Introduction…. 3 [302811]

Contents

Introduction……………………………………………………. 3

The abstract theme…………………………………………….. 3

Theoretical aspects of lipids and of the cell membrane………… 4

Micro mechanical and electromechanical models……………… 9

The bionic study and applications……..……………………….. 12

The controlled rotation of the biological particles by using rotating electric fields…………………………………………………… 14

– The effective moment method……………………………………………………………………………………. 14

The Lipids as a carrier of medication…………………………… 19

– The general method of liposomes preparation……………………………………………………….. 20

– [anonimizat]…………………………………………………. 23

– The model (s) of rheological micromecanics of lipid and drug structure……………………………………………………………………………………………………………….. 26

Program…………………………..……………………………. 35

Conclusion……………………………………………………… 39

10. Bibliography…….…………………………………………….. 40

Introduction

This paper deals with the general aspects of the mechanism of the biological movements with applications in microeletromechanics and a possible procedure of drug delivery directly in the damaged cells.

Also, this paper presents the theoretical aspect of cytoplasmic movements and presents a possible collection of miniaturized motors in analogy with the study of cytoplasmic movement. [anonimizat].

The abstract theme

Knowing the microelectromechanical and thermodynamics properties of the lipid bilayer (for example those from the structure of the cell membrane) we are trying to conduct a theoretical and experimental research on lipid applications in the field of MEMS (Microelectromechanics).

We can estimate some practical objectives but those does not cover all the applicative field aspects:

Electrostatic micromotors.

Microelectromechanical issues such as; [anonimizat].

Micro or nano electrostatic movements.

The approach to the theme involves the following subjects:

– Theoretical aspects regarding microelectromecanics and thermodynamics of the lipids ([anonimizat]).

-Experimental models and methods for determining specific parameters; [anonimizat], [anonimizat], micro and nano movements.

– [anonimizat], and biological unit of all known living organisms. Surrounding every living cell there is a cellular membrane with many useful characteristics. A very important characteristic for our project is the membrane's capacity of controlling the electrostatic charged ions exchange between the external environment and the internal environment. In the next paragraphs we will talk about the cellular membrane and its electrostatic properties.

The cellular membrane is the "wall" that surrounds the cell. It is made of a lipid bilayer. The lipids which form this layer are: phospholipids (75%), cholesterol and glycolipids.

The most common phospholipids from the cell membrane are phosphatidylcholine(lecithin) and phosphatidylethanolamine.

Each of these molecules has the shape of a nail with a hydrophilic end (it is the end which is attracted to water and contains the positive charges) and a hydrophobic end (it "hates" the aqueous substance and contains the negative charges)

Lipids from the cell membrane are classified in 2 big groups: phospholipids and glycolipids(Fig.5). Glycolipids are used to confer stability to cell’s membrane. It is made of a lipid who has got an attached carbohydrate. They appear in the moment that a phospholipid has contact with a carbohydrate forming on the exoplasmatic surface.

Figure 5 lipids classification

The lipid bilayer is a good isolating material, its conductance on the surface has the value: = .

The electrical capacity can be calculated because both(the interior and the exterior) are solutions of salts in water we can talk about 2 conductors. These 2 conductors are separated by an insulating environment, the lipid bilayer (see above). Now, if we can separate a q charge and apply an electrical potential V on the cell surface, the membrane has the capacity: C= .

Knowing the thickness of the lipid layer (6 x m), we obtain the membrane capacity on the surface unit: c==F.[2]

The characteristics and parameters of the cell

The estimative calculation of the lipid layer’s permittivity

Considering the spherical model of the cell with the outside lipid layer it results the next modeling as shown in Fig.6.

And so the cylindrical surface is as it follows:

Obs. Measurement units:

,.

Where the formula of the spherical surface is S=4 (1)

The calculation formula of the spherical condenser including the lipid model is:

(2)

Where , and maximum radius (see also fig 6) ~ ,

And the absolute permittivity:

(3)

With the void permittivity; = 8,885·, and -relative permittivity of the lipid layer which we want to estimate.

