DOI: 10.31038/NAMS.2024721

Abstract

In this overview work the changes in the structure and properties of commercially pure niobium and tantalum under conditions of hard cyclic viscoplastic deformation are studied. During linear compression-tension deformation of the sample, wich was carried out in the strain control mode in the range from ε=±0.2% to ε=±3.0% with a frequency f=0.2-2.5 Hz and with a number of cycles in the range from 20 up to 40, respectively. In addition to classical methods of severe plastic deformation, this method can be used to improve and stabilize the microstructure, mechanical, physical and functional properties of single crystalline, coarse-grained, ultrafine and nanocrystalline metallic materials. The experimental results obtained can be used to study the stability and viability of metallic materials, as well as predict their suitability over time in harsh environments such as space and military applications, and thereby expand new understandings and connections in materials science.

Impact Statement

This overview article comprehensively reviews recent advantages of the development of niobium and tantalum structure and properties studyied by severe plastic deformation (SPD) and hard cyclic viscoplastic deformation (HCVD) at room temperature.

Keywords

Severe plastic deformation, Hard cyclic viscoplastic deformation, Microstructure, Mechanical properties, Physical properties, Wear, Tribological properties, Viability, Electrical conductivity, Hydrogen storage, Young´s modulus

Introduction

Written science in the field of SPD first appeared in the late 20th century [1,2], but archaeological research has shown that the process was known and used at least 2,700 years ago [3] in the production of knives and swords. Humanity has been working with metals since the Bronze Age and has created a common and understandable terminology for all communities. For example, the metalworking process with severe plastic deformation (SPD) in turn contains about a hundred technological processes and a large number of terms to describe these processes and their results. The field of SPD is constantly being improved with new methods already developed and partially patented for more than a hundred names. Currently, more than 1000 papers are published annually in the field of SPD. The emergence and application of new processes in materials science also require the development and addition of new terminologies.It is well known, that the SPD methods are popular due to their ability to modify the microstructure [4-6] and mechanical properties [7-10] of various plastic metal materials. At that time, it was well known that the mechanical properties of SPD-processed materials were significantly better compared to their coarse-grained counterparts [11-15]. Experimental results show that it is possible to change the initial microstructure from a coarse-grained (CG) to an ultrafine-grained (UFG) structure with grain sizes in the range from 1000 to 100 nanometers at ECAP and to a nanocrystalline (NC) structure with a crystal size below 100 nanometers [16-21] at HPT. Unfortunately, the scientific works on SPD listed in [1-21] have so far mainly studied only changes in the microstructure and mechanical properties of materials, such as hardness and strength. At the same time, a number of recent scientific articles have shown that changes in microstructure and mechanical properties during SPD also lead to changes in electrical conductivity [22-27], phase transformations [28-31], wear resistance [32-35], cyclic plasticity [36-41], and so on. Unfortunately, in these works relatively little attention was paid to changes in functional properties, which limits the widespread use of these materials in modern industry.

Components and entire systems are characterized by time-varying cyclic loads and often random load sequences that can cause material fatigue and damage. Therefore, understanding the relationship between fatigue damage and random cyclic loading is a necessary prerequisite for reliable sizing of components and structures. However, this design of fatigue components is motivated not only by the desire to avoid damage to products and their repair. Today, issues of materials and energy efficiency are becoming increasingly important, and therefore increasing their sustainability during operation, which requires accurate knowledge of the operating loads of the systems and the corresponding fatigue behavior of the materials. Sustainability in today’s sense means making the most efficient use of available resources, and this goal can only be achieved for many components and structures if the load sequences present in the operation are known and taken into account when optimizing materials, design and production in industry. Information on the latest developments in the field of variable load fatigue, new scientific approaches and industrial applications of materials, components and designs is up to date. The achievements and results of research in recent years, new approaches and the latest processes in various industries are highly appreciated.

Tension-compression amplitudes, as characteristic features of typical workload sequences in various mechanisms, are becoming very important parameters in the design and optimization of components and structures. Material testing methods such as low cycle fatigue (LCF) [42] and high cycle fatigue (HCF) [43], ratchet [44], Bauschinger effect [45-47], Young’s modulus [54], are very important to determine the durability of materials in actual use.

For example, the number of cycles to failure for the LCF test method is typically less than 10,000, and the failure mode is typically ductile failure. During HCF testing, the material or component fails after a large number of cycles, typically greater than 10,000. Thus, HCF is typically associated with very low strain amplitude at tensile, elastic deformation, crack initiation and growth. The difference between these test methods, LCF and HCF, depends on the level of strain under tensile stresses, the ductility of the material and the degree of elastic deformation. Fatigue behavior is characterized by loading frequency, loading history, loading type, ambient temperature, microstructure, defects and residual stresses in the material.

The ratcheting method uses only tensile deformation with controlled tensile strain and a very small number of cycles. The ratcheting method is based on the well-known Bauschinger effect. The method for testing of metallic materials in viscoplastic states is so called as Hard Cylic Viscoplastic Deformation (HCVD) is described in [55-59]. The viscoplastic behavior and hardening/softening of metallic materials allows you to very quickly, simply and cheaply change and study the structure and properties of metallic materials. For example, this method has been used at firstly to study the microstructure, mechanical and functional properties of metallic materials such as coarse grained (CG) copper [60], ultrafine-grained copper alloys [61], pure niobium [62-65], pure tantalum [66-69] with oligocrystalline structure and also Ni-based single-crystal superalloy [70-73], etc.

This overview study on Nb and Ta by uising HCVD technique is based primarily on my own research work in which I have studied materials using various SPD techniques. HCVD principles were first presented in 2004 at the TMS Ultrafine Grained Materials III Annual Meeting, Charlotte, North Carolina, USA [74] and at the 4th DAAAM International Conference on Industrial Engineering – Innovation as a Competitive Advantage for SMEs, Tallinn, Estonia. [75]. Unfortunately, HCVD as a new process in materials science has not yet been widely used in studying the evolution of the structure and properties of metallic materials. At present time the stability and viability of metallic materials, and predicting their suitability over time in harsh environments such as space and military applications is actual. Studying the behavior of metallic materials in viscoplastic states using HCVD method allows us to expand concepts and new connections in materials science.

Experimental Section

Materials

The materials for present experimental work were technically pure niobium (Nb) and tantalum (Ta) ingots, which were produced by electron beam melting (EBM) technique on Neo Performance Materials (NPM) Silmet AS, Estonia. The chemical analysis of NPM Silmet AS showed that the pure Nb ingots, with diameter of 220 mm, contained the following non-metallic elements: N (30 ppm), O (72 ppm), H (˂10 ppm), c (˂20 ppm), and metallic elements: Ta (160 ppm), Si (˂20 ppm), P (˂15 ppm), Mo (˂10 ppm), and W+Mo (˂20 ppm), respectively.

The Ta inots diameter was 120 mm and an oligocrystalline macrostructure. The chemical composition of Ta was: Al, Mg, Pb, Cu, Fe, Mo, Mn, Na, Sn (for all ˂5 ppm), Nb (˂20 ppm), W (˂10 ppm), and Si (˂10 ppm) and non-metallic elements: N (˂ 20 ppm), O (˂ 30 ppm), H (˂10 ppm), S (˂10 ppm), C (˂10 ppm), respectively. These ingots had a oligocrystalline macrostructure up to 15-20 cm in length and approximately 5-6 cm in thickness (Figure 1). The Nb and Ta samples were before for recrystallization heat treated in vacuum furnace at 1100°C for 30 min.

