**7. 3D printing of magnetic polymer nanocomposites for medical applications**

Magnetic nanoparticles in their pure form are rarely used for therapeutic purposes. Usually, they are encapsulated and/or placed in biologically inert matrixes (oligomers or polymers, including those of natural origin) with the view of reducing a possible toxic influence of the magnetic phase, raising its physicochemical stability and creating of the immobilization conditions on the surface of drugs capsules or matrixes. This problem is successfully solved by the AT methods [51]. The capsulation is usually conducted in ultrafine ferri-, ferro- and superparamagnetic particles, containing stabilizing reagents called "magnetic liquids" [52, 53]. Magnetic nanodots are essentially the same class of nanoparticles, that are respondent to the magnetic field influence. Such particles usually consist of magnetics, such as iron, nickel, and cobalt, and of their chemical mixtures. The increased interest to these objects is explained by their possible application in the catalysis, biomedicine, magnetic-resonance (MR) spectro‐ scopy, and data storage.

Physicochemical characteristics of the magnetic nanoparticles are strongly dependent on the method of their preparation and chemical structure. In most cases, these are particles of the size ranging from 1 up to 100 nm with the apparent superparamagnetism.

During their motion by the blood flow, the nanoparticles could become coated with the blood plasma protein, or absorbed by the immune protectors (macrophages). In order to extent the nanoparticles lifetime in the organism, the polymeric chains are fastened to the nanoparticles. Another method consists in the attachment to nanoparticles of antibodies for malignant tumorous cells since they "know" the pathway to the target (the cancer tumor). The magnetic nanoparticles behavior inside the organism is caused by the surface phenomena, size of nanoparticles and their magnetic characteristics (magnetic moment, remanent magnetism) [54]. The surface phenomena chemistry is particularly important for the elimination of the influence of reticular-endothelial system (RES) being the part of the immune system, and for the elongation of the nanoparticles lifetime within the bloodstream. The nanoparticle coating by a neutral and hydrophilic compound (i.e., polyethylene glycol (PEG), polysaccharides, etc.) enlarges the circulating time of the particle existence from minutes to hours and even days [55].

One more possible way is the reduction of the particles size. However in spite of all the efforts, the RES effect has not been completely avoided, and toxicological problems due to the undesirable displacement into other organism areas are still remaining.

Magnetic nanoparticles have found a lot of efficient applications in biomedicine that open new possibilities for therapy and diagnostics of a number of heavy diseases. Alive organisms are built of cells with a typical size of about 10 μm. And in turn, the cell components are much smaller and have the size less than 1 μm. For medical applications, it is important that nanoparticles have controllable sizes within the range of several nanometers to hundreds nanometers, which are comparable with the sizes of intracellular biological objects—(10–100 nm), viruses (20–450 nm), proteins (5–50 nm), and genes (about 2 nm in the transverse direction and 10–100 nm lengthwise). By their size (from 4 to 1000 nm) and their mass, nanoparticles are intermediate between molecules and alive cells.

This size range opens great freedom for promissory medical application of nanoparticles at the AT.

## **7.1. Magnetic hyperthermia**

**7. 3D printing of magnetic polymer nanocomposites for medical**

Magnetic nanoparticles in their pure form are rarely used for therapeutic purposes. Usually, they are encapsulated and/or placed in biologically inert matrixes (oligomers or polymers, including those of natural origin) with the view of reducing a possible toxic influence of the magnetic phase, raising its physicochemical stability and creating of the immobilization conditions on the surface of drugs capsules or matrixes. This problem is successfully solved by the AT methods [51]. The capsulation is usually conducted in ultrafine ferri-, ferro- and superparamagnetic particles, containing stabilizing reagents called "magnetic liquids" [52, 53]. Magnetic nanodots are essentially the same class of nanoparticles, that are respondent to the magnetic field influence. Such particles usually consist of magnetics, such as iron, nickel, and cobalt, and of their chemical mixtures. The increased interest to these objects is explained by their possible application in the catalysis, biomedicine, magnetic-resonance (MR) spectro‐