It results a permittivity domain:

Micromechanic and electromechanic models

In this chapter we will talk about some mechanical devices which are using lipid structures in their mechanism.

To understand the micro and nano actuators it is important to mention a characteristic of the lipid bilayer: it forms micelles around aqueous substances.

We are using 2 types of these micelles: when the concentration of water is smaller than the concentration of the lipids, we will observe the micelles as presented in the figure in the left(Fig.7) and in the opposite case, when the concentration of the water is higher than the concentration of the lipids, the micelles are presented in the right figure(Fig.8).

The first micro actuator that we will talk about is a micro-bearing device. It will have a circular shape full of micelles (above) which surrounds a carbon ax.

Surrounding the ax, there will be an aqueous solution to help us orientate the lipid bilayer which will form the next layer. We will have a few such sequences and in the end some electrodes to power the micro bearing device.

It will be further followed by a similar sequence to the one described. And so this will form the central part of the micro-actuator. Normally in the bearing device (there) will be seven rods with their substrates(fig.9,10).

Micro- strengths present in this device are:

F – Resultant force;

– Friction viscosity force;

– Surface tension force;

– Electrostatic force;

– Force of attraction van der Waalls;

= +++

In the figure above (fig.11) there is presented another type of bearing, still using lipids. In this figure the lipid bilayer is similar to cell membrane (having its protein component).

Also, as described above, aqueous substances are used to obtain the desired lipid orientation. And the electrodes are mounted on a carbon support to get the bearing rotation.

And finally, we will describe a last linear motor (fig.12).

It does not differ from the other engines only due to the sense of running: which is along a line.

It has in its composition a lipid bistro, an aqueous medium with the same function as described above (to order the lipids) and electrodes to assist the engine in its operation.

The bionic study and applications

The substances used for the ions transport are called ionophores and a special method is used for the study of the membranes. Their diversity consists of the type of ions that each one carries along. The ionophores are a must for the transport of the ions through the cell membrane.

One of the most used ionophores is Valinomycin, this is a cyclicdodecapeptide(it contains 12 chains of amino acids). This ionophore is used for the transportation of ion forming a complex in molar ratio 1:1. With the potassium ion support,some potentials are to be designed at the level of the cell membrane.

Another ionophore is Nigericin. Nigericin is a carboxylic acid, also soluble in lipids like Valinomycin. This ionophore can carry 3 ions: , and . Because of its carry proprieties, it is used for balancing a chemical gradient without affecting the potential of the cell membrane.

The last ionophore we’ll talk about is Gramicidin. This ionophore has the property to form pores in the membrane so as to allow the transfer of monovalent cations. Therefore, it can dissipate the potential, the chemical components and electric components of the electrochemical potential

Some deficient/dissconect agents are also used for the transport of the protons . They are in general weak acids with a low electrical charge delocalized into a π orbital system. Some examples of deficient/disconnect agents are presented below. (Fig.13, Fig.14, Fig.15).

In the above figure (Figure 16) there is a liposome analysis we have used in the following experiments.

6. The controlled rotation of the biological particles by using rotating electric fields

The forces exerted by a nonuniform electric field can damage the polarized particles we want to manipulate.

Using electric rotation fields can induce the rotation of the polarized particles (phospholipids) suspended in an aqueous medium having an extended applicability in MEMS, in our case in the process of developing (bio)micro-electric motors with the lipids support. An extended variety of structures starting with simple planar structures to 3D structures may be theoretically developed for these purposes. [44]

The implication on this theme with applications in biotechnology are still in the early stage of development, the objective being a long term one.

For example, the cells and their components can be collected, sorted, gathered and transported with the help of microelectrode structures (with the reference dimensions between 10-6 m to 10-4 m).

We will try to present a theory of motion induction and of particle orientation by using these electric fields. We will also present multiple methods for these, including the necessary calculations.

The effective moment method.

The effective moment method involves multiples, including the dipole, the quadrupole, and other larger terms, facilitating a near-eccentric-median field force and the calculations needed for the torque (torque force) of particles.