Figure 1: Oligocrystalline macrostructure of Ta after EBM by industrial processing

The IEAP Technique and Test Samples Manufacturing

Using hard-to-deform Nb and Ta samples, the ECAP matrix was modified and a new so-called “indirect extrusion angle pressing” (IEAP) method was developed [34,63,66,67,76]. IEAP format channels do not have the same cross-section. The cross-section of the output channel, taking into account the elastic deformation of the base metal, was reduced to 5-7%, which makes it possible to use the conveyor method when pressing without intermediate processing of the cross-section of the workpiece. This is due to elastic deformation of the matrix and an increase in the cross-section of the sample during pressing. To process workpieces under HCVD, the developed IEAP technology was used. In the work under consideration, the microstructure of the samples under study was modified up to 12 passes of the IEAP along the B_C route. The maximum degree of von Mises deformation during one pressing was 1.155, and after 12 passes – up to ~13.86, respectively. As experiments have shown, this IEAP die is convenient for processing high-strength materials, since at higher extrusion passes, when the strength of the materials increases sharply, the friction between the punch and the matrix during pressing also increases, and thus the risk of damage to the matrix or plunger increases. [67]. For comparison, the same metals (Ta and Nb of the oligocrystalline as well as recrystallization structure received at heat treatment) were used so that the results could be compared. Using the IEAP method, samples with dimensions of 12x12x130 mm are produced. The processing steps of IEAP samples are shown in Figure 2.

Figure 2: Diagram of the IEAP stamp and the corresponding stages (a, b, c, d) of sample processing using the so-called conveyor method, with this method in the stamp at the final stage two samples are simultaneously processed, the second sample pushes out the first (d).

The specimens for hard cyclic viscoplastic deformation (HCVD) were manufacturing from EBM and IEAP-treated samples (Figure 3a and 3b). The mechanical cutting and electroerosion tchniques were used. The samples for electrical conduction, hardness, gases content, density, XRD, and microstructure study were cut off from HCVD sample (Figure 3c) and tensile tests minisamples Figure 3f) were cut off by electrical discharge method from HCVD sample (Figure 3d and 3e). The strain amplitude at HCVD testing was measured by extensometer with base length of 10 mm and it was mounted on sample with minimal cross section (Figure 3c). The strain amplitude for other cross sections were calculated. IEAP of the samples was carried out on a hydraulic press with a capacity of 100 tons [68].

Figure 3: Mechanically cut sample from EBM ingot and heat treated at 1100°C for 30 minutes (a), IEAP treated sample (b), test sample for Young’s modulus measure by HCVD with stepped cross section (specimens A1, A2, A3, A4, A5 and A6 (as cast) with 5 mm in length) for measuring microhardness, density, XRD, gases content and electrical conductivity (c), mini-specimens (d) for tensile strength tests (MS1, MS2, MS3, MS4, MS5 and MS6-as cast), cut from the sample after HCVD in diametrical section in three layers 1, 2 and 3 (e), cut out using the electrical discharge method, and a mini-specimen for tensile testing with dimensions in mm is shown in (e).

The HCVD Technique

The HCVD technique was elaborated for materials structure modifing and properties testing [53,58,74,75]. The HCVD as a new process is not yet widespread in the study of metallic materials structure and properties evolution. It is well known that “viscoplasticity” is a response of solids involving time-dependent and irreversible deformations. In this research, we investigate the viscoplasticity of metallic materials and the accompanying changes in microstructure and properties at room temperature. To do this, we use cyclic deformation with a constant strain amplitude at each stage of the experiment. In the HCVD process, the strain amplitude ranges from ε=±0.2% to ±3.0% per cycle. The HCVD was conducted on an Instron-8516 metrials tester, Germany.This method is characterized by the generation of cyclic stress, the magnitude of which depends on the strength properties of the material at a given compression-tension deformation or strain amplitude. Therefore, this research method of metallic materials is called hard cyclic viscoplastic deformation (HCVD). The name of this new process begins with the word “hard”, which means that tensile and compressive deformations are used in the high-amplitude viscoplastic field in both tension and compression. The evolution of the microstructure of mixed metal materials is mainly studied from the deformation rate, the number of cycles, and the deformation stress amplitude of the HCVD method. The effect of HCVD on the improvement of the mechanical and physical properties of test materials has been described in various works [61,69,70,73]. In present overview work these large strain amplitudes of ε₁=±0.2%, ε₂ ±0.5%, ε₃ ±1.0%, ε₄ ±1.5%, ε₅ ±2.0%, ε₆ ±2.5%, and ε₇±3.0% are used, respectively. At each degree of deformation, up to 20÷30 cycles are performed. The cycles number depend on material mechanical properties and viability. The frequency of cycling was chosed in the interval of ƒ=0.5 to 2.5 Hz, and were ƒ₁=0.5 Hz, ƒ₂=1.0 Hz, ƒ₃=1.5 Hz, ƒ₄=2.0 Hz, and ƒ₅=2.5 Hz, respectively. The number of tests of the HCVD method starts from 20 cycles and up to 30 cycles per test for a series with the corresponding constant strain amplitude. The maximal number of cycles was not more then 100 for one sample. The frequency and strain amplitude at HCVD influenced on the strain rate and corresponding changes in the microstructure and properties.

To achieve the required results, the rated voltage, frequency, and a number of cycles are selected based on the test results. Usually, the technical strength is the strength of various constructions in calculations in elastic strain up to ε₁=0.2% at tensile deformation, that is, until the beginning of plastic deformation of the material. In the LCF and HCF tests, the amount of elastic deformation is small, less than 0.2% of the deformation. At such a value of deformation, the metal material has an elastic behavior. The HCVD method determines the magnitude of the controlled amplitude of deformation and is controlled by an extensometer using a computer program that controls the process and displays the corresponding results on the computer screen. Typically, the fatigue test of metallic materials checks the tensile strength but does not check the deformation, which develops automatically according to the mechanical properties of the material. Micromechanical multiscale viscoplastic theory has been developed to relate the microscale mechanical responses of amorphous and crystalline subphases to the macroscale mechanical behavior of fibers, including cyclic hardening and stress recovery responses. The HCVD method can be used as a new test method in materials science when it is necessary to determine the behavior of a material under stresses that can exceed the elastic limit and deform under extreme operating conditions. For example, such extremes may occur in aviation, space, or military technology because these devices have a minimum calculated strength or margin of safety compared to other devices. For example, the compressor blades of a turbojet engine for military fighters have a safety margin of no more than 3-5%.