Physicochemical characteristics of the magnetic nanoparticles are strongly dependent on the method of their preparation and chemical structure. In most cases, these are particles of the

During their motion by the blood flow, the nanoparticles could become coated with the blood plasma protein, or absorbed by the immune protectors (macrophages). In order to extent the nanoparticles lifetime in the organism, the polymeric chains are fastened to the nanoparticles. Another method consists in the attachment to nanoparticles of antibodies for malignant tumorous cells since they "know" the pathway to the target (the cancer tumor). The magnetic nanoparticles behavior inside the organism is caused by the surface phenomena, size of nanoparticles and their magnetic characteristics (magnetic moment, remanent magnetism) [54]. The surface phenomena chemistry is particularly important for the elimination of the influence of reticular-endothelial system (RES) being the part of the immune system, and for the elongation of the nanoparticles lifetime within the bloodstream. The nanoparticle coating by a neutral and hydrophilic compound (i.e., polyethylene glycol (PEG), polysaccharides, etc.) enlarges the circulating time of the particle existence from minutes to hours and even days [55].

One more possible way is the reduction of the particles size. However in spite of all the efforts, the RES effect has not been completely avoided, and toxicological problems due to the

Magnetic nanoparticles have found a lot of efficient applications in biomedicine that open new possibilities for therapy and diagnostics of a number of heavy diseases. Alive organisms are built of cells with a typical size of about 10 μm. And in turn, the cell components are much smaller and have the size less than 1 μm. For medical applications, it is important that nanoparticles have controllable sizes within the range of several nanometers to hundreds nanometers, which are comparable with the sizes of intracellular biological objects—(10–100 nm), viruses (20–450 nm), proteins (5–50 nm), and genes (about 2 nm in the transverse direction

size ranging from 1 up to 100 nm with the apparent superparamagnetism.

undesirable displacement into other organism areas are still remaining.

**applications**

248 New Trends in 3D Printing

scopy, and data storage.

Magnetic nanoparticles can be incorporated into a bioresorbable polymer matrix so that they could reverberatory respond on the alternating external magnetic field (EMF) of a certain frequency and amplitude, and concurrently effectively absorb the EM energy and transfer it as a heating to the surrounding biological tissues. For instance, a magnetic nanoparticle can be used as hyperthermia agent heated in the applied EMF and delivering mortal doses of thermal energy to the tumors cells [56]; or as facility capable of increasing the efficiency of chemotherapy, beam and laser therapy, where magnetic nanoparticles lead to a moderate degree of heating resulting in a more efficient destruction of the malignant tissue. For the magnetic hyperthermia the particles are to possess high SAR (specific absorption rate) allowing their fast heating in the alternating magnetic field. The cancerous cells are known to be ruined under 42–43°C.

Study on the absorption rate of the EME by the magnetic liquid SAR with nanoparticles is important for the certification of fluid-magnetic hyperthermia (FMH) drugs. Along with the parameters, such as Curie point, value of saturation-specific magnetization, and toxicity, the SAR as an attribute of the magnetic liquid determines the possibility and efficiency of medical applications. For the FMH, it is necessary to develop in polymers the magnetic nanoparticle compositions, capable of releasing a dosated portion of magnetic particles. At present, superparamagnetic particles on the magnetite base have been developed, with the substitution of Fe2− by manganese and zinc, and Fe3−—by the gadolinium. At a slight decrease in the specific magnetic receptivity and specific magnetization saturation, the Curie temperature reduction from 575°C (magnetite) to 70°C was achieved. A similar problem was also solved for man‐ ganites.

