3.1.5. Construction

Table 7 presents studies conducted in the construction field using RULA.

### **Table 7.** Construction.

Shanahan et al. [132] analysed the usefulness of three assessment methods (RULA, REBA and the Strain Index) when used in non-fixed tasks and comparing them with four psychophysical scales from Borg 10. Fourteen construction workers without MSD were followed up. They concluded that the best method for this type of task was the Strain Index.

Another study proposed a more accurate way of measuring the angles in the postures adopted by construction workers in order to use the RULA method [131].

Finally, Li et al. [129,130] also focused on the field of construction. They developed a 3D system that allows one to simulate the working environment and perform an ergonomic assessment. They also applied REBA and RULA for the analysis.

3.1.6. Wholesale and Retail Trade; Repair of Motor Vehicles and Motorcycles

In this category, only three studies are presented (Table 8).

**Table 8.** Wholesale and retail trade; repair of motor vehicles and motorcycles.

Wholesale and Retail Trade and Repair of Motor Vehicle and Motorcycles

Risk factors and the onset of MSD were studied in car repair mechanics. In total, 191 workers participated. The modified Nordic Questionnaire was used with RULA, in addition to other tools. Most workers were shown to have this type of disorder [133].

Retail Trade, Except Motor Vehicles and Motorcycles

Capodaglio [134] conducted an ergonomic study on 70 clothing store vendors. RULA, REBA, the Strain Index and OCRA were used. The results showed a high risk in the upper extremities for the postures adopted. Another study was carried out at supermarket check-outs. A tool was developed to carry out a postural assessment of the workers. It was a portable and wireless system based on RULA and the Strain Index. It allowed the assessment to be performed as the task was being undertaken [135].

3.1.7. Transportation and Storage

Table 9 contains the studies available in the Transportation and Storage category.

### **Table 9.** Transportation and storage.


*Supporting open minds since 2005*

Hepatocellular Carcinoma - Challenges and Opportunities of a Multidisciplinary Approach http://dx.doi.org/10.5772/intechopen.94813 Edited by Georgios Tsoulfas

#### Contributors

Cchanchai Charonpongsuntorn, Haichao Zhao, Changzhou Chen, Jiefeng He, Muntaser S.Ahmad, Osama Makhamrah, Mohammad Hjouj, Wei Zhang, Mahmoud Aryan, Ellery Altshuler, Xia Qian, Ioannis Hatzaras, Nikolaos Arkadopoulos, Melina Vlami, Guangwen Cao, Wenbin Liu, Aditya Kale, Alexandros Giakoustidis, Apostolos Koffas, Dimitrios Giakoustidis, Vasileios N. Papadopoulos, Lekshmi Kalinathan, Deepika Sivasankaran, Amritha Sennappa Sudharsan, Janet Reshma Jeyasingh, Hareni Marimuthu, Emine Turkmen Samdanci, Evangelos Felekouras, Spyridon Davakis, Michail Vailas, Alexandros Kozadinos, Panagiotis Sakarellos, Anastasia Karampa, Dimitrios Korkolis, Georgios Glantzounis, Alexandros Papalampros, Hoang Van Tong, Pham Van Dung, Nguyen Thi Mong Diep, Nguyen Linh Toan

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**1. Introduction**

Nucleobase complexes with transition metals are continuously under investigation due to their applications as advanced functional materials, their biologic importance, structural diversity and use as molecular recognition models for nucleic acids [1–6]. The majority of structural information available in these systems is mainly dedicated to the adenine nucleobase [7–16] and a variety of N-alkylated derivatives as ligands [17–31]. In contrast, available structural information in the Cambridge Structural Database (CSD) on metal complexes, co-crystals and salts with 2,6-diaminopurine (Hdap) nucleobase is much more limited, despite the fact that Hdap is an analog of adenine. Interestingly, the Hdap nucleobase is able to form the same coordination bonds than adenine and, additionally, the extra exocyclic amino group of Hdap can further function as H-bond donor. Therefore, Hdap can generate novel metal complexes, coordination polymers and supramolecular assemblies.

This study reports the synthesis, X-ray structure and density functional theory study of a new metal complex of formula H2(N3,N7)dap[Cd(HEDTA)(H2O)]·H2O (**1**). A comparison with the previously reported analog of adenine, [Cu(HEDTA)(H2O)]·2H2O [5,32], was also performed. The H-bonding networks that are established at both faces of H2dap were also studied using DFT calculations and the relative strength of each H-bond was estimated using the QTAIM theory. The antiparallel π,π-stacking interactions that were formed between the cations were also studied, focusing on the effect of the counter-ions.

## **2. Materials and Methods**


7. Potential target for multiple myeloma

#### 7.1. Constraint of GEP in existing clinical practice

Important impediments still present to prevent application of this important investigation in general clinical practice. Although many specific GEP signatures have been recognized and a recent study has joint some of these signatures to create a unique signature [32] but no consensus have been accepted to date for universal use for every MM patients. GEP remains a research tool and is not yet authenticated by the FDA. For clinician point of view, the GEP data have been created generally in a setting of certain treatments that includes thalidomide, lenalidomide and bortezomib with or without auto-transplant. Since the therapeutic landscape is largely progressing in MM, re-assessments are required for each novel drug and/or combination. In particular the arrival of new therapeutic classes such as antibody drug conjugates, targeted agents (Elotuzumab, Daratumumab) and new IMiDs and proteasome inhibitors [106, 107] markedly improve the prognosis and may need different GEP studies and signatures [107, 114]. GEP has been utilized to date in few myeloma centers and mostly for investigational purposes. The development of investigators friendly and quicker methods should be considered. Simple quantitative PCR has been assessed in a group of 157 newly diagnosed patients proved good acceptable results [115]. However, a final conclusion about this test is still pending. Most importantly an integrated approach that includes gene signatures, mutational profile and microRNA expression will be requisite to allow a wider application of genomic information to direct for treatment selection as well as prognostication. Taking the current understanding of these landscape genetic assessment to the next level, it will be essential to understand the clinical influence of clonal content and advancement along with identification of sub-clonal variants and molecular alterations on disease outcome [141]. The current information about mutational load that predicts outcome will need to be re-investigated for treatment purpose. These algorithms will be amended with the arrival of immunotherapeutic strategies which may have great achievement in malignancies with high mutational load. Again, as demonstrated by Rashid NU et al. with other colleagues Mutations must be studies further as predictive markers for treatment decisions [97].