Methods for Other Properties Testing

The microhardness in cross section of samples A1, A2, A3, A4, A5, and A6 was measured using a Mikromet-2001 tester after holding for 12 s at a load of 50 and 100 g. At follows, the mini-samples (MS1, MS2, MS3, MS4, MS5 and MS6-as cast) at tension up to fracture were tested on the MDD MK2 Stand test system manufactured in the UK. The tribological behavior of materials under dry sliding conditions was investigated before and after IEAP, HCVD and heat treatment to provide a comparison over a range of material properties as well as collected strain to understand their influence on the coefficient of friction and on the specific wear rate. Dry sliding wear was studied in a ball-plate system with a tribometer (CETR, Bruker, and UMT2) using an aluminum oxide (Al2O3) ball with a diameter of 3 mm as a counter surface. The coefficient of friction (COF) was obtained automatically. For wear volume calculations, the cross-sectional area of the worn tracks was measured by the Mahr Pertohometer PGK 120 Concept 7.21. The content of metals inclusions (in ppm) were studied according to MBN 58.261-14 (ICP-OES Agilent 730) and gases concentration according to method of MBN 58.266-16 (LECO ONH-836) and S according to method of MBN 58.267-16 (LECO CS-844), respectively. The electrical conductivity (MS/m and/or %IACS) of metal materials was determined with a measurement uncertainty of 1% for different orientations on flat samples by means of the Sigmatest 2.069 (Foerster), accordingly to NLP standards at 60 and 480 kHz on a calibration area of 8 mm in diameter. The electrical conduction was measured at room temperature of 23.0±0.5°C and humidity of 45±5% according to the international annealed copper standard (IACS) in the Estonian national standard laboratory for electrical quantities. To obtain one electrical conductivity data, 30 measurement tests were automatically performed and the result was displayed on the computer screen.

The samples density after IEAP with different pressing number was measured by OHAUS Scout-Portable balances, Italy at room temperature. The dislocation density was calculated by the Rechinger method according to the results of the X-ray investigation by the D5005 AXS (Germany) and Rigaku (Japan) diffractometer. To study the microstructure, the samples were mechanically polished with silicon papers up to 4000, and then with diamond paste on Struers grinder. After the grinding, the samples were etched by an ion polishing/etching facility using precision etching system at 30 kV for 30 min in an argon atmosphere. The microstructure of the samples was studied using an optical microscope Nikon CX, Japan, and electron microscopes Zeiss EVO MA-15 and Gemini Supra-35, Germany, equipped with an EDS apparatus.

Results

Microstructure Evolution of Nb and Ta during HCVD

For example, full-scale diagrams of the HCVD of the Nb manufactured with various processing methods, microstructure, and properties at different strain amplitudes are shown in Figure 4a-4e [63].

Figure 4: HCVD curves of pure Nb for the viscoelastic tension-compression straining at an amplitude of ε = ±0.1% and corresponding deformation amplitude of v ꞊ ± 0.01 mm in the base length of 10 mm (a), viscoelastic tension-compression straining at strain amplitude of ε = ±0.5% and v ꞊ ± 0.05 mm (b) and at strain amplitude of ε = ±2.0% with the corresponding deformation amplitude of v ꞊ ± 0.2 mm (c). The sample E12 HCVD time-deformation (d) and time-stress (e) curves received at ε = ±2% of strain amplitude. The effect of the elastic-plasticity of Nb on the deflection of the curves during the compression (C) and tension (T) cycles is shown by arrows.

As can be seen in Figure 5, high-purity niobium as well as tantalum EBM ingots contain very large millimeter-sized grains connected by a fully wetted triple grain boundary (GB) (Figure 5a). This width of GBs is in nanometers because the metal is of high purity with thin grain boundaries as shown in the figures. Unfortunately, such large grains contain gas pores with dimensions in micrometers (Figure 5b). Under hydrostatic pressure in the shear region of the IEAP die, these pores are compressed and velded to zero. Such pores and GB defects can be completely repaired by hydrostatic compression and simple shear in the IEAP die. These changes take place in sample for 4 passes of IEAP by BC route (c) and for 12 passes of IEAP by BC route (d), respectively. Microstructural evolution in bulk Ta samples during HCVD are presented in Figure 6. As you can see the microstructure of high purity Ta has GB-s on atomic level [63,68].

Figure 5: The triple grain boundary (a) and pores (b) in EBM as-cast Nb, and SEM pictures of microstructure evolution via grains fracture by slip lines (SL is shown by arrows) in the shear region of IEAP at von Mises strain of Ɛ_vM=4.62 by B_C route (c) and UFG microstructure formed at Ɛ_vM=13.86 (d), respectively.

Figure 6: Microstructure evolution of pure Ta processed by HCVD at 5 test series (5 x 20 cycles with strain step-by-step increase up to ε₅ ± 2.0%) for 100 tension-compression cycles in sum (a) and atomic level GB-s with different orientations of two grains is presented in (b, c).

The microstructure forming in Nb and Ta samples from initial to 8 passes by B_C route for Nb and for 12 passes by B_C route for Ta is shown in Figure 7a-7d. The relative frequency of grain size in mm was calculated by by ImageJ software and is presented in Figure 7e-7h. As you can see the grain size of Nb was decreased about 3 times and Ta grain size was decreased about 2.5 times, respectively [67].

Figure 7: Distribution of grains sizes of Nb (a, b) for initial (Nb0) and after eight passes (Nb8) and Ta (c, d) for initial (Ta0) and after twelve (Ta12) passes by B_C route of IEAP. The corresponding grain size measurements were made by ImageJ software (e, f, g, h), respectively.

The microstructure evolution of IEAP Nb sample during HCVD, with a number of 100 cycles for 5 test series is shown in Figure 8a. For comparison, the IEAP Nb after LCF testing for 100 cycles in Figure 8b. The fatigue cracks are formed during LCF. The TEM images of SB-s with a lowered dislocation density at HCVD in Figure 8c and with high dislocation density after LCF of IEAP sample in Figure 8d, respectively [64].

Figure 8: Optical pictures of double-banded microstructure forming in Nb sample at HCVD for 100 cycles (5 x 20 cycles) (a) [64,69] at increased strain amplitude to ε₅ ± 2.0% and cracks initiation during LCF testing (b) for 100 cycles of the ECAP sample [69]. TEM images of SB-s with a lowered dislocation density at HCVD (c) and with high dislocation density after LCF of IEAP sample (d).

Young´s Modulus Evolution of Nb at IEAP and at HCVD

The evolution of physical properties during HCVD depends on the microstructure and properties of the metallic material achieved by IEAP treatment, as well as on the strain rate, which depends on the strain amplitude (measured in mm) during HCVD (Figure 4a-4c). As shown in the diagram (Figure 9a), the increase in tensile strength during HCVD at a strain amplitude ε₄=±1.5% for all IEAP samples (E2, E4, E6, E8 and E12) with different accumulated von Mises strains is maximum. With an increase in deformation to ε₅=±2.0%, the tensile strength of samples E8 and E12 decreased, since these workpieces had a UFG microstructure obtained in IEAP, with higher tensile strength and hardness. During the HCVD process, at a deformation amplitude ε₅=±2.0%, softening occurs, since the GS begins to increase during the coalescence process. In these workpieces, Young’s modulus also decreases as they soften (Figure 9b) during HCVD treatment. The Young’s modulus of IEAP-treated samples decreases during the HCVD process as the dislocation density decreases (Figure 8c and 9) [63,64].