The tendency to reducing the size resulted in a dominating use of superparamagnetic systems (for instance, superparamagnetic iron nano-oxides (SPIO)) without a hysteresis loop. The magnetic nanoparticles used for therapeutic purposes, can consist of ferromagnetic, ferrimag‐ netic, or superparamagnetic materials. Their main advantage is the possibility of contactless control of their displacement in the organism under the EMF. In our researches, it was shown that promissory materials are iron oxide nanoparticles with spinel structure (magnetite, maghemite) and even high-temperature superconducting ceramics (SrFe12O19) [31].

## **7.2. Radio-absorbing coatings from polymers with nano inclusions**

To protect against the EMF, radioabsorbed materials (RAM) are widely used, in particular polymer composites with ferrimagnetic or ferromagnetic nanoadditives are used as RAM. Efficient RAM should satisfy a number of requirements: maximum absorption of electromag‐ netic waves within a wide frequency range, minimum reflection and lack of harmful fumes, fire safety, small dimensions, and light weight.

Two types of RAM are distinguished: interference type, wherein the electromagnetic waves are weakened due to the destructive interference, and absorbing type in which the electro‐ magnetic energy is converted into thermal one due to scattered currents, dielectric or magnetic relaxation. Depending on the main source of relaxation, the RAM can be of dielectric or magnetodielectric types, and depending on the operating range of the absorption frequencies, there exist narrow band or wide band RAM.

As the alternative, the transparent in visual light materials (glass, polymer) can be used with embedded magnetic nanoparticles (particularly, magnetite Fe3O4 nanoparticles and hexagonal strontium ferrite SrFe12O19 nanoparticles) [11, 31]. It is known that spinel ferrites and their composites effectively absorb EMR within the frequency band of 0.8–2.0 GHz. Hexagonal ferrites intensively absorb in the range of tens of GHz. So, by combining the nanoparticles of magnetite and hexaferrites (e.g., strontium hexaferrite), it is possible to improve the RAM performance at the edges of the frequency band, i.e., at few GHz and at tens GHz, thus significantly increasing the operating range of RAM.

Earlier, we have obtained the 3D parts from polymers with nano inclusions of Fe3O4 and SrFe12O19 by the SLS/M. By the proposed method, it is possible to fulfill easy polymer coatings with nanoparticles of the above-mentioned ferrites on the surface of medical equipment thus providing its protective covering [57, 58].

#### **7.3. Magnetic nanoparticles for targeted drug delivery systems**

The targeted drug delivering (TDD) is one more promissory sphere for the medical application of magnetic nanoparticles [49]. Its main advantages are significant reducing of the drug toxic effect on other organs and systems, possibility to direct and retain the drug-containing nanoparticles in a certain place with the help of magnetic field, and to visualize them by the magnetic resonance imaging (MRI) methods. An important property of magnetic nanoparti‐ cles is a possibility of their local heating by the high-frequency magnetic field for the initiating of the drug desorption/decapsulation mechanism or for magnetic hyperthermia. Usually for the TDD, the superparamagnetic particles are used as the magnetic carrier since after the magnetic field influence they are not aggregating. However, there exists the problem of the reduction of magnetic influence power after the drug delivery, resulting in complicating of the particles retaining in close proximity from the target object, particularly under the powerful blood flow effect.

For a long time, already various one- and multicomponent liposomes generating in lipid solutions have been well known. For the practical purposes, liposomes with sizes of 20–50 nm are of interest since they are used as drug delivering systems to a biological target [59]. There is also a whole set of natural nanocarriers, for instance, viruses. Especially, processed adeno‐ viruses can effectively be used for vaccination through the skin. Other examples of biogenic nanoparticles capable of the targeted delivering are lipid nanotubes, nanoparticles and nanoemulsion of natural origin, some cyclical peptides, chitozans, and nucleic acids [60].