## 8. Future trend

The documentation of specific micro-RNA expression profile can also be exploited to guide therapy. Several microRNAs are being researched as treatment targets with hopes for devel-

Similarly, GEP has been employed to predict resistance to antimyeloma drugs with an interpretation that harmful agents are avoided that are not helpful. With the help of number of B-cell lines including multiple myeloma cell lines, a microarray-based GEP signature was established to predict resistance of melphalan. Although the expression profile was able to predict sensitivity vs. resistance in cell lines, its practical application needs further studies to be done [102, 103]. Interestingly, a pharmacogenomic study of global GEP of myeloma cells recovered from myeloma patients and specific time after administration of different drugs have been assessed [104, 105]. Prognostic information was acquired from GEP of refined plasma cells 2 days after providing thalidomide and dexamethasone or bortezomib to newlydiagnosed myeloma patients. An 80-gene signature was recognized following bortezomib

administration that will guide us in future for better patients' risk stratification [105].

From treatment as well as prognostic points, it is also important to consider persistent changes in genome which occurs without stimulus or as well as under the influence of microenvironment, epigenomic changes or therapy. Therefore, assessment by GEP at a single time point may not be meaningful. The advancement of GEP from diagnosis, response and relapse should be interpreted intelligently to have an answer for proper selection of the most appropriate

Important impediments still present to prevent application of this important investigation in general clinical practice. Although many specific GEP signatures have been recognized and a recent study has joint some of these signatures to create a unique signature [32] but no consensus have been accepted to date for universal use for every MM patients. GEP remains a research tool and is not yet authenticated by the FDA. For clinician point of view, the GEP data have been created generally in a setting of certain treatments that includes thalidomide, lenalidomide and bortezomib with or without auto-transplant. Since the therapeutic landscape is largely progressing in MM, re-assessments are required for each novel drug and/or combination. In particular the arrival of new therapeutic classes such as antibody drug conjugates, targeted agents (Elotuzumab, Daratumumab) and new IMiDs and proteasome inhibitors [106, 107] markedly improve the prognosis and may need different GEP studies and signatures [107, 114]. GEP has been utilized to date in few myeloma centers and mostly for investigational purposes. The development of investigators friendly and quicker methods should be considered. Simple quantitative PCR has been assessed in a group of 157 newly diagnosed patients proved good acceptable results [115]. However, a final conclusion about this test is still pending. Most importantly

opment of small molecules that target these micro-RNA function.

7. Potential target for multiple myeloma

7.1. Constraint of GEP in existing clinical practice

therapy.

52 Update on Multiple Myeloma

There is tremendous progress has reported so far, newer high-throughput technologies are being added with clinical parameters [142]. Array-based methodologies, sequencing-based method, and newer bio-informatics methodologies are in process of development. Furthermore, integrative oncogenomic work are merging new markers such as mutations, splicing events, noncoding RNA, miRs with older ones to help in better prognostication [143]. The personalized medicine depends on the assortment of a targeted therapy guided by the specific mutation or GEP signature is attractive tool treatment option. However, in future, in MM patients, treatment option selection depends on coexistence of sub-clones, dynamic evolution of the disease and triggering mutations in pathway, i.e., KRAS and BRAF for the ERK pathways [144].

To conclude, gene expression profile studies provide important knowledge regarding MM pathogenesis, and establish a powerful tool for prediction of outcome and to direct clinicians for selection of therapy [145]. The grouping of mutational profile, gene expression and splicing events with ISS and cytogenetic may become a standard of care in MM care [97].


2.2.1. Microemulsions

Microemulsions are thermodynamically stable transparent delivery systems formed by droplets dispersed on a liquid phase, which are capable of forming spontaneously and have low interfacial energy and size, ranging from about 10 nm to 100 nm (Figure 3A) [33,34]. Zhou et al. [35] developed AST oil/water microemulsions and checked the effect of different antioxidants either alone or in combination as additives to improve their stability. The microemulsion prepared with AST alone, with Tween 80 as an emulsifier and ethanol in buffer solution, retarded AST degradation, thereby proving to be an excellent alternative to improve emulsions for AST delivery.


**Acknowledgements**

*in Iraq (REXNet)* project. The project idea is to create a remote experimentation network to use online experiments, which are developed and located in the United States universities for serving teachers and students in the Kurdistan region of Iraq. In conclusion, it has been accepted for implementation in collaboration with Oklahoma State University (OSU). In general, REXNet project aims to develop a virtual lab, which is based on virtual environment "virtual reality (VR)", for serving engineering and science students from the University of Duhok, the University of Zakho, and Duhok Polytechnic University. It introduces fundamentals of robotics to students by including several experiment modules that allow

This chapter outlines some indicators related to the higher educational systems in the MENA region, such as the support given by instructional technologies to academics working in this region. The research instrument consisted of a series of questions for collecting data from the respondents by using three techniques: questionnaires, online meetings, and interviews.

**1.** Providing materials and instructional technologies (i.e. online labs) to researchers, teach-

**3.** Increasing collaborative and cooperative work among the MENA researchers by sharing

A community of practice can be task and goal oriented to satisfy the need for cooperative

This research provides a feasible idea for more achievements in higher educational sectors in the MENA region by including instructional technologies that facilitate the students' skills

It is also hoped that by setting the online labs indicator, this chapter may be useful to guide the development of higher educational systems in other regions. Similarly, it may find other indicators or activities related to learning that can develop and assist the higher educational systems in the MENA region and increase collaborative and cooperative work among their

Hopefully, for the middle/long term, involving other universities, in Iraq and other MENA countries in general, to become a part of this online labs community, either using the VISIR system or through the REXNet project, for sharing resources and knowledge among them and

**2.** Building a community of practice around online labs in the MENA region.

achievements of goals and provide support for online learning [47].

increasing collaborative and cooperative work among their researchers.

students to run experiments via the Internet.