Figure 9: The IEAP samples E2, E4, E6, E8 and E12 tensile strength increases up to strain amplitude ε₄=± 1.5%, as well as the strain rate (v=0.3 s^-1) increases during HCVD and decrease for E8 and E12 by strain amplitude increase to ε₄=±1.5%, (a) and the Yung modulus (b) increases when the von Mises strain increases to Ɛ_vM=11.55 by B_C route during IEAP, and the Young’s module decreases in samples E12 by increased von Mises strain up to Ɛ_vM=13.86 by B_C route as well by cycles number increase up to 100 cycles during HCVD, respectively.

Ta Physical Properties Evolution at HCVD

The Vickers hardness of Ta was measured, and it was found that with increasing of von Mises strain at IEAP in sample with stepped cross-section, the hardness of Ta increased mainly during the first pressing. By this, the hardness depends on the measurement of orientation to the sample; it is higher in the transverse direction (TD) and lower in cross directions (CS). As shown in Figure 10, a, the Vickers hardness of Ta was increased by increasing the von Mises strain at HCVD. The Vickers microhardness of Ta was increased from 100 HV0.2 to 285 HV0.2, respectively. It should be noted that the methods for measuring hardness according to Martens and Vickers are different. The Marten’s hardness is calculated from the difference between the maximum depth of indentation and after removing the load, when the Vickers hardness is calculated from the length of the diagonal, indentation load and only hardness are measured. The electrical conductivity of Ta (Figure 10b) has similar dependence on strain level and orientation of measure in the heat-treated sample [68].

Figure 10: The evolution of Vickers microhardness (a), and electrical conductivity (b) depends on measuring orientation and heat treatment temperature from 20°C to 165°C with a heating rate of 1°C•min⁻¹. TD: Transverse Direction and CS: Cross-Section.

A well-known fact from the scientific literature is that the Young’s modulus is constant in materials at room temperature. This modulus decreases with increasing temperature and increases with increasing the density of materials. Young’s modulus of Ta is about 186 GPa at room temperature and the maximum value is 193 GPA at 10−6 K. As can be seen in Figure 11, this modulus may also be affected by the amount of strain applied to the material (or the number of passes in IEAP) and the change in equivalent strain-stress amplitude during HCVD. The changes of Young’s module in the Ta samples (S1-initial, S2 – 5 pressings of IEAP, Ɛ_vM=5.77, and S3 – 12 pressings of IEAP, Ɛ_vM=13.86) are shown in Figure 11. Before Young module measure the samples were processed by HCVD at strains of ε₂=±0.5%, ε₃=±1.0%, and ε₄=±1.5% for 20 cycles at one strain level. It should be mentioned that Young’s modulus of each sample was measured for three times in the intervals of tensile strains from 0÷0.06% and from 0÷0.1% to ensure about the reliability of results. Was established, that this modulus depends on von Mises strain, strain rate as well on the interval of strain, at which this parameter was measured. When the material is harder, Young’s modulus is higher at the tension in the interval of the strain of 0-0.1% (S2) and when the material is softer, Young’s modulus is higher for 0÷0.06% strain interval (S1) and lowers at 0÷0.1%, respectively [68].

Figure 11: Change of Young’s modulus in Ta at uniaxial tension (measured after IEAP and HCVD) at strain of 0–0.06% (blue) and of 0–0.1% (red) of samples S1 (a), S2 (b) and S3 (c), respectively.

Changes in electrical conductivity and Vickers microhardness in IEAP samples (S1, S2, and S3) were measured with different orientations (Figure 12). These values vary depending on the strain applied during processing or hardness, as well as on the orientation of the measurement, in cross-section (CS) or transverse (TD) direction. As you can see (Figure 12), when the Vickers microhardness is higher, the conductivity is lower when the heating rate is low. In work is shown, that the electrical conductivity depends on the hardness and strength properties of CuCr-alloys. In the works [39] is shown, that the electrical conductivity and Vickers microhardness of CuCr-alloys increase with temperature increase and revealed maximal values at ~550°C. Accordingly, these parameters depend not only on the microhardness because the density of dislocations was lowered during heat treatment. In the present work, the Ta samples were heat treated at a very low heating rate of 1°C·min⁻¹, and the Vickers microhardness and electrical conductivity increased in sample S2 and decrease in sample S3, respectively. The conductivity is expressed as a percentage of the International Standard Annealed Copper (%IACS), which is 5.80 × 107 Siemens/m at 20°C. Results show, that the electrical conductivity varied in dependence on energy associated with dislocations, grain boundaries state, and vacancy concentration in Ta samples during ECAP and HCVD, respectively (Figures 12 and 13) [68,69].

Figure 12: Influence of processing routes as well as microstructure on microhardness, and dislocation density (a), electrical conductivity and density (b), oxygen and hydrogen contents (c) of pure Niobium. Designations: E12-12 passes of IEAP by B_C route, H5-five test series by strain rate increase during HCVD, E12-350°C- heat treatment temperature of sample E 12.

Figure 13: Creep and Relaxation of different materials vs. manufacturing technologies (a). Designations: N1 – By electrical forging (EF) processed Ni-based Fe containing superalloy, N2 – SC Ni-based superalloy, N3 – Cold-drawn pure Cu, N4 – Recrystallized pure Cu, and N5 – ECAP processed nanocrystalline pure Cu [78]. Density evolution of pure Ta processed by IEAP and HCVD (b). Designations: (A4) IEAP processed only, and (A1, A2, and A3) after followed HCVD with different strain amplitude (see Figure 3c) (b).

XRD Investigation of Changes in the Tantalum during EBM, IEAP, and HCVD

Anisotropic deformation during IEAP, and HCVD processes, as well as anisotropic properties in samples, can lead to the formation of anisotropic crystallites and, therefore, anisotropic peak intensities. The X-ray diffraction patterns of the samples: Ta, 2x EBM, Ta, 5x IEAP, Ta, 12x IEAP, and Ta, 5x HCVD are presented in Figure 14. As you can see the X-ray diffraction patterns of the HCVD Ta with compare to EBM and IEAP are differ significantly from other samples. It should be noted that this sample (5x HCVD) had a recrystallized microstructure before HCVD. During HCVD, the microstructure changed, and only one peak appeared in the X-ray diagram at ~ 55.6°. Such an X-ray pattern with a single peak is characteristic of a single-crystal metal and a single-crystal Ni-based superalloy [71]. XRD investigation revealed that at the phase transformation took place at the SPD processing [70,72]. The crystallite size and the dislocation density is possible to determine by X-ray line profile analysis [67,68].

Figure 14: X-ray diffractogram (a) of the Ta samples. Designations: Ta, 2x EBM, initial, Ta, 5x IEAP, Ta, 12x IEAP, and Ta, 5x 5HCVD), respectively.

Influence of HCVD on Wear and Tribological Properties of Nanocrystalline Materials

The specific wear rate (the volume loss per distance per normal load) and coefficient of friction (COF) measurements show their dependence from sample material chemical composition, sample (surface) hardness as well material wear track surface softening/hardening [68,76] during wear testing (Figure 15). Results show that HCV deformed sample in surface was hardened from 77HV0.05 to 90HV0.05 and on the wear track surface from 115 HV0.05 to 126HV0.05, respectively. In this case the surface hardening was induced by cyclic straining and wears track hardening as result of sliding [69].

