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INSTITUTULUI

POLITEHNIC

DIN IAI

Fasc. 1

2012

Editura POLITEHNIUM

PUBLISHED BY

Editorial Office: Bd. D. Mangeron 63, 700050, Iai, ROMANIA

Tel. 40-232-278683; Fax: 40-232-237666; e-mail: polytech@mail.tuiasi.ro

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

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

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

BULLETIN OF THE POLYTECHNIC INSTITUTE OF IAI

Tomul LVIII (LXII), Fasc. 1

2012

SUMAR

Pag.

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

VOLOV, Un nou model al carcinogenezei i progresiei tumorale n

cadrul dinamicii neliniare (I) (engl., rez. rom.). . . . . . . . . . . . . . .. . . . . .

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

BULLETIN OF THE POLYTECHNIC INSTITUTE OF IAI

Tomul LVIII (LXI), Fasc. 1

2012

CONTENTS

Pp.

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

VOLOV, A New Carcinogenesis and Tumor Progression Model in

the Framework of Non-linear Dynemics (I) (English, Romanian

summary). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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

Publicat de

Universitatea Tehnic Gheorghe Asachi din Iai

Tomul LVIII (LXII), Fasc. 1, 2012

Secia

MATEMATIC. MECANIC TEORETIC. FIZIC

BY

MUGUR B. RU

Al. I. Cuza University of Iai,

Department of Physics

Received: November 28, 2011

Accepted for publication: December 5, 2011

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

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.

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)

= 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)

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)

= 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 .

(9)

Mugur B. Ru

1

GM + 2

rc =

.

(10)

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

v = ( GM )

1

1

2 2( + 2)

1

2( + 2)

(11)

account the Tully-Fisher empirical expression it results

v L M ,

1

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)

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

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).

(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.

Publicat de

Universitatea Tehnic Gheorghe Asachi din Iai

Tomul LVIII (LXII), Fasc. 1, 2012

Secia

MATEMATIC. MECANIC TEORETIC. FIZIC

PROGRESSION MODEL IN THE FRAMEWORK

OF NON-LINEAR DYNAMICS (I)

BY

CLIN GHEORGHE BUZEA1, MARICEL AGOP2

and SIMONA RUXANDRA VOLOV3

1

2

Gheorghe AsachiTechnical University of Iai

3

University of Medicine and Pharmacy Gr. T. Popa, Iai

Accepted for publication: January 15, 2011

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.

10

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

11

(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

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

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.

through multiple genetic mutations.

2.2. Distinguishing Traits of Cancer

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.

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).

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

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).

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

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).

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

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.

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

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).

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

Fig. 6 Hologram recording: the interference pattern produced by the reference wave

and the object wave is recorded.

the object wave.

4.1. Early Development

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

21

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

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.

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

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

2

(1)

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)

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)

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.

23

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

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.

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

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

(6)

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)

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

+ 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.

25

4.4. Recording Materials

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

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

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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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.

Publicat de

Universitatea Tehnic Gheorghe Asachi din Iai

Tomul LVIII (LXII), Fasc. 1, 2012

Secia

MATEMATIC. MECANIC TEORETIC. FIZIC

PROGRESSION MODEL IN THE FRAMEWORK

OF NON-LINEAR DYNAMICS (II)

BY

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

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

34

(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

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)

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)

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)

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

c

= Dc 2 c + f n c,

t

(4)

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

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

= 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

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

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

f = 0.025.

(7)

3.1. Laser as a Lorenz System

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

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)

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

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)

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

C2 ,

iC1 = E1C1 + H12

C1 ,

iC 2 = E2C2 + H 21

(14)

= 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)

iC1 =

0C1

C2 ,

+ H12

2

0C2

C1.

+ H 21

2

iC 2 =

(18)

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

1 ex 2 dV .

(19)

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)

can make 12 real so H`12, H`21 to be also real.

Eq. (19) suggests considering the expression

41

(21)

through the equation

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

(22)

We further consider the combinations

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

2

Z = C2 C1 22 11.

(23)

(24)

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

again and using (26). It results

+ 2 P = 20 2 EN .

P

0

12

(30)

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)

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

43

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)

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

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

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)

45

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

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

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

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

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.

49

50

(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.

51

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

haptotactic cell movement

n

=

t

f

k3 n

x x

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

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

G ( f , m) = k4 mf ,

(54)

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

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

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 ,

and f0, hence justifying our classification of the steady state (n, f) = (1, 0) as

stable.

4.3. Travelling Wave Analysis

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

54

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)

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.

55

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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Am. J. Pathol.,144, 1958-1967 (1994).

Zervoudaki A., Economou E., Pitsavos C., Vasiliadou K. et al., The Effect of Ca2+

Channel Antagonists on Plasma Concentrations of Matrix Metallopro ases

in Metastasis. J. Natl. Cancer Inst., 89, 1260-1270 (1997).

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).

Publicat de

Universitatea Tehnic Gheorghe Asachi din Iai

Tomul LVIII (LXII), Fasc. 1, 2012

Secia

MATEMATIC. MECANIC TEORETIC. FIZIC

PROGRESSION MODEL IN THE FRAMEWORK

OF NON-LINEAR DYNAMICS (III)

BY

1

National Institute of Research and Development for Technical Physics, Iai

Accepted for publication: January 15, 2011

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.

Medium with Holographic Properties

1.1. Extracellular Matrix and Tumor Microenvironment

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;

60

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.