**7. Conclusion and future direction**

102 Global Voices in Higher Education

Overall, the major goals of this chapter are:

ers, and students in the MENA region.

resources and online experiments.

researchers.

acquisition and assist higher educational systems.

The authors would like to thank the University of Duhok, the University of Zakho, and Duhok Polytechnic University for supporting, partially, this chapter. Authors would also like to show their gratitude to the IREX organization for funding and supporting the REXNet project to serve these three universities.


**1. Introduction**

Macrophages have an essential role both in osteoblast-mediated bone formation [1] and in osteoclast development [2,3], but the detailed function of these cells is not yet fully understood. In addition, the cytokines and other soluble factors secreted by macrophages can induce bone formation in vitro and in vivo [1,4–8].

For a long time, in vitro cultures were used to study the phenotypic characterization of macrophages as a model to control the extracellular environment [9–11]. In vitro macrophages can be classified into two families: (i) M1 macrophages and (ii) M2 macrophages. The M1 family expresses pro-inflammatory cytokines, such as tumor necrosis factor (TNF), interleukin-1 beta (IL-1β), interleukin-6 (IL-6), interleukin-12 (IL-12), interleukin-15 (IL-15), interleukin-18 (IL-18), interleukin-23 (IL-23), and interleukin-28 (IL-28) mediating inflammation. The M2 family expresses anti-inflammatory cytokines, such as interleukin-10 (IL-10), interleukin-1β receptor antagonist (IL-1RA), transforming

**Citation:** Nikovics, K.; Durand, M.; Castellarin, C.; Burger, J.; Sicherre, E.; Collombet, J.-M.; Oger, M.; Holy, X.; Favier, A.-L. Macrophages Characterization in an Injured Bone Tissue. *Biomedicines* **2022**, *10*, 1385. https://doi.org/10.3390/ biomedicines10061385

Academic Editor: Chikafumi Chiba

Received: 25 May 2022 Accepted: 8 June 2022 Published: 11 June 2022

**Publisher's Note:** MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

**Copyright:** © 2022 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/).

growth factor-beta (TGF-β) and proangiogenic cytokines (vascular endothelial growth factor (VEGF) that resolve inflammation and also modulate the extracellular matrix (ECM). In vitro studies have shown that the M2 family characterization is more complex and can be subdivided into four subtypes: M2a, M2b, M2c, and M2d [12–16]. Each subtype expresses a distinctive panel of cytokines and plays a different role in tissue regeneration (Figure 1) [17–23]. Surprisingly, M2b and M2d macrophages also express pro-inflammatory cytokines including TNF, IL-1β, IL-6, or IL-12 [16,24]. This division is not perfect because specific (nontypical) macrophages do not belong to either group but play an important immunoregulatory role. An in vitro approach does not allow the study of other immune cells and their respective secreted cytokines normally present at the site of the regeneration. Indeed, the host response in vivo is more complex highlighting the difficulty to deduce in vivo results from in vitro observations. The knowledge of macrophage phenotypes under in vivo conditions is still poorly understood and further investigations are essential, especially in our case, to study macrophage involvement during bone regeneration. Accordingly, in vivo macrophages are named M1-like and M2-like macrophages or resolving macrophages (Figure 1) [23,25–30].

**Figure 1.** Macrophage polarization subtypes; different cytokine expressions and functions of the macrophage populations in vitro and in vivo.

An additional category of macrophages called "Tissue-resident macrophages" is thought to participate in bone repair. Contained in almost all tissues, they are called 'osteomacs' when localized in the bone [1,2,31,32].

Biomaterial-based therapy is a useful method to improve bone regeneration; however, its underlying repair mechanism is not yet elucidated [33–40]. About 30 years ago, the French surgeon Alain-Charles Masquelet developed a new technique to repair bone defects called the Masquelet induced membrane [41]. The surgeon places a fixator along

the bone and completes its missing parts with a biomaterial, an inert polymer that has been engineered for interacting with biological systems, usually polymethylmethacrylate (PMMA). Later on, a membrane called the Masquelet induced membrane will be generated all around the biomaterial as an immune reaction against a foreign body. It is essential for further bone regeneration [41–43]. In the literature, biomaterials are described to induce the appearance of the macrophages at the bone injury site [1,7,31,32,44–46].

One approach to characterize macrophages is the identification of their expressed cytokines. Different techniques, such as Northern blot, qPCR, microarray, flow cytometry analysis, and next-generation deep sequencing methods can be used. These methods only provide a result from a mixture of different cell types. In addition, measuring the expression level of the cytokines is not sufficient; the localization of the cytokine-expressing cells in the tissue should also be determined [47].

To localize the cytokine-expressing cells in the tissue, different methods are available: (i) expression of reporter constructs, but the limitation of this technique is the requirement of a transgenic animal; (ii) classical immunostaining techniques using antibodies against markers to detect specific proteins of the macrophages. However, since cytokines are generally secreted, it is difficult to determine exactly which cells produce this protein or peptide [48]. This technique can only distinguish between M1-like and M2-like macrophages. However, it is not appropriate for identifying M2-like subtypes, as there is currently no cell surface marker available to distinguish between the different subtypes; and (iii) in situ hybridization is one of the most convincing methods to identify the cytokine-expressing cells because it is based on messenger RNA (mRNA) detection of the targeted genes [47].

In the present study, the cryosections of non-decalcified rat femur surrounded by muscle were investigated by immunostaining, in situ hybridization, and in situ HCR to identify phenotypes of macrophages involved in bone regeneration. In these challenging conditions, expression of CD68, CD163, IL-1β, IL-6 and β-actin genes was successfully detected resulting for the first time in the identification and localization of M2b-like macrophages in vivo in the bone of rats during bone regeneration.