Firstly, we will present the effective dipole leaving the bigger ones in the end. In Figure 17(a) there is a small electric dipole of the moment vector =q located in a homogeneous and isotopic dielectric liquid with the permittivity. The dipole experiences a non-uniform, electrostatic field ,imposed by the electrodes that are not added to the figure.

To define the actual moment it is normal to start with the electrical potential due to this dipole. [45]

(1)

Where is the radial vector, the distance is being measured from the center of the dipole and r is . The radial depends on the potential. If the dipole is small in comparison with the length of the uniformity scales imposed by the field ,then the torque and the force are approximately:

(2a)

(2b)

The contribution of the dipole to the total electric field cannot exert a force on it and is therefore not included in .

Imagining that we are replacing the dipole with a small dielectric sphere of R-ray and permittivity at the same position in the structure as shown in the figure (fig.17 -b),then the particle has an perturbator effect in the electric field.

Expressing as an electrostatic potential, the perturbation has the following formula:

(3)

Where it is assumed that the radius of this particle is small compared to the scale length imposed by the field of non-uniformity, the equation (3) has the same form as equation (1) and the momentum is defined by comparing these two expressions.

Where is Clausius-Mossotti factor.

The equation(4) defines the moment of the equivalent, free-charge, electric dipole that would create a perturbation field identical to and indistinguishable from that of the dielectric sphere for all > R. The only distraction between the induced dipole and a general electric dipole is that, because the particle is a sphere and because it is lossless, the moment will be always be parallel to .

To evaluate the force on the dielectric particle, the effective moment of (4) is substituted directly into (2a). The validity of this procedure may be argued from the energy standpoint An even simpler approach is to note that, if the Maxwell stress tensor is used to calculate the force, then the cases of the physical dipole and the dielectric sphere must yield the same result because by definition, the fields are indistinguishable on any surface enclosing the particle. Combining (2a) and (4) gives the well-known expression for the DEP force on a dielectric sphere in a dielectric medium [3], [4]:

(5)

According to (5), a particle will be either attracted to or repelled from a region of strong electric field intensity, depending on whether Kw > 0 (e2 > e1) or K" < 0 (e2 < El), respectively. Note that combining (2b) and (4) gives zero for the torque, because the dipole moment and electric field are always parallel. To escape this restriction, the particle must be electrically lossy, nonspherical, or possess a permanent dipole moment.

Experiments.

Experiment # 1- The values measurement

Experiment # 2

In these experiments we put the liposomes in a 4-electrode pot and above the liquid we put a ping-pong ball. Gradually we increase the system voltage to see if we get a rotation of the vessel. Not successful, because the lipids are sensitive to high temperatures.

Pictures of experiments.

Experiment # 3

In another pot we put lipids and a propeller. We try again to pass the electric power in order to turn the propeller on. This time we passed the current on through the liquid with an electrostatic machine.

Experiment # 4

F=0.2 gram-force=0.00196

R=6mm=0.006m

7. The lipids as a carrier for medication

The formulation of the research topic on the transport of the lipid-based medicines

Knowing the patterns and the modeling related to;

-A. The geometric structure.

-B. The model(s) of rheological micromecanics of lipid and drug structure

– C. The electrostatic pattern of the lipid and drug structure and the physical and chemical characteristics of the lipids; L() and of the drugs to be transported M( ) to carry out a study of drug transport, highlighting micro and mechanical, electrostatic, thermodynamic nanosciences and identifying unconventional technologies and procedures for this transport.

The clinical applicability of liposomes is well known because of the very attractive biological properties such as biocompatibility, the ability to contain dissolved drugs in aqueous (hydrophilic) solutions and lipophilic drugs. Compared to other drug carriers, liposomes have several other advantages:

The delivery of the lipid-based medicines is a new concept that is very promising.

The lipid delivery system applies to medicines that are soluble in aqueous solutions, so this type of transport expands on most treatments available today.

The transport routes are either oral, ocular, intranasal, dermal, transdermal and vaginal, but our preferred is the oral one because it is noninvasive and much cheaper and has fewer side effects than an injection.