Figure 15: Influence of the load applied on the COF and wear track cross/sectional area of IEAP-12 Niobium (a) and specific wear rate of pure Niobium for different passes number and temperatures for a load of 50 gr (b).

The SEM investigation of the worn track surface shows (Figure 16a) that the UFG microstructure of Nb was abrased by the alumina ball during the dry sliding testing. In our experiments, the wear debris was not removed from the contact zone during testing, which has an influence on the results [35]. The damaged surface of the worn track has wear debris with size of approximately 100 nm. The test results show that the as-cast sample has the lowest amplitude of COF then UFG Nb. The as-cast material has the lowest COF (0.78) and the lowest specific wear rate (2.1, ×10^-2×mm²×g^-1) when compared to sample E12 (Figure 15b). The maximal COF was obtained for samples after HCV deformation and samples that were tested in directions that crossed the slip band direction. The specific wear rate was significantly increased after heat treatment at a temperature of 350°C (Figure 16) [69].

Figure 16: SEM picture of wear track surfaces for 15, 50, 100 and 150 g (a) and UFG Nb wear surfaces with debris formed under a load of 100 g (b), and worn surfaces at high magnification of 100000x of samples after 6 passes of IEAP (c).

When comparing our results with the results presented in previous work, the mass loss decreased remarkably as the number of ECAP passes increased, being affected more by the sliding distance than by the applied load under the experimental conditions. From these data, it has been shown that the wear mechanism was observed to be adhesive and delaminating initially, and an abrasive mechanism appeared as the sliding distance increased. In our experiments, the abrasive wear mechanism did not show any dependence on sliding distance.

Discussion

In the papers, a series of experiments were carried out to study the effect of IEAP and HCVD on the microstructure and properties of metallic materials at room temperature. During the subsequent HCVD, we studied the effect of the strain value during tension-compression with a gradual stepwise increase in strain, strain amplitude, and the corresponding strain rate on the microstructure, functional, physical, chemical, and mechanical properties of the studied Nb and Ta. Then, a series of experiments were carried out to study the influence of the number of deformation cycles, the magnitude of axial deformation, the frequency of cycling, and the strain rate during HCVD and followed heat treatment on the microstructure and evolution of the properties of materials in comparison with their initial state. A comparative analysis was carried out, according to the results of which the following conclusions can be drawn: This owerview study evaluated the impact of a new processing method so called as “Hard Cyclic Viscoplastic Deformation” (HCVD) on microstructure, mechanical, physical, chemical, functional, performance, etc. properties of metallic materials such as niobium, and tantalum. To expand the capabilities of the new processing method, the metal materials Nb and Ta with various structures were tested, such as oligocrystalline, coarse-grained, ultrafine-grained, and nanocrystalline. For pre-treatment, multiple methods of severe plastic deformation were used, such as “Indirect Extrusion Angular Pressing” (IEAP). With this new HCVD test method, it is possible to initiate and study the processes occurring in the microstructure of materials before their destruction. HCVD is based on the application of a cyclic tensile/compressive load by controlled strain amplitude on materials at a constant frequency at a given strain level. In this test method, the main parameters are the strain amplitude of compression/tension in the range from 0.2% to 3.0% with the number of cycles from 20 to 40 for one level of deformation and with a frequency of 0.5 to 2.5 Hz. The rest of the process parameters are set automatically depending on the strength properties of the tested metal material in general.

Conclusions

This review study evaluates the effect of a new processing method, the so-called HCVD, on the microstructure microstructure evolution, and mechanical, physical, chemical, functional, tribological properties change, as well as on phase transformations and interatomic interactions, and service life of various metallic materials. To expand the capabilities of the new processing, metallic materials selected for the study, such as Nb and Ta, with different structures: oligocrystalline, coarse-grained, ultrafine-grained and nanocrystalline were tested.

Using this new test method, it is possible to initiate and study the processes occurring in the microstructure and properties of materials during HCVD before their fatigue failure. HCVD is based on the application of cyclic tensile and compressive loads to materials through a controlled strain amplitude at a constant frequency and a specified level of strain. In this test method, the main parameters are the compression-tensile deformation amplitude in the range from ε=±0.2% to ε=±3.0% with a number of cycles from 20 to 40 for one level of deformation amplitude and with a frequency ƒ=from 0, 5 Hz to 2.5 Hz. The rate of deformation depends on the basic strength parameters of the material. The remaining process parameters are set automatically depending on the strength properties of the metal material being tested as a whole. The main outcomes of this overview work can be summarized as follows:

• The microstructure of Nb and Ta processed by HCVD is significantly different from the microstructure obtained by other SPD methods.
• During IEAP processing of EBM as-cast Nb or Ta samples, the gases pores and any defect in GB-s at hydrostatic compression pressure concurrently with the simple shear stress are eliminated.
• The electrical conductivity in SPD processes decreases with increasing hardness, tensile stress and dislocation density and increases when HCVD is combined with heat treatment and lowering of dislocation density.
• The density of pure Nb increased from 8.27 g/cm³ in the as-cast condition to 8.65 g/cm³ after IEAP and HCVD processing, whit’s is higher than the theoretical (8.55 g/cm³) density.
• The density of pure Ta incrased from 16.26 g.cm^-3 to 16.80 g.cm^-3 during HCVD.
• During the followed HCVD, the nanostructure (20-90 nm) was formed in shear bands.
• The electrical conductivity during IEAP decreased and during HCVD it increased as a result of the dislocation density decreasing from 5E + 10 cm⁻² to 2E + 11 cm⁻² since the dislocations are the main obstacles for electrons moving.
• During IEAP, Young’s modulus of Nb was increased to 105 GPa at the von Mises strain Ɛ_vM = 13.86 and then decreased to 99 GPa during the HCVD. The Young modulus (89 GPa) was minimal for sample E12 after HCVD at strain amplitude (Ɛ₅= ±2.0%).
• The softening of the material is related to the decrease of Young’s modulus at the HCVD with the increase of the strain rate higher than έ (t)  = 0.3 s⁻¹.
• In turn, the decrease in Young’s modulus indicates a decrease in the attraction of interatomic forces in the metal.
• The micromechanical properties differ for IEAP and HCVD samples, as well as for SB and in-body metal. For example, after IEAP for 12 passes by B_C route, the SB maximal Vickers nano-hardness was NH = 4.78 GPa and the indentation modulus was Er = 177.7 GPa, respectively.
• During the followed HCVD, these parameters were reduced to NH = 3.29 GPa and Er = 111.4 GPa, respectively.
• The GB width of pure Nb is so small that it is not possible to measure its micromechanical properties by the nano-indentation method used in the present study.
• The gas content in Nb depends on the microstructure condition and it is minimal for UFG pure Nb.
• Compared to the LCF and HCF tests, the HCVD tests require a shorter timeframe.
• Using the HCVD method, it is also possible to study the viability of different metallic materials during operation in aviation, space, and defense under conditions of high load, and close conditions before failure, when the margin of safety is only a few percent.
• Accordingly, this overeview article provides a brief overview of the structure and properties of metallic materials that change as a result of HCVD and thereby extending materials science with new relationships.