### **2. Materials and Methods**

### *2.1. Rat Animal Model*

All experiments were approved by the IRBA Institutional Animal Care and Use Committee (protocol 65 DEF\_IGSSA\_SP). Surgeries were carried out in an accredited animal facility. Eight-week-old (200 g average weight) male Sprague Dawley rats (Charles River Laboratories, Freiburg, Germany) were housed individually in cages in a temperature and light-controlled environment with food and provided water ad libitum. Before collecting femurs with muscles, animals were euthanized at 12 weeks old with an overdose of sodium pentobarbital (150 mg/kg) administrated intraperitoneally.

### *2.2. Embedding and Cryosectioning of the Entire Femur (Bone and Muscle Together) of the Rat*

Embedding and cryosectioning methods were performed as described in [49]. RNasefree instruments, materials, and buffers were used to collect bone samples. After euthanasia of the rat, the whole femur was cleaned rapidly, and a part of the muscles around the bone was kept. The femur was placed at the bottom of the embedding mold and covered with cryomount medium (CM) (00890-EX, HistoLab, Askim, Norway). Samples were snap-frozen with 2-methyl butane cooled in liquid nitrogen to obtain a block.

### *2.3. Histological Staining*

Histological staining was performed as described in [49]. Hematoxylin and phloxin (HP) staining was performed as follows: the sections were incubated in several successive baths: 40 s in a hemalum (11,487, Merck, Darmstadt, Germany) buffer (0.2 g hemalum, 5 g aluminum potassium sulfate in 100 mL distilled water), 3 min in water, 30 s in a phloxin (15,926, Merck, Darmstadt, Germany) buffer (0.5 g phloxin in 100 mL distilled water), 1 min in water, 2 min in 70% ethanol, 30 s in 95% ethanol, 1 min in 100% ethanol, and 1 min in 100% ethanol. In the end, nuclei were colored in blue and cytoplasm in pink.


*Article* **High Quality Pt–Pt Metal Bonding for High Temperature Packaging**

**Jiazheng Liu 1,2, Junqiang Wang 1,2,\* , Mengwei Li 1,2,\* and Haikun Zhang 1,2**

	- **\*** Correspondence<EMAIL_ADDRESS>(J.W<EMAIL_ADDRESS>(M.L.); Tel.: +86-158-1133-8056 (J.W.); +86-139-3424-8366 (M.L.)

**Abstract:** Platinum is an ideal material for high-temperature resistant device packaging due to its higher melting point and good electrical properties. In this paper, the thermocompression bonding of Pt–Pt metal electrodes was successfully realized through process exploration, and the package interconnection that meets the requirements was formed. A square bump with a side length of 160 µm and a sealing ring with a width of 80 µm were fabricated by magnetron sputtering. Different pressure parameters were selected for chip-level bonding; the bonding temperature was 350 ◦C for about 20 min. Analysis of the interface under a scanning electron microscope found that the metal Cr diffused into Pt. It was found that two chips sputtered with 300 nm metal Pt can achieve shear resistance up to 30 MPa by flip-chip bonding at 350 ◦C and 100 MPa temperature and pressure, respectively. The leakage rate of the sample is less than 2 × 10–3 Pa·cm3/s, the bonding interface is relatively smooth, and the hot-pressed metal bonding of Pt electrodes with good quality is realized. By comparing the failure rates at different temperatures and pressures, the process parameters for Pt–Pt bonding with higher success rates were obtained. We hope to provide new ideas and methods for the packaging of high-temperature resistant devices.

**Keywords:** Pt–Pt interconnection; high-temperature resistant packaging; metallic bonding

## **1. Introduction**

Sensors working with graphene as a sensitive material have received extensive attention in recent years. The unique thermal properties, electrical properties, and hightemperature resistance [1–3] of graphene show a strong potential for enhancing performance and improving the reliability of devices operating at high temperatures and harsh environments. However, the lack of reliable high-temperature packaging technology impedes the application of graphene in the field of high-temperature MEMS devices. Burla et al. [4] achieved nickel wire bonding for high-temperature packaging, and Ni wire bonds were found to be electrically stable for temperatures up to 550 ◦C. However, the hightemperature oxidation of nickel limits its practical application. On the other hand, Pt has almost perfect corrosion resistance, making it a better high-temperature encapsulation material than nickel. Brachmann et al. [5] demonstrated a Pt wire bonding method that can withstand an 1100 ◦C environment. The investigated Pt films were composed of a 50 nm thick e-beam evaporated Cr seed layers and an approximately 1 µm electrodeposited Pt film. This study proved the excellent prospects of Pt in the field of high-temperature packaging. To the best of our knowledge, the current high-temperature packaging mostly uses wire bonding technology, while wire bonding technology can no longer meet the requirements of miniaturization, light weight, high performance, and low power consumption of modern electronic products [6]. Notably, the flip chip is obviously more in line with the future development trend of the electronics industry.

**Citation:** Liu, J.; Wang, J.; Li, M.; Zhang, H. High Quality Pt–Pt Metal Bonding for High Temperature Packaging. *Micromachines* **2022**, *13*, 1543. https://doi.org/10.3390/ mi13091543

Academic Editor: Wensheng Zhao

Received: 25 August 2022 Accepted: 15 September 2022 Published: 17 September 2022

**Publisher's Note:** MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

**Copyright:** © 2022 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/).

The common electronic packaging method is realized by forming flip chips [7,8] by thermocompression metallic bonding [9] or direct bonding [10]. The essence of metallic bonding is the mutual diffusion of atoms on the surface of two metals [9], which relies on metallic bonds, metal melting, and other factors in order to bond firmly. On the one hand, it combines the excellent properties of the material and, on the other hand, completely utilizes the benefits of the metal film to improve the photoelectric performance of the device. Direct bonding involves cleaning and activating the surface of the bonding sheet [11], directly bonding it at room temperature, and finally combining it with heat treatment to form an interconnected interface. The difference between the two methods is that metallic bonding involves the same kind of metal material, while direct bonding can be carried out with two different materials. Therefore, defects such as the dislocations generated in the process of metal bonding only exist near the interface of metal bonding and do not extend to the entire material and thus hardly affect the performance of the material before bonding. Since a thin oxide film is formed on the surface of the metal in the air, the oxide film blocks the mutual diffusion of atoms on the two metal surfaces, restricting the diffusion of atoms unconditionally. Additionally, the bonding interface of metal bonding cannot add a dielectric layer. Metal bonding is usually achieved by heating and pressing and is different from the eutectic interface interconnection formed between different metals [12]. For example, Au–Au, Cu–Cu [13,14] and Al–Al [15,16] make atomic-level contact under the simultaneous action of heat and pressure. Under the movement of atoms, the two layers of metals undergo diffusion movement, and the diffused atoms connect the two layers of metals together.