Liposomes were discovered in the early 1960s by Bangham and his colleagues becoming the most researched field of the lipid delivery. At first they studied the "in vivo" biomembrane.

The name liposome comes from Greek. Liposuction means fat and Soma means body.

Liposomes have been used predominantly in medicine, but also in non-medical areas for cosmetic catalysts and ecology.

Paul Egrlitch invented the term 'magical bullet' in the 20th century proposing the simple use of system liposomes involving drug support on a well-defined target on which to act.

Their predominance in the provision of drugs allowed us to use them as a therapeutic tool in areas such as targeting to tumors, gene therapy, genetic vaccination, immune modulation, fungal infection treatment, and the introduction of regular treatments in a form much more efficient.

The general method of liposomes preparation.

For a proper drug delivery, the liposomal formulations should have high entrapment efficiency, narrow size distribution, long-term stability and ideal release properties. These demands require a suitable preparation method, able to produce stable liposomes by using a wide range of lipids/phospholipids.

Positive liposomes were prepared by the most widely technique, thin film hydration method (TFHM) using a suitable concentration of lipids mixture, phosphatidylcholine (PC), dioleoylphosphatidylethanolamine (DOPE), Chol and stearylamine (SA), in 4:2:3:1 molar ratio (8.5 mg/ml lipids).

A lipid phase was prepared by dissolving the lipids in chloroform/methanol solution (95:5) in a round bottom flask. The thin dry lipid film resulted after the solvent removal (continuous rotary evaporation, 150 rpm, at 40 °C, for 30 min, under reduced pressure), at a Rotavapor IKA (RV 10 digital V, Ika-Works Inc). (fig 18)

MLV spontaneously formed by gently mechanical shaking of the flask upon hydration of the dry thin lipid film with phosphate buffered saline (PBS), pH 7.4 containing CS (10 mg/ml). The dispersion was left undisturbed, at room temperature, for 2-3h, to allow complete swelling of the lipid film and hence to obtain vesicular suspension. MLV was downsized by sonication, at 37° C, in a bath type sonicator (Grant) (Fig.19), for 3×30 min, followed by probe sonication (Bandelin Sonopuls, Germany) (Fig.20), at 70% amplitude, 4 cycles of 10 sec, until a homogeneous population of SUV was obtained. After sonication, the suspension could stand at 37 °C, for 10 min, rapidly cooled in an ice bath and centrifuged at 10,000 rpm, at 4 °C, for 5 min, to remove any titanium fragments. Cycling of the MLV suspension was performed through polycarbonate membrane filters with 200nm pores, following the provided methodology. Before their use in cell culture experiments, free liposomes and liposomal systems containing CS were filtered under sterile conditions through 0.22µm filter (Millipore, Bedford, MA, USA). Vesicular structures thus formed were kept at 4 °C, in N2 atmosphere to prevent lipid peroxidation.

Some models of geometric structures [32,33] used for medication transport can be imagined using lipids.

It will be added some equivalent micromechanical schemes and equivalent electrostatic schemes.

Cilindrical strucuture A.1 (Fig.24)

Structure model with spherical geometry A.2

Sandwich pattern model A.3

Figure 27 The model of the sandwich geometric structure A.3

Structure model structure type random chains. A.4

Figure 28 The geometric pattern of the random chain type. A.4

The development of the lipid transport of drugs includes the following specific modeling;

A. Geometric models (2 structures of development presented above) [32,33,34]

B. Rheological micromechanical models [32,33,34].

C. Microelectrostatical models [40,41,42,43].

Rheological micromechanical models (B) assimilates both the lipid support structure and the drug structure as a continuous medium [37,39].

B. The rheological micromechanical model (s) of the lipid structure and the drug [37,38,39]

The study of the classical rheological models and of the complex rheological models included the classic rheological models of the continuous environments, the complex rheological models (with the index from the table), and rheological models generalized with g in the table. The study is based on the bibliography noted in the title and is a study necessary for a better micro or nanomechanical characterization of both the lipid structure and the drug structure.

It is suggested that each lipid or drug structure be characterized by different rheological models.