Acknowledgment

This research was sponsored by the Estonian Research Council (Grant No. PRG1145).

ORCID Lembit Kommel http: //orcid.org/0000-0003-0303-3353.

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DOI: 10.31038/NAMS.2024714

Abstract

Today, the use of CT scan as a type of diagnostic tool has increased dramatically. Therefore, controlled use and in accordance with protective regulations in order to reduce the harmful  effects of radiation, it is necessary. The purpose of this study was to measure the dose received by patients in computed CT scan protocols and compare it with Monte Carlo simulation using GEANT4 software. Radiation parameters were collected from 11 patients referred to Tohid Hospital in Sanandaj to measure DLP quantity in common protocols. In this study, DLP values for Chest Abdomen protocol were measured and compared with simulation values. Our results show Monte Carlo software outputs experimental data well and is a good benchmark for this software. Thus, the simulated and measured doses agreed well.

Keywords

Computed tomography, Chest CT scan, Monte Carlo, Dose during scan, Reference dose limit

Introduction

CT scan is an advanced imaging technique that provides cross- sectional and transverse images of body parts using X-rays using computer algorithms and calculations [1]. Today, use of CT scan as a type of diagnostic tool has increased dramatically. Specific information is required including activity distribution and organ boundaries for patient-specific dosimetry. CT data provides anatomical information which can be used for defining volume of interests specifying internal organs [2,3]. Nevertheless, using CT images for segmentation of anatomic structures of patient body, despite being more accurate, is time consuming. The alternative is using phantoms or Atlas data with already segmented organs and known organ boundaries. The anatomical structures are derived from these databases very easily [4]. In the United Kingdom, CT scans ranged from 250,000 to about 5 million from 1980 to 2013, representing a 20-fold increase, while in the United States, CT scans ranged from 2 million to 85 million. It has been shown to show a growth of approx. 43 [5]. In the United Kingdom and the United States, CT scans account for 11% and 17% of all medical X-ray tests and 67% and 49% of the cumulative effective dose, respectively. Absorption dose in tissues in CT scan is a higher component of the doses received by patients in diagnostic radiology methods [6,7]. Different parameters affect the dose received by patients in CT imaging. One of the most important factors influencing the dose received by patients is the intensity of the current in the tube (current generated in the tube due to the flow of electrons inside it) as a determinant of the amount of X-rays. For dosimetry calculations GATE (GEANT4) application to Tomographic Emission) [8], a Monte Carlo based script interface dedicated to nuclear medicine, was used. Different versions of this free open source toolkit are available on the open GATE collaboration website [9]. For dosimetry applications, GATE is capable to take either patient’s CT or a digital atlas phantom as input [10]. GATE has certain attractive features; some of them are inherited from GEANT4 [11] and some are additionally developed. These include flexible simulation geometry capable of accommodating a large variety of detector and source details and the physical events. In this study we review the evaluation skin and organ dose of patients caused by CT scan and comparison with Monte Carlo simulation software GEANT4 using DLP index.

Methods

Patient Study

This study was performed on 11 patients referred to Tohid Hospital in Sanandaj for chest CT scan. GE Light Speed RT, a third generation standard radiotherapy CT (GE Medical Systems, Milwaukee WI), was used in this study. The scanner has a large bore (80 cm), distance X-ray tube and isocenter 60.6 cm and performs 4-slice helical scanning. The tube voltage 80-140 kV step 20, tube current 10-440 mA step 5, rotation times of 1, 2, 3 and 4 seconds are available. Images were acquired with slice thicknesses of 2.5 mm on 10.0 mm collimation (4 × 2.5 mm) (GE Light Speed RT CT scanner technical evaluation November 2005). This scanner is used routinely for obtaining patient images for radiotherapy treatment planning at the Akdeniz University School of Medicine Department of Radiation Oncology. The regular quality assurance (QA) for image quality, 120-200 kV-mA measurement and mechanical tests based on national and international processes was performed. Three different body regions of the Rando phantom (head, chest and pelvic) were scanned by applying typical clinical protocols. The scan parameters kV, mA, pitch, FOV (field of view), rotation time, slice thickness of the CT examinations which were used in this study are given in Table 1. The scan length for each scanning protocol is also shown in Figure 1.

Table 1: Quality control tests include the accuracy and reproducibility of the parameters of each scan

Figure 1: A typical transverse slice of CT image of two patients

Monte Carlo Simulation

For both simulations of patient-specific dosimetry with the CT and XCAT phantom, the simulations were performed in GATE Monte Carlo code (version 6.0.0). The data of SPECT, CT and XCAT phantoms were processed to prepare suitable input file formats for GATE. The results of the internal dosimetry for the real activity distribution in the patient body based on the computed CT data were calculated for the CT image and the XCAT phantom in skin as well as in the total body. Photon absorption, Compton and Rayleigh scattering, ionizations, multiple scattering photons were simulated. After completion of simulations, GATE produced two binary files, containing respectively the absolute absorbed dose delivered into the voxels as DLP index (mGy) and the corresponding uncertainties [12]. Dycom photos of each case with VV the 4D slicer software converted into an MHA file or in another way with Mimics Medical 21.0 software converted to 3D STL files. Then, dosimetry separate programs were written for each of these inputs, in MHA and STL formats, and the output of both was almost the same, but in the 2D mode the results were closer to reality.

Dosimetry Calculations

Dose length product (DLP) measured in mGy*cm is a measure of CT tube radiation output/exposure. It is related to volume CT dose index (CTDIvol), but CTDIvol represents the dose through a slice of an appropriate phantom. DLP accounts for the length of radiation output along the z-axis (the long axis of the patient).

DLP = (CTDIvol) * (length of scan, cm)

[units: mGy*cm]

DLP does not take the size of the patient into account and is not a measure of absorbed dose. If the AP and lateral dimensions of the patient are available, then the size specific dose estimate (SSDE) can be used to estimate the absorbed dose.

It is important to remember that the dose length product is not the patient’s effective dose. The effective dose depends on other factors including patient size and the region of the body being scanned. Some multipliers, called k-factors, have been estimated to convert DLPs into effective doses, depending on the body region. If interested, consult reference.

Results

Organ dose simulations were performed using the scan parameters for the chest and abdomen-pelvis CT examinations. The scan range used for the chest CT contained the entire pulmonary area and that used for the abdominal-pelvic CT extended from the diaphragm to the pubic symphysis. In each simulation the obtained results of DLP values for the dedicated GE Light Speed RT CT scanner for organ were about 250 mGy (Table 2). The reported values by manufacturer are 30.16 mGy and 23.9 mGy (GE Report 2005) so Commutated CT is used these values as standards at spreadsheet. The obtained results of DLP values from this study were less then reported values. As a general in the literature, the DLP value for conventional CT scanner is reported to be from 17 to 48 mGy [13-15]. For this dedicated CT scanner, the DLP values were in the range of values from conventional CT. In this study, the organ dose values were obtained by another measurement using the GATE Monte Carlo code (version 6.0.0) calculator and the two methods were compared for each scan protocol. The organs that were in the scanned region are blind listed in Table 3. First result of this study showed that the organ dose is relatively higher in helical mode by using GATE Monte Carlo simulation scanning.