In this paper, we have focused on the high-temperature packaging needs of MEMS devices [17–19] and used Pt with excellent performance at high temperatures as the bonding material [20,21] to explore the process required for its packaging and its performance after packaging.

## **2. Materials and Methods**

There are three steps to realize Pt–Pt interconnection: test sample design, fabrication of fine-pitch bumps followed by bumps surface pretreatment, and finally Pt–Pt thermocompression bonding.

## *2.1. Test Sample Design*

The top and low substrates of the bonding are two chips of 6 × 6 mm2 and 8 × 8 mm2 , respectively. The total bonding area is approximate to 5.5 mm2 . The schematic diagram of the mask is shown in Figure 1. The outer side length of the sealing ring of the single repeating unit is 1.31 mm, the inner side length is 1.15 mm, and the side length of the small square of the bonding bump is 160 µm. The side length of the total mask structure is 5 × 5 mm, and each structure contains 16 repeating units. The figure on the right of Figure 1a shows a single, repeating unit, which is located on a substrate with a size of 8 × 8 mm. The figure on the right of Figure 1b shows a single, repeating unit, which is located on a substrate with a size of 6 × 6 mm. The above shapes are made of silicon as the substrate through photolithography, sputtering, and other processes. The lithography was performed using an MA6 model lithography machine produced by SUSS MicroTec in Germany. The top and bottom two substrates are bonded by thermocompression to ensure a firm connection between the sealing ring and the bump, forming a closed space.

*Micromachines* **2022**, *13*, 1543 3 of 11

**Figure 1.** Schematic diagram of mask and bonding structure. (**a**) Mask of the top substrate. (**b**) Mask of the bottom substrate. (**c**) Cross-sectional diagram of bonded structure. **Figure 1.** Schematic diagram of mask and bonding structure. (**a**) Mask of the top substrate. (**b**) Mask of the bottom substrate. (**c**) Cross-sectional diagram of bonded structure. thick silicon wafers were routinely cleaned, followed by ultrasonic cleaning with acetone, isopropanol, and water for 5 min each, and finally dried under N2 [Figure 2a] [22].  Substrate Fabrication 2.2. Substrate Fabrication* plasma-enhanced chemical vapor deposition (PECVD), and a mask structure was creat-

The fabrication process of the top substrate is shown in Figure 2. First, the 400 µm thick silicon wafers were routinely cleaned, followed by ultrasonic cleaning with acetone, isopropanol, and water for 5 min each, and finally dried under N2 [Figure 2a] [22].  Subsequently, the bottom Cr/Pt electrodes with thicknesses of 50 and 300 nm, respectively, were deposited on the SiNx layer by magnetron sputtering [Figure 2b]. The electrode should not be too thick because an excessively thick bonding interface layer may cause the formation of microcracks and lead to poor bonding quality [23,24]. Finally, the negative adhesive peeling was completed in acetone to produce the top substrate. The process for fabrication of the bottom substrate is the same as that of the top substrate. The fabrication process of the top substrate is shown in Figure 2. First, the 400 µm thick silicon wafers were routinely cleaned, followed by ultrasonic cleaning with acetone, isopropanol, and water for 5 min each, and finally dried under N2 [Figure 2a] [22].  Subsequently, the bottom Cr/Pt electrodes with thicknesses of 50 and 300 nm, respectively, were deposited on the SiNx layer by magnetron sputtering [Figure 2b]. The electrode should not be too thick because an excessively thick bonding interface layer may cause the formation of microcracks and lead to poor bonding quality [23,24]. Finally, the negative adhesive peeling was completed in acetone to produce the top substrate. The process for fabrication of the bottom substrate is the same as that of the top substrate. ed on the SiNx passivation layer using a negative photoresist. Subsequently, the bottom Cr/Pt electrodes with thicknesses of 50 and 300 nm, respectively, were deposited on the SiNx layer by magnetron sputtering [Figure 2b]. The electrode should not be too thick because an excessively thick bonding interface layer may cause the formation of microcracks and lead to poor bonding quality [23,24]. Finally, the negative adhesive peeling was completed in acetone to produce the top substrate. The process for fabrication of the bottom substrate is the same as that of the top substrate. To remove surface oxide film, both the top substrate and bottom substrate were pretreated by Ar (a small amount of H2) plasma with a gas flow rate of 250 sccm under the power of 200 W for 180 s. After the metal surface is activated, the degree of atomic diffusion is increased by heating and pressing to tightly combine the two structures. The bonding adopts the electronic packaging FC150 flip-chip welding machine.

**(e) (d) Figure 2.** Schematic of the process for fabrication of the top substrate. (**a**) Cleaning. (**b**) SiNx passivation layer deposited by PECVD. (**c**) Negative photoresist masks and lithography. (**d**) Sputtering Cr/Pt electrodes. (**e**) Negative adhesive stripping. **Figure 2.** Schematic of the process for fabrication of the top substrate. (**a**) Cleaning. (**b**) SiNx passivation layer deposited by PECVD. (**c**) Negative photoresist masks and lithography. (**d**) Sputtering Cr/Pt electrodes. (**e**) Negative adhesive stripping.