"Magnetic" bacteria can deliver drugs, for instance they can be used as a system for the point delivery of drugs to the diseased tissues also. The MC-1 bacteria are capable of a fast moving owing to the rotating of their own flagellums. Besides, they contain magnetic nanoparticles and are therefore sensitive to the magnetic field and are enforced to move along the lines of force. As a generator of these lines of force the MRT device, for instance, can serve.

netic waves within a wide frequency range, minimum reflection and lack of harmful fumes,

Two types of RAM are distinguished: interference type, wherein the electromagnetic waves are weakened due to the destructive interference, and absorbing type in which the electro‐ magnetic energy is converted into thermal one due to scattered currents, dielectric or magnetic relaxation. Depending on the main source of relaxation, the RAM can be of dielectric or magnetodielectric types, and depending on the operating range of the absorption frequencies,

As the alternative, the transparent in visual light materials (glass, polymer) can be used with embedded magnetic nanoparticles (particularly, magnetite Fe3O4 nanoparticles and hexagonal strontium ferrite SrFe12O19 nanoparticles) [11, 31]. It is known that spinel ferrites and their composites effectively absorb EMR within the frequency band of 0.8–2.0 GHz. Hexagonal ferrites intensively absorb in the range of tens of GHz. So, by combining the nanoparticles of magnetite and hexaferrites (e.g., strontium hexaferrite), it is possible to improve the RAM performance at the edges of the frequency band, i.e., at few GHz and at tens GHz, thus

Earlier, we have obtained the 3D parts from polymers with nano inclusions of Fe3O4 and SrFe12O19 by the SLS/M. By the proposed method, it is possible to fulfill easy polymer coatings with nanoparticles of the above-mentioned ferrites on the surface of medical equipment thus

The targeted drug delivering (TDD) is one more promissory sphere for the medical application of magnetic nanoparticles [49]. Its main advantages are significant reducing of the drug toxic effect on other organs and systems, possibility to direct and retain the drug-containing nanoparticles in a certain place with the help of magnetic field, and to visualize them by the magnetic resonance imaging (MRI) methods. An important property of magnetic nanoparti‐ cles is a possibility of their local heating by the high-frequency magnetic field for the initiating of the drug desorption/decapsulation mechanism or for magnetic hyperthermia. Usually for the TDD, the superparamagnetic particles are used as the magnetic carrier since after the magnetic field influence they are not aggregating. However, there exists the problem of the reduction of magnetic influence power after the drug delivery, resulting in complicating of the particles retaining in close proximity from the target object, particularly under the powerful

For a long time, already various one- and multicomponent liposomes generating in lipid solutions have been well known. For the practical purposes, liposomes with sizes of 20–50 nm are of interest since they are used as drug delivering systems to a biological target [59]. There is also a whole set of natural nanocarriers, for instance, viruses. Especially, processed adeno‐ viruses can effectively be used for vaccination through the skin. Other examples of biogenic nanoparticles capable of the targeted delivering are lipid nanotubes, nanoparticles and nanoemulsion of natural origin, some cyclical peptides, chitozans, and nucleic acids [60].

fire safety, small dimensions, and light weight.

250 New Trends in 3D Printing

there exist narrow band or wide band RAM.

significantly increasing the operating range of RAM.

**7.3. Magnetic nanoparticles for targeted drug delivery systems**

providing its protective covering [57, 58].

blood flow effect.

Nanospheres and nanocapsules are referred to the polymer nano objects. The nanospheres are solid matrixes with an active material spread over their polymer surfaces, while in nanocap‐ sules the polymer coatings form the cavity filled with liquid. Hence, the active material is released into the organism by different mechanisms—the release from the nanospheres is of an exponential nature, whereas from the nanocapsules it happens with a constant velocity and for a long time. Polymer nanoparticles could be received via the SLS/M process as core/shell composites. They are polysaccharides, polyglycolic acids, polylactides, polyacrylates, acrylic polymers, polyethyleneglycol (PEG), etc. Polymer materials are characterized by a whole number of useful properties for the medical transportations, such as biocompatibility, ability to be biologically decomposed, and multifunctionality.