Table 2: Results about dosimetry based on computed CT

Table 3: Comparison between dosimetry based on CT and GATE Monte Carlo simulation

Discussion

We observed similar organ dosimetry results based on phantom with and patient’s CT data (Table 2). The similarity of the whole body dosimetry shows that the phantom and the calculation/simulations are generally acceptable. Variation between the organ boundaries and geometry of organs between patient and phantom may cause the differences and affect the organ dosimetry. In this study we used the GATE Monte Carlo code for calculation of absorbed dose. GATE code is already validated for dosimetry in many clinical situations including brachytherapy, external beam radiotherapy with photons/electrons, systemic radiotherapy, and proton-therapy. One of the main privileges of GATE is the capability to support both imaging and therapy modeling procedures [16]. The method we used has been employed with variations in other studies [17] for example to study mathematical phantom derived from the MIRD-type adult phantom. The use of phantoms is already validated for internal dosimetry purposes. Another reports showed that the dosimetry based on phantom is different from those based on the Zubal phantom as well as different dosimetry estimations obtained from different BMIs. We showed, the calculated doses have a good approximation in the simulated software and the higher percentage of dose in the simulation can be attributed to the use of this approximation that the use of mono energy source in the simulated CT scan. the energy spectrum of the tube is not mono, and in a wide spectrum with a peak of one-third of energy, it sleeps like a rabbit. So in general, the computational results of DLS were similar.

Conclusion

In this study, we showed that the results of dosimetry Similar when the CT phantom is used in place of patient’s CT image and GATE Monte Carlo code simulation. Providing a simulation method could be an option to give less right to CT scams.

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DOI: 10.31038/NAMS.2024713

Abstract

In situ vaccination (ISV) is an established and growing cancer therapy strategy. Preclinical studies show that ISV antitumor efficacy is achievable by of plant virus nanoparticles (PVNPs), in which PVNPs are directly administered into the tumor. It had previously shown that some PVNPs are potent in inducing long-lasting antitumor immunity when used as an in situ vaccine. Here, we investigate a filamentous plant virus nanoparticle, potato virus Y (PVY), for in situ vaccination treatment of 4T1, the very aggressive and metastatic murine triple-negative breast cancer model. PVY used as ISV does not significantly slow down tumor progression. Data indicate that some PVNPs are more suitable for application as in situ vaccines than others; understanding the intricate differences and underlying mechanisms of immune-activation may set the stage for clinical development of these technologies.

Keywords

Immunotherapy, Cancer, In situ vaccination, Plant virus nanoparticle, Potato virus Y

Introduction

Over 120 years ago Dr. William Coley set the framework for cancer immunotherapy. It was directly administrated live and attenuated bacteria to tumor. This approach led to cancer regression and complete cures in subset of patients [1,2]. The mechanism is now partially understood to involve activating macrophages and lymphocytes, producing immune’s mediator such as cytokines and chemokines [3]. In this approach that known in situ vaccination (ISV), the tumor itself serves as the source of the antigen and what is introduced is an adjuvant [4]. One particular type of ISV involves the use of attenuated mycobacteria known as Bacille Calmette-Guérin (BCG), which has been the established standard of care for superficial bladder cancer for more than four decades [5]. Another type of ISV that has recently received FDA approval is talimogene laherparepvec (T-VEC) developed by Amgen. T-VEC is a therapeutic treatment that utilizes an attenuated herpes simplex virus. T-VEC is injected directly into identified tumors and its therapeutic effects are achieved through the recruitment and activation of immune cells through the secretion of granulocyte-macrophage colony-stimulating factor (GM-CSF) [6,7]. Recently, plant virus nanoparticles (PVNPs)-based nanotechnologies have provided evidence that can induce a strong immune response against tumors when administered as ISV [3,8,9]. The effectiveness of this approach has been demonstrated in mouse models of melanoma, breast cancer, ovarian cancer, and colon cancer [3,7,10,11]. The data suggests that antitumor effects leading to the development of immune memory and providing protection against tumor recurrence [11]. Investigations have revealed antitumor effects in these models was associated with activation of a broad spectrum of immune cells [3,12,13]. A subset of immune cell such as APCs, neutrophils have been become activated upon engulf PVNPs, resulting in an early inflammatory phase characterized by upregulation of pro-inflammatory cytokines, leukocyte recruitment [7,13]. Toward this end, have recently demonstrated that ISV with various shapes/sizes of PVNPs such as icosahedral cowpea mosaic virus (CPMV) [7], rod-like papaya mosaic virus (PapMV) [14] and tobacco mosaic virus (TMV) [7], bacillus alfalfa mosaic virus (AMV) [15] can induce immune-mediated antitumor responses. It has been demonstrated that filamentous such as potato virus X (PVX) also can exhibit antitumor effectiveness in the context of melanoma [16]. Here, we specifically asked whether other filamentous viruses qualify as in situ vaccine for cancer immunotherapy. In this regard, we employed a library of structurally similar plant virus; specifically, potato virus Y (PVY). PVY virions have a filamentous, flexuous form, with a length of 730 nm and a diameter of 12 nm and a single-stranded, positive sense RNA genome [17,18].

Material and Methods

Preparation and Characterization of PVY Nanoparticles

PVY was propagated within Nicotiana benthamiana plants and purified as previously reported [18]. Transmission electron microscopy (TEM) imaging was conducted to validate the integrity of PVY filaments. The Malvern Zetasizer (Malvern Instruments, Worcestershire, United Kingdom) was utilized to determine the electrostatic surface map and zeta potential measurements.

Determination of Inherent Immunogenicity

For the assessment of canonical pro-inflammatory cytokine IL-6 levels, the inherent immunogenicity was determined by previous method. Summary, purified PVY added in vitro cultures of peripheral human blood mononuclear cells (PBMCs) with a cell density of 10⁶ cell/ml that were purified as previously reported.

Cell Culture and Cell Viability Assay

Cell culture and a cell viability assay were performed using 4T1 cells (ATCC). These cells were cultured in RPMI, supplemented with 10% (v/v) fetal bovine serum (FBS, Atlanta Biologicals) and 1% (v/v) penicillin-streptomycin (penstrep, Life Technologies). The cells were maintained at a temperature of 37 °C and a CO2 concentration of 5%. Upon reaching confluency, the cells were detached with 0.05% (w/v) trypsin-EDTA (Life Technologies), seeded at a density of 2 × 103 cells/100 μL/well in 96-well plates, and incubated overnight at 37 °C and 5% CO2. On the following day, the cells were washed twice with PBS and exposed to PVY at concentrations of 0, 0.5, 1, 2.5, 5, 10, 25, 50, 75, 100 μg/ml for duration of 24 h, in triplicate. Cell viability was assessed using an MTT proliferation assay as suggested by the manufacturer (ATCC, catalog number: 30-1010K™).