**Figure 2.** Schematic of the process for fabrication of the top substrate. (**a**) Cleaning. (**b**) SiNx passivation layer deposited by PECVD. (**c**) Negative photoresist masks and lithography. (**d**) Sputtering Cr/Pt electrodes. (**e**) Negative adhesive stripping. *2.3. Pt-Pt Thermocompression Bonding*  The relationship between bonding time and temperature is shown in Table 1. The present work attempts to use four sets of bonding parameters to determine the range of parameters that can achieve better Pt–Pt bonding interconnections. There are two pur-To remove surface oxide film, both the top substrate and bottom substrate were pretreated by Ar (a small amount of H2) plasma with a gas flow rate of 250 sccm under the power of 200 W for 180 s. After the metal surface is activated, the degree of atomic diffusion is increased by heating and pressing to tightly combine the two structures. The bonding adopts the electronic packaging FC150 flip-chip welding machine.

#### *2.3. Pt-Pt Thermocompression Bonding 2.3. Pt-Pt Thermocompression Bonding*

The relationship between bonding time and temperature is shown in Table 1. The present work attempts to use four sets of bonding parameters to determine the range of parameters that can achieve better Pt–Pt bonding interconnections. There are two pur-The relationship between bonding time and temperature is shown in Table 1. The present work attempts to use four sets of bonding parameters to determine the range of

parameters that can achieve better Pt–Pt bonding interconnections. There are two purposes for using these four sets of parameters. On the one hand, it can be identified whether the interconnection interface can be formed after bonding, and on the other hand, whether the shear resistance of the sample after bonding is good within this pressure range can be ascertained. Finally, parameters that can form an interconnected interface and have a certain shear resistance are selected. The variables of these four sets of parameters are all pressure, the temperature is 350 ◦C, and the bonding time is 1200 s. Due to the high melting point of platinum, it is more difficult to bond by thermocompression than other metals such as gold and copper. Therefore, when flip-chip welding is used for thermocompression bonding, the bonding temperature and bonding time are both selected to be close to the upper limit of the instrument. hand, whether the shear resistance of the sample after bonding is good within this pressure range can be ascertained. Finally, parameters that can form an interconnected interface and have a certain shear resistance are selected. The variables of these four sets of parameters are all pressure, the temperature is 350 °C, and the bonding time is 1200 s. Due to the high melting point of platinum, it is more difficult to bond by thermocompression than other metals such as gold and copper. Therefore, when flip-chip welding is used for thermocompression bonding, the bonding temperature and bonding time are both selected to be close to the upper limit of the instrument. **Table 1.** Case of bonding parameter. **Parameter Force Temperature Time**

poses for using these four sets of parameters. On the one hand, it can be identified whether the interconnection interface can be formed after bonding, and on the other

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**Table 1.** Case of bonding parameter. Case1 165 N 350 °C 1200 s

From Figure 1a,b, the bonding area of the bonding pair can be calculated to be about 5.5 mm2 . According to the formula P = F/S, the pressure of case 1 is 30 MPa, the pressure of case 2 is 50 MPa, the pressure of case 3 is 80 MPa, and the pressure of case 4 is 100 MPa during thermocompression bonding. pressure of case 2 is 50 MPa, the pressure of case 3 is 80 MPa, and the pressure of case 4 is 100 MPa during thermocompression bonding. **3. Results and Discussion**

about 5.5 mm2. According to the formula P = F/S, the pressure of case 1 is 30 MPa, the

#### **3. Results and Discussion** Four different tests, including interfacial analysis, shear strength analysis, hermeti-

Four different tests, including interfacial analysis, shear strength analysis, hermeticity detection, and failure analysis were performed to evaluate the bonding performance. city detection, and failure analysis were performed to evaluate the bonding performance.

#### *3.1. Interfacial Analysis 3.1. Interfacial Analysis*

After polishing at the 10 µm and 1 µm fine levels, the cross-sectional interface of Pt–Pt bonding under SEM can be clearly seen in Figure 3. It can be observed from the backscatter mode of the electron microscope that the bonding interface is relatively flat with no obvious cracks or gaps. This suggests that after the thermocompression bonding described in this article, the Pt–Pt metal electrodes are interconnected. After polishing at the 10 µm and 1 µm fine levels, the cross-sectional interface of Pt– Pt bonding under SEM can be clearly seen in Figure 3. It can be observed from the backscatter mode of the electron microscope that the bonding interface is relatively flat with no obvious cracks or gaps. This suggests that after the thermocompression bonding described in this article, the Pt–Pt metal electrodes are interconnected.

**Figure 3.** X-ray image. (**a**) Overall SEM image of the chip. (**b**) Enlarged view of a single unit. **Figure 3.** X-ray image. (**a**) Overall SEM image of the chip. (**b**) Enlarged view of a single unit.

Figure 4 is the bonding image of the bump obtained by the SEM mode under the electronic scanning electron microscope. The bright part in the middle is the metal layer. The thickness of the metal layer is measured to be about 700 nm, which is consistent Figure 4 is the bonding image of the bump obtained by the SEM mode under the electronic scanning electron microscope. The bright part in the middle is the metal layer.The thickness of the metal layer is measured to be about 700 nm, which is consistent with the thickness of 50 nm Cr and 300 nm Pt plated during sputtering. Further, no obvious cracks were observed in the metal layer, and the whole surface tends to be smooth, forming

**Figure 4.** SEM image of the bump.

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a good interconnection interface. Interestingly, no obvious delamination phenomenon of Cr and Pt resulting from the diffusion of Cr is observed in the metal region on each side. nomenon of Cr and Pt resulting from the diffusion of Cr is observed in the metal region on each side. on each side.

with the thickness of 50 nm Cr and 300 nm Pt plated during sputtering. Further, no obvious cracks were observed in the metal layer, and the whole surface tends to be smooth, forming a good interconnection interface. Interestingly, no obvious delamination phe-

with the thickness of 50 nm Cr and 300 nm Pt plated during sputtering. Further, no obvious cracks were observed in the metal layer, and the whole surface tends to be smooth, forming a good interconnection interface. Interestingly, no obvious delamination phenomenon of Cr and Pt resulting from the diffusion of Cr is observed in the metal region