Dendrimers are becoming of a high interest. This is a new type of polymers, having a branch‐ ing, dendrite-like structure instead of the usual linear one. Dendrimers are often mentioned in the context of their nanotechnological and medical applications. Dendrimers are a unique type of polymers since their size and shape can be superaccurately specified under the chemical synthesis that is extremely important for the TDD. Dendrimers are obtained from monomers by conducting their consequent convergent and divergent polymerization (including the use of the peptide synthesis methods), thus determining the pattern of branching.

Typical monomers used in the synthesis are polyamide-amine and amino acid—lysine. The "target" molecules are linked with dendrimers either by means of forming complexes with their surface, or by means of embedding deep between their separate chains. It is also possible to place in a stereo-specific way the necessary functional groups on the dendrimers surface so that they could interact with viruses and cells.

Carbon nanoparticles (fullerenes and nanotubes) are well known material for the TDD. Nanotubes can be used as microscopic containers introduced by the SLS/M process for the transporting of many chemical or biologically active materials: proteins, poisonous gases, fuel components, and even melted metals. For medical applications, the nanotubes possess an important increased affinity to lipid structures, they are able to form stable complexes with peptides and DNA-oligonucleotides and even encapsulate these molecules. Taken together, all these characteristics and properties provide their application as efficient drug delivering systems for vaccines and genetic material.

Promissory platform technologies are microcapsulation, technology for manufacturing of matrix, multilayered, and coated tablets and capsules. Designed and described in the literature are the platform technologies for making the nanosize complexes of active materials with biocompatible and biodegradable synthetic and natural polymers [6, 18]. The nanosize may result in the increase in a drug activity by several times and also in the reinforcement of therapeutic characteristics. Preclinical studies of known drugs in new nanopacking are already carried out (e.g., taksol or nurophene of a prolongation effect). Platform technologies for a controllable drugs release are very important for the targeted delivery of high toxic antineo‐ plastic drugs.

Traditional cancer drugs are evenly distributed by the whole organism, thus reaching both the diseased and healthy organs. This problem can be solved with the help of directed DDS (drug delivery system) when the drug is delivered along with a biodegradable polymer used as transport. In this case, the drug is released not immediately, but gradually, in the process of the polymer degradation.

There exist the target drugs delivering by nanoparticles of a genetic material, DNA or RNA. For the magnetic target influence, the drug or therapeutic radionuclide is attached to magnetic compound, which is entered into the organism, and then concentrated in the area of the target influence by means of a magnetic field (here the implanted constant magnet or the EMF could be used).

The magnetic DDS in its current state is mostly applicable to well-studied tumors, whereas the medical treatment of metastatic and/or small tumors at their early stage of development still remains an unsolved problem. The therapy of emerging tumors implies the development of a new generation of nanoparticles of teradiagnostics type, capable of recognizing small clusters of cancerous cells and delivering the elements (drugs or hyperthermia materials) required for their destruction. Teradiagnostics will ensure a permanent control of the course of treatment with a concurrent checkup of the drug delivery results and influences.

#### **7.4. Magnetic resonance imaging**

Lately, a number of directions in the molecular visualization sphere have got a wide devel‐ opment via the 3D printing. MRI is one of the most powerful noninvasive methods of visual‐ izations intensively used in clinical medicine [61]. Contrast agents based on the magnetic nanoparticles are one of the most perspective medical applications and are considered as the following MRI-agents generation. Magnetic SPIO are also actively researched as contrast agents for the MRI. New biological applications of these contrast agents are the following: checking of a bloodstream, cancer and tissue engineering scaffolds agents, the MRI contrasts, checking the cells motion, and biomolecular study. In contrast to paramagnetic ions, the SPIO nanoparticles have a higher molecular relaxation. Therefore, in case of their use under low concentration for the bloodstream checkup, they can have some advantages. The MRI yields to positron spectroscopy in its resolution but it gains in its cost. An inexpensive MRI procedure with the SPIO nanoparticles use, distinguishes tumor metastasis of approximately 1 mm size.