Tumor Model

Female Balb/C mice of six weeks of age were acquired from the Pasteur Institute of Iran. Subcutaneous injection of the breast cancer cell line (4T1) was performed at the right side of the abdomen of a mouse with a seeding density of 10⁶ cell/ml. The tumor volume was measured using a digital caliper and calculated using the equation volume=0.5 (length × width²). Mice were then randomly assigned to either the untreated group (PBS) or the group treated with PVY (n=4). In situ vaccination was conducted on day 10 post-tumor induction, where 100 μg of PVY in 50 μL of PBS was intratumorally injected with 72 h intervals. Tumor size was monitored daily, and mice were sacrificed when the tumor volume exceeded 1000 mm³, as per the approved protocol of the institutional animal care and use committee (IACUC) of Tabriz University of Medical Science.

Immunohistochemistry

Immunohistochemistry was performed using antibodies obtained from Santa Cruz Biotechnology, Inc., Santa Cruz, CA, USA. The tumors were fixed in PBS and sent to the Sara-Co lab (https://www.sara-co.com) for sectioning and staining. Optic densities (OD) were quantified using Fiji image analysis software.

Statistical Analysis

Data analysis and chart generation were performed using GraphPad Prism 8 software for Windows (GraphPad Software, San Diego, CA, USA). Statistical significance was determined using two-way or one-way analysis of variance (ANOVA). A significance level of P≤ 0.05 was considered for comparisons between groups.

Results

Characterization of PVY

In this study, our objective was to investigate whether PVY could be utilized as an in situ vaccine against 4T1 tumors. PVY is filamentous virus with a length of 730 nm and a diameter of 12 nm. The ratios of RNA to protein (A260/280=1.7) indicated that the preparation consisted of uncontaminated and intact PVY (Figure 1A). Figure 1B displays the zeta potential of the PVY particles, which is recorded as-4.4 millivolts (Figure 1B).

Figure 1: PVY characteristics A) Transmission electron microscopy confirms the structural stability of PVY particles. B) Dynamic light scattering was used to measure the zeta potential of PVY.

PVY is Immunogenic and Non-cytotoxic for Cancer Cells

4T1 cell line for evaluating the anticancer efficacy of the PVY nanoparticles (100 μg/ml) was used for cytotoxicity assay, the results did not exhibit direct cell toxicity on treated cells (Figure 2A). PVY possesses immunogenic properties and does not exhibit cytotoxic effects on cancer cells. When Human PBMCs were exposed to PVY for 24 hours, there was a significant increase in the expression of interleukin-6 (IL-6), a well-known pro-inflammatory cytokine, compared to the control cells that were left untreated (Figure 2B). This observation suggests that PVY inherently stimulates the immune cells.

Figure 2: A) Cell viability of 4T1 cancer cell line exposed to PVY. B) Human PBMCs exposed to PVY produce elevated levels of IL-6 pro-inflammatory cytokine in vitro. C) Therapeutic efficacy of PVY in a breast tumor model. Balb/C mice inoculated with 1 × 10⁶ 4T1 cells followed by 100 µg of PVY, once tumors were approximately 100> mm³, 10 days post-inoculation. Tumor growth followed by measuring volume (n=4).

PVY ISV Treatment has not Potent Efficacy in Treating the 4T1 Model

PVY treatment was done 5 times for each mouse in three days intervals starting 10 days after 4T1 cell injection and tumors well established. Control group mice were injected with PBS on the same schedule. The tumor growth (volume) was no significantly delayed in PVY treated groups compared to untreated control (Figures 2C). Inflammatory cytokines were assayed by Immunohistochemistry. Intra-tumor concentrations of pro-inflammatory cytokines, IFN-β, IL-1β, IL-12 andIL-6 don’t significantly increased in PVY-treated animals compared to untreated control animal tumors (Figures 3).

Figure 3: Immunohistochemistry don’t reveal dramatic changes in cytokines associated with treatment. Tumor sections stained for INF-β, IL-1β, IL-12 and IL-6. Quantitative analysis was performed using Fiji software to determine relative optical densities of the stained sections (p<0.05), magnification 20.

Discussion

We have elected filamentous plant virus, namely PVY as ISV for the first time. Intratumoral injection of the viral nanoparticles (VNPs) achieved with the combination of virus genome and multivalent capsid proteins (wild virus) with diameters of approximately 12 nm and long 700nm (Figure 1A). In order to assess their inherent immunogenicity, we introduced of the PVYs into in vitro cultures of PBMCs extracted from human. After duration of 24 hours, we measured the level of pro-inflammatory cytokine, IL-6 secreted using ELISA (Figure 2B). We have observed that in the context of dermal 4T1 in mice, the utilization of PVY as an in situ vaccine don’t leads to a suboptimal antitumor immune response against breast tumors. In contrast, it could not be showed with the effectiveness of CPMV, AMV, and PapMV. However, it did observe a relative similarity with PVX. When comparing the formulation of PVY with PVX, no apparent differences in antitumor efficacy were observed [16]. It demonstrated that there was no statistical difference in tumor growth rate or survival time between PVX-DOX complex versus PVX or DOX alone, but PVX+DOX did significantly slow tumor growth rate versus PVX and DOX alone [16]. Furthermore, PVX in mixture with OVA did not prove to be an effective adjuvant. Unexpectedly, no differences in IgG titers between mice immunized with individual OVA and a composition of OVA+PVX were revealed [19]. Furthermore, TMV used as an in situ vaccine elicits a weak antitumor immune response against melanoma [7]. Analysis of cytokines indicated no statistical difference. Prominent cytokine included IL-6, this cytokine also play crucial roles in inducing pro-inflammatory responses to infection and inflammation. In stark contrast, PVY elicits an immune response at in vitro, characterized by the production of pro-inflammatory cytokine, primarily IL-6. It has been observed that IL-6 signaling is associated with attributes that promote tumor growth, such as the ability to control the differentiation of macrophages and neutrophils into their tumor-promoting phenotypes, specifically M2 and N2 [20]. Our results don’t show very significant stimulation of INF-β, IL-1β, IL-12 and IL-6cytokines by PVY in situ vaccination. These cytokines are particularly intriguing due to their significance in eliciting immune responses against tumors through the mediation of T cells [21]. Regardless of their origin, interferons possess the ability to potentially exert antitumor effects either directly or indirectly [22]. The cytokine IL-12 holds great importance in the realm of cancer immunotherapy as it has the capability to activate immune cells with antitumor properties, including those that combat melanoma, by stimulating IFN-γ signaling and production [23]. It can exhibit that PVY can be suitable for epitope presentation. It is demonstrated that the preS1 epitope displayed on PVY (chimeric PVY CP particles) can immunize of mice with a strong anti-preS1 immune response, even in the absence of adjuvants [24].

Conclusion

Plant virus-based materials have emerged as innovative in situ vaccines, potentially initiating an immune response against tumors. These nanoparticles interact with innate immune sensors, reprogramming the immunosuppressive tumor microenvironment to an immune-activated state. This reactivation of the cancer-immunity cycle leads to systemic elimination of cancer cells through the adaptive immune system. It has been documented that CPMV, PapMV, PVX, TMV, and AMV-based ISV can induce anti-tumor responses, reduce tumor growth, and improve survival rates when administered directly to the tumor site. In this study, we present evidences that PVY-based ISV, in compare with them, no efficacy or immune-stimulation in a mouse model. Nevertheless, it can exhibit that PVY can be suitable for epitope presentation. Further research is required to fully elucidate the mechanism of plant viral in situ vaccines.

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