Figure 5 shows the result of the line scan of the bonding interface. Through the longitudinal line scan of the bonding interface, the content of three elements is analyzed. It can be found that most of the Si elements are distributed on both sides of the metal layer, which is more in line with the actual situation, indicating that the hot-press bonding does not cause the non-metallic surface to diffuse inward. Moreover, the content of Pt element is mainly concentrated in the metal layer area, the middle part is more concentrated, and the two sides are more symmetrical and uniform, which shows that the interconnection interface formed after thermocompression bonding has no displacement, and the Pt–Pt interface is better connected with fewer impurities. Additionally, the widely distributed Cr element is essentially more concentrated between the Si layer and the Pt layer, and is consistent with the SEM image shown in Figure 4. The Cr layer is sandwiched between the metal layer and the dielectric layer as an adhesion layer. After thermocompression bonding, a small amount of diffusion of Cr element occurred be-Figure 5 shows the result of the line scan of the bonding interface. Through the longitudinal line scan of the bonding interface, the content of three elements is analyzed. It can be found that most of the Si elements are distributed on both sides of the metal layer, which is more in line with the actual situation, indicating that the hot-press bonding does not cause the non-metallic surface to diffuse inward. Moreover, the content of Pt element is mainly concentrated in the metal layer area, the middle part is more concentrated, and the two sides are more symmetrical and uniform, which shows that the interconnection interface formed after thermocompression bonding has no displacement, and the Pt–Pt interface is better connected with fewer impurities. Additionally, the widely distributed Cr element is essentially more concentrated between the Si layer and the Pt layer, and is consistent with the SEM image shown in Figure 4. The Cr layer is sandwiched between the metal layer and the dielectric layer as an adhesion layer. After thermocompression bonding, a small amount of diffusion of Cr element occurred between the Pt metal layers. gitudinal line scan of the bonding interface, the content of three elements is analyzed. It can be found that most of the Si elements are distributed on both sides of the metal layer, which is more in line with the actual situation, indicating that the hot-press bonding does not cause the non-metallic surface to diffuse inward. Moreover, the content of Pt element is mainly concentrated in the metal layer area, the middle part is more concentrated, and the two sides are more symmetrical and uniform, which shows that the interconnection interface formed after thermocompression bonding has no displacement, and the Pt–Pt interface is better connected with fewer impurities. Additionally, the widely distributed Cr element is essentially more concentrated between the Si layer and the Pt layer, and is consistent with the SEM image shown in Figure 4. The Cr layer is sandwiched between the metal layer and the dielectric layer as an adhesion layer. After thermocompression bonding, a small amount of diffusion of Cr element occurred between the Pt metal layers.

**Figure 5.** EDS line scan of the bonding interface. **Figure 5.** EDS line scan of the bonding interface.

**Figure 5.** EDS line scan of the bonding interface. Figure 6 is the distribution of silicon and Pt in the backscattered SEM image of the interconnect interface. The blue dots in Figure 6a represent the distribution of silicon, and the yellow dots in Figure 6b indicate the distributed Pt, and Figure 6c shows the effect of integrating the two SEM images. Through elemental surface scanning analysis, it Figure 6 is the distribution of silicon and Pt in the backscattered SEM image of the interconnect interface. The blue dots in Figure 6a represent the distribution of silicon, and the yellow dots in Figure 6b indicate the distributed Pt, and Figure 6c shows the effect of integrating the two SEM images. Through elemental surface scanning analysis, it Figure 6 is the distribution of silicon and Pt in the backscattered SEM image of the interconnect interface. The blue dots in Figure 6a represent the distribution of silicon, and the yellow dots in Figure 6b indicate the distributed Pt, and Figure 6c shows the effect of integrating the two SEM images. Through elemental surface scanning analysis, it can be observed that the bonded Pt element is still in the bonding area with no dislocation or drift.

*Micromachines* **2022**, *13*, 1543 6 of 11

tion or drift.

tion or drift.

**Figure 6.** EDS surface scanning element analysis diagram of the bonding interface. (**a**) Distribution diagram of silicon element, (**b**) distribution diagram of platinum element, (**c**) consolidated diagram of element distribution. **Figure 6.** EDS surface scanning element analysis diagram of the bonding interface. (**a**) Distribution diagram of silicon element, (**b**) distribution diagram of platinum element, (**c**) consolidated diagram of element distribution. **Figure 6.** EDS surface scanning element analysis diagram of the bonding interface. (**a**) Distribution diagram of silicon element, (**b**) distribution diagram of platinum element, (**c**) consolidated diagram of element distribution.

can be observed that the bonded Pt element is still in the bonding area with no disloca-

can be observed that the bonded Pt element is still in the bonding area with no disloca-

In Figure 7a, the green dots in Figure7b represent the Si element, the red dots in Figure7c represent the N element, the pink dots in Figure7d represent the Cr element, and the yellow dots in Figure7e represent the Pt element; the yellow dots representing the Pt element, Figure7a , are a visual SEM image of the final integration of each element. The combination of (Si + Cr + Pt = 100) and (Si + N + Cr + Pt = 100) elements were selected for analysis. The delamination of each element in the bonded sample was more obvious and no dislocation diffusion or element drift was observed. In Figure 7a, the green dots in Figure 7b represent the Si element, the red dots in Figure 7c represent the N element, the pink dots in Figure 7d represent the Cr element, and the yellow dots in Figure 7e represent the Pt element; the yellow dots representing the Pt element, Figure 7a, are a visual SEM image of the final integration of each element. The combination of (Si + Cr + Pt = 100) and (Si + N + Cr + Pt = 100) elements were selected for analysis. The delamination of each element in the bonded sample was more obvious and no dislocation diffusion or element drift was observed. In Figure 7a, the green dots in Figure7b represent the Si element, the red dots in Figure7c represent the N element, the pink dots in Figure7d represent the Cr element, and the yellow dots in Figure7e represent the Pt element; the yellow dots representing the Pt element, Figure7a , are a visual SEM image of the final integration of each element. The combination of (Si + Cr + Pt = 100) and (Si + N + Cr + Pt = 100) elements were selected for analysis. The delamination of each element in the bonded sample was more obvious and no dislocation diffusion or element drift was observed.