The constituent elements include the elasticity element characterized by the constant k and the damping element (plasticity) characterized by the coefficient c.

Regarding the micro or the nanosystems of forces there are some synthetic models below:

We consider an acceptable modeling of the Kelvin model for both the lipid structure and the drug structure [6,8] with the general representative equation:

With the pattern in the figure below:

The electrostatic development.

For the transport of the lipid-drug structure (to be mentioned that the dimensional domain is between 10 nm and 10 microns), it becomes interesting how the structure is manipulated (considering the spherical model). Thus, the transport of drugs using the lipid support (both presenting electrostatic qualities) can be done by using an electric field of intensity [42,43,48,49].[6.The controlled rotation of the biological particles by using rotating electric fields]

For the computation and drug delivery design, the spherical model is associated with an electrostatic dipole [42,43,49] as in Fig. 31 below.

For the transport in the linear direction, the required electrostatic force can be calculated with the formula:

( )

Where the ∇-operator of Hamilton [49], and the moment of the electrical dipole q and length d is;

( )

For the rotation of the structure (spherical model) the required micro torque calculation is the vector product between the moment of the dipole and the field strength;

= ( )

If the spherical structure characterized by a common or mediated permittivity is and the structure is in another biological environment characterized by the permittivity , and in an uneven electric field the moment of the dipole (Fig.32) is calculated with the relation [48,49 ]:

( )

Where R- is the lipid-drug structure radius (with the range between 20nm and 5 micrometers), the Clausius-Mossoti coefficient [42,49] is;

( )

Under these conditions, the force that ensures linear displacement is given by the relationship;

= ( )

And the torque needed to rotate the structure;

( )

The advantages of using liposomes in the drug delivery:

[20].[21],[22],[23],[24].

The liposomes can increase the efficiency and the effect of the treatment

The liposomes can increase the stability of the medication to their capsule.

The liposomes are non-toxic, they are flexible, biocompatible, completely biodegradable, non-immune for immunogenic viewpoints.

The liposomes are much more flexible when we attach ligands, and so it is easier to reach its target.

The liposomes help reducing the toxic effect of the encapsulated medication by avoiding exposing the sensible tissue to the medication.

The liposomes decrease the toxicity.

The liposomes improve the efficiency of the medication against intracellular and extracellular pathogenic agents.

The liposomes can have specific actions depending on the place where they act.

The liposomes can integrate the hydrophilic and hydrophobic medication in their bilayer. The structure of the compartment as lipid membrane and the aqueous core.

Pharmaceutical products based on incorporating medication in liposomes are very stable contrary to the effect of inactivity of the extreme condition and doesn’t cause unwanted side effects

The properties of the liposomes: dimensions, encapsulated medication and the surface can be easily modified before and during their preparation.

The disadvantages of liposomes in drug delivery

The production of liposomes is very expensive

The liposomes can determine the drain and the fusion medication/molecule encapsulated.

The liposomes have a short expiration date

The liposomes can affect the stability of the formula

The substance from liposomes can oxidize or can produce the reaction of hydrolysis

The liposome has a low solubility.

The main factors for this branch of our project are:

Solubility;

Dispersion;

Digestion;

Absorbtion.

The effective absorption of the drug by intestinal mucosal cells is the ultimate goal of any formulation based on this type of oral delivery. This figure (figure 22) represents the processes that take place in the intestinal environment.

Program

We wrote a program that helps us to calculate the lipid forces we use in microactuators.

This program reads the initial values of the electrical loads (charges in the lipid arm (the distance between these and the hydrophobic arms).

Enter the liquid / vacuum permisivity data and the angle of the lipid arms (depending on the lipid culture we use).

Also, the program is able to generate graphs based on culture used in experiments or microactuators.

Below we will attach screenshots with the program (calculation, graph and structure).

English version:

9. Concluzie

All in all, we believe that our project is very promising at all levels and we hope that in the future we can develop it more.

Both, the lipids microelectromechanical (MEMS) project and the drug carrying project in injured cells are a complex research topic that deserves further development with extensive applicability in the field of engineering and pharmaceuticals.

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