who have used the online Physics Test has increased from 75 % in the
first semester up to 92 % in the second semester and this e-learning tool is
useful to improve their knowledge.
We also notice that there is an increasing in the using of the online
Physics Test both for female students and male students, but the increasing in

Bul. Inst. Polit. Iai, t. LVIII (LXII), f. 1, 2012

95

the number of male students is greater that the increasing in the number of
female students.
Students percentage (%)

100
90
80
70
60
50
40
30
20
10
0
First semester 2010

Second semester 2010

Fig. 2 Statistic about the students who used the online Physics Test,
performed by semester.

In Fig. 3 we have a statistic made by gender in 2010 and present the


percentages that are 32 % up to 57 % for the female students and 43 % up to 87
% for the male students, respectively.
We believe that the increasing of confidence in our online Physics Test is
greater for the male students than for the female students because of two
reasons. Firstly, this is motivated in one way because the number of our male
students is greater than the number of the female students. Second, even both
the male and female students are interested in using our physics simulations, the
Virtual Physics Lab and the Virtual Physics Tests, from the experience with the
first-semester course in Physics at our faculty we have noted that the male
students are more interested to work with these computational tools.
The results of over 250 grades from students who have used the physics
simulations, the Virtual Physics Lab and the online Physics Test show that they
have succeeded to build a good background in physics and have improved their
final grade.

96

Irina Radinschi et al.


Students percentage (%)
100
90
80
70
60
50
40
30
20
10
0
First semester
2010 female

Second semester
2010 female

First semester
2010 male

Second semester
2010 male

Fig. 3 Percentage of students who have worked with the online Physics Test,
performed by gender

3. Concluding Remarks
1. The online Physics Test is a good tool that engages our students in
challenging learning experiences. The students can test their knowledge without
the direct supervision of the teacher and improve their final grade. We give
them the opportunity to save the online Physics Test on their computers and
work with it at home or in campus. The online Physics Test asks a good
understanding of the content of the Physics course and also of other
bibliographic items. Using the provided material the students will be well
prepared for the seminars and exams.
2. We notice an improvement in the understanding of the chapters of
Physics that we teach and also an increasing in the number of students who use
the online Physics Test and who want to improve their final grade with this elearning tool. We also point out that the male students have a greater confidence
to use the test than the female students. The majority of students successfully
have improved their final grade on average over two semesters. For determining
what problems the remaining percentage of students faced we have to discuss
with them and to work more together or to propose them to work more in
groups with their colleagues.

Bul. Inst. Polit. Iai, t. LVIII (LXII), f. 1, 2012

97

3. From our analysis, we aim at deriving what a better online Physics Test
could be and how we can improve it. As a conclusion, very important for
improving the learning process has been to bring the pieces together, the Virtual
Physics Laboratory, the Physics Course and seminars and the Virtual Physics
Test designated for the first and second semester at our faculty. Having these elearning tools our students are able to access a well structured material, evaluate
information, solve problems, interprets formulae, work in teams, discuss and
make progresses.
4. Our strategy to integrate the physics simulations, the Virtual Physics
Lab and the online Physics Test in the Physics curriculum has contributed to our
success to attract more students to use these tools and to improve their results in
Physics learning, and obtain a better grade at the exams.
5. As a future project we intend to increase the number of questions of the
online Physics Test for testing the students performance.
REFERENCES
Escalada L.T., Grabhorn R., Zollman D.A., Application of Interactive Digital Video in a
Physics Classroom, Journal of Educational Multimedia and Hypermedia, 5, 1,
73-97 (1996).
Radinschi I., Scripcariu L., Ciobanu B., Frunz M. D., Online Quizzes, an Application
of PHP-Triad and MySQL. Romanian Journal of Physics, 53(1-2), 423-427
(2008).
Murariu G., Toma D., A Note about the Simulation Programs for Heat and Molecular
Physics Laboratory. xxx.lanl.gov physics/0505053.
Murariu G.,, Interactive Computer Simulations of Electrokinetic Physics Phenomena.
xxx.lanl.gov physics/0609215
Radinschi I., Frunz M.D., Ciobanu B.nline Virtual Model for Testing the Knowledge,
In IATED, Eds., Proceedings of International Technology, Education and
Development Conference INTED 2007, March 7-9; Valencia, Spain, 2007, pp.
42-47.
Radinschi I., Damoc C., Cehan A., Cehan V., Computer Simulations of Physics
Phenomena Using Flash. 5th International Conference on Hands-on Science
Formal and Informal Science Education, October 13-17, 2008, Espao Cincia,
Olinda-Recife, Brazil, Edited by Manuel Filipe Pereira da Cunha Martins Costa
(Universidade do Minho), Jos Benito Vazquez Dorro (Universidade de Vigo),
Antnio Carlos Pavo (Espao Cincia), Mikiya Muramatsu (Universidade de
So Paulo), 2008, pp. 147-151; Radinschi I., Damoc C., Cehan A., Cehan V.,
The Role of Computer simulations in Teaching-learning Process. In Research,
Reflections and Innovations in Integrating ICT in Education, pp. 1450 1454,
Zurbaran 1, 2a Planta, Oficina 1, 06002 Budajoz, Spain, BA-224-2009 (Book
contains a compilation of paper presented at the V International Conference on
Multimedia and Information & Communication Technologies in Education mICTE2009, Lisbon, Portugal); Radinschi I., Damoc C., Aignatoaie B., Cehan V.,
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98

Irina Radinschi et al.

8th International Symposium Computational Civil Engineering 2010, Iasi,


Romania, May 28, 2010; In New Computational Concepts in Civil Engineering,
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Propagation of Binary Signals in Weakly Damped, Mechanical Systems of
Coupled Oscillators. Phys. Lett. A 366(4-5), 447-450 (2007).
*** www.myphysicslab.com/
*** http://phet.colorado.edu/
Radinschi I., Aignatoaie B., Efficiency of Using a Virtual Physics Laboratory, Bul. Inst.
Polit. Iai, LVI(LX), 4, s. Matematic. Mecanic Teoretic. Fizic, 141-146,
(2010).
*** www.adobe.com/products/flash

TEST DE FIZIC ONLINE N ADOBE FLASH CS4 PENTRU


MBUNTIREA PERFORMANEI STUDENILOR
(Rezumat)
S-a elaborat un test online de fizic n Adobe Flash CS4 destinat pentru a fi
utilizat n semestrul al doilea de ctre studenii Facultii de Construcii i Instalaii din
cadrul Universitii Tehnice Gheorghe Asachi din Iai. Acest test online cuprinde
ntrebri din capitolele Mecanica II, Electricitate i Magnetism, Unde Electromagnetice
i Fizica Corpului Solid. Testul online poate fi utilizat pentru pregtirea seminariilor i
pentru mrirea notei la examen. S-au efectuat de asemenea dou statistici. Una dintre
statistici evideniaz o cretere a numrului de studeni care utilizeaza testul online.
Aceast statistic a fost efectuate pe semestre. A doua statistic indic o cretere a
numrului de studeni de sex masculin n comparaie cu numrul de studente care au
utilizat testul online de fizic.