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

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-

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

For = eiS , with the amplitude and S the phase of , the

complex speed field (2), using (5) takes the explicit form

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

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)

,

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)

V ( 0 = c , ) = c,

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

(12)

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)

65

speed field

2

2

c 2 +

( 0 )

0 c

,

2i

V ( 0 , ) =

2

2

2 2

2 2

2

2

+

+

(14)

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)

Q ( 0 , ) = 0 2i 2

( 0 , c ) 2

2 2 2 2

+

+ 2i 2

1

2

2

+ 2

(16)

2

2 2

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

.

(17)

ImV ( 0 , ) - c), Re j ( 0 , ) - d), Im j ( 0 , ) - e), Im Q ( 0 , ) - f)

and Im F ( , ) vs. ( ) and are given.

0

66

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

( 0 ) and .

67

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

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).

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

regressive one for various values of normalized speed, c.

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

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

regressive one for various values of normalized speed, c.

( 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)

71

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

E=

= ln dx.

D

(26)

( r ) rdr ,

(27)

(r )dr 1,

(28)

r=

implies the expression

( r ) = exp( r ), , = const.

(29)

or in notations

exp( ) 0 ,

2

,

a

2r

( r ) = 0 exp .

a

(30)

(31)

u=D

d

2D

(ln ) =

= const.

dr

a

(32)

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)

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

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

dH

=

dt

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

(35)

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).

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

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

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

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

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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77

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Chiarugi P., Giannoni E., Anoikis: A Necessary Death Program for Anchoragedependent Cells. Biochemical Pharmacology, 76, 1352-1364 (2008).

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in Vivo. Invest. Ophthalmol. Vis. Sci., 43, 1922-1927(2002).

Cringle S..J., Yu D-Y., A Multi-layer Model of Retinal Oxygen Supply and

Consumption Helps Explain the Muted Rise in Inner Retinal PO2 During

Systemic Hyperoxia. Comp. Biochem Physiol., 132, 61-66 (2002).

Dogru M., Nakamura M., Inoue M., Yamamoto M., Long-term Visual Outcome in

Proliferative Diabetic Retinopathy Patients after Panretinal Photo-coagulation.

Jpn. J. Ophthalmol., 43, 217-224 (1999).

Enderling H., Anderson A.R.A., Chaplain M.A.J., Beheshti A., Hlatky L., Hahnfeldt P.,

Paradoxical Dependencies of Tumor Dormancy and Progression on Basic Cell

Kinetics. Cancer Research, 69(22), 8814-8821 (2009).

Fong D. S., Ferris F. L. III, Davis M. D., Chew E. Y., Causes of Severe Visual Loss in

the Early Treatment Diabetic Retinopathy Study. ETDRS Report no. 24, Early

Treatment Diabetic Retinopathy Study Research Group. Am. J. Ophthalmol.,

127, 137-141 (1999).

Framson P. E., Sage E. H., SPARC and Tumor Growth: Where the Seed Meets the Soil.

Journal of Cellular Biochemistry, 92, 679-690 (2004).

Giannoni E., Buricchi F., Grimaldi G. et al., Redox Regulation of Anoikis: Reactive

Oxygen Species as Essential Mediators of Cell Survival. Cell Death and

Differentiation, 15, 867-878 (2008).

Harris A. L., Hypoxia A Key Regulatory Factor in Tumour Growth. Nat. Rev. Cancer,

2, 38-47 (2002).

Hofmann U. B., Houben R., Brocker E. B., Becker J. C., Role of Matrix Metalloproteinases in Melanoma Cell Invasion. Biochimie, 87, 307-314 (2005).

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Cycle, 8, 3267-3273 (2009).

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Changes in Intraretinal Oxygen Distribution in Pigmented Rabbits. Invest.

Ophthalmol. Vis. Sci., 46(3), 988-999 (2005).

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

memorizare, coeren, surs de for prin intermediul energiei informaionale etc. Se

trag concluziile generale asupra modelului.

Publicat de

Universitatea Tehnic Gheorghe Asachi din Iai

Tomul LVIII (LXII), Fasc. 1, 2012

Secia

MATEMATIC. MECANIC TEORETIC. FIZIC

UV-PHOTO-GRAFTED WITH GLUCOSE

BY

1

Gheorghe Asachi" Technical University of Iai,

2"

Accepted for publication: December 5, 2011

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.

80

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).

81

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).

2. Experimental

Commercial Polypropylene (PP) membranes with thickness = 80 m

were purchase from SC CEPROINV SA. The monomer used was acrylamide

82

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

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)

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)

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

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.

versus UV exposure time.

UV exposure time.

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.

exposure time.

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.

versus UV exposure time.

85

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

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.

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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

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.

Publicat de

Universitatea Tehnic Gheorghe Asachi din Iai

Tomul LVIII (LXII), Fasc. 1, 2012

Secia

MATEMATIC. MECANIC TEORETIC. FIZIC

TO IMPROVE STUDENTS KNOWLEDGE

BY

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

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.

90

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

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.

the second-semester course in Physics.

92

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

{

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

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;

}

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

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

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

performed by semester.

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

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.

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.,

Improving the e-Learning of Engineering Physics with the Aid of Adobe Flash,

98

Romania, May 28, 2010; In New Computational Concepts in Civil Engineering,

Eds. Scnteie R., Plescan C., Ed. "Matei - Teiu", Iai, 2010, pp. 219-226.

Macas-Daz J. E., Puri A., An Application of Nonlinear Supratransmission to the

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

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.

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