**Figure 7.** EDS surface scanning element analysis diagram of the bonding interface. (**a**) Consolidated diagram of element distribution, (**b**) distribution diagram of silicon element, (**c**) distribution diagram of nitrogen element, (**d**) distribution diagram of chromium element, (**e**) distribution diagram of platinum element. **Figure 7.** EDS surface scanning element analysis diagram of the bonding interface. (**a**) Consolidated diagram of element distribution, (**b**) distribution diagram of silicon element, (**c**) distribution diagram of nitrogen element, (**d**) distribution diagram of chromium element, (**e**) distribution diagram of platinum element. **Figure 7.** EDS surface scanning element analysis diagram of the bonding interface. (**a**) Consolidated diagram of element distribution, (**b**) distribution diagram of silicon element, (**c**) distribution diagram of nitrogen element, (**d**) distribution diagram of chromium element, (**e**) distribution diagram of platinum element.

## *3.2. Shear Strength Analysis*

Figure 8 is a schematic diagram of the shear force test. The equipment used in the experiment is Dage4000 bond tester which can provide testing of bond shear force and

tensile force. The sample in the picture is denoted by the blue part in the middle. After the lower substrate is fixed, the push knife moves in the horizontal direction until the upper and lower bonded substrates are separated. At the moment of separation, the force required to stop the pushing knife is the force of bonding at that moment. tensile force. The sample in the picture is denoted by the blue part in the middle. After the lower substrate is fixed, the push knife moves in the horizontal direction until the upper and lower bonded substrates are separated. At the moment of separation, the force required to stop the pushing knife is the force of bonding at that moment. the lower substrate is fixed, the push knife moves in the horizontal direction until the upper and lower bonded substrates are separated. At the moment of separation, the force required to stop the pushing knife is the force of bonding at that moment.

Figure 8 is a schematic diagram of the shear force test. The equipment used in the experiment is Dage4000 bond tester which can provide testing of bond shear force and

Figure 8 is a schematic diagram of the shear force test. The equipment used in the experiment is Dage4000 bond tester which can provide testing of bond shear force and tensile force. The sample in the picture is denoted by the blue part in the middle. After

**Figure 8.** Schematic diagram of shear force test. **Figure 8.** Schematic diagram of shear force test.

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*Micromachines* **2022**, *13*, 1543 7 of 11

*3.2. Shear Strength Analysis*

*3.2. Shear Strength Analysis*

Based on theoretical inferences, increasing the pressure can enhance the bonding strength. Importantly, the pressure applied should not exceed the threshold of the substrate's withstanding ability. Excessive pressure may cause an overflow of sputtered metal or cracks in the substrate. The shear resistance test in the effectively bonded sample in this experiment is shown in Figure 9. A total of 12 bonding samples were selected and divided into four groups according to the different bonding pressures: 30 MPa, 50 MPa, 80 MPa, and 100 MPa. Their shear resistance was found to be in the range of 12.2– 14.3 MPa, 15.1–17.6 MPa, 16.9–18.9 MPa, and 17.3–31.8 MPa. The bonding pressure is positively correlated within the withstandable range of the substrate, and its shear resistance can reach a maximum of 30 Mpa as the pressure increases. When the bonding pressure is 100 MPa, the measured value is the maximum shear force that the silicon wafer can withstand, and the average shear resistance can reach 25 MPa; thereby, the shear strength of Pt–Pt bonding meets the standard. Based on theoretical inferences, increasing the pressure can enhance the bonding strength. Importantly, the pressure applied should not exceed the threshold of the substrate's withstanding ability. Excessive pressure may cause an overflow of sputtered metal or cracks in the substrate. The shear resistance test in the effectively bonded sample in this experiment is shown in Figure 9. A total of 12 bonding samples were selected and divided into four groups according to the different bonding pressures: 30 MPa, 50 MPa, 80 MPa, and 100 MPa. Their shear resistance was found to be in the range of 12.2–14.3 MPa, 15.1–17.6 MPa, 16.9–18.9 MPa, and 17.3–31.8 MPa. The bonding pressure is positively correlated within the withstandable range of the substrate, and its shear resistance can reach a maximum of 30 Mpa as the pressure increases. When the bonding pressure is 100 MPa, the measured value is the maximum shear force that the silicon wafer can withstand, and the average shear resistance can reach 25 MPa; thereby, the shear strength of Pt–Pt bonding meets the standard. Based on theoretical inferences, increasing the pressure can enhance the bonding strength. Importantly, the pressure applied should not exceed the threshold of the substrate's withstanding ability. Excessive pressure may cause an overflow of sputtered metal or cracks in the substrate. The shear resistance test in the effectively bonded sample in this experiment is shown in Figure 9. A total of 12 bonding samples were selected and divided into four groups according to the different bonding pressures: 30 MPa, 50 MPa, 80 MPa, and 100 MPa. Their shear resistance was found to be in the range of 12.2– 14.3 MPa, 15.1–17.6 MPa, 16.9–18.9 MPa, and 17.3–31.8 MPa. The bonding pressure is positively correlated within the withstandable range of the substrate, and its shear resistance can reach a maximum of 30 Mpa as the pressure increases. When the bonding pressure is 100 MPa, the measured value is the maximum shear force that the silicon wafer can withstand, and the average shear resistance can reach 25 MPa; thereby, the shear strength of Pt–Pt bonding meets the standard.

**Figure 9.** Bonding strength of substrates. **Figure 9.** Bonding strength of substrates. **Figure 9.** Bonding strength of substrates.

Figure 10 shows the microscope schematic diagrams of the Pt metal sealing ring before thermocompression bonding and the Pt metal sealing ring of the debris after the shear force test. The shear test is generally divided into three fracture modes: IMC mode, Figure 10 shows the microscope schematic diagrams of the Pt metal sealing ring before thermocompression bonding and the Pt metal sealing ring of the debris after the shear force test. The shear test is generally divided into three fracture modes: IMC mode, Figure 10 shows the microscope schematic diagrams of the Pt metal sealing ring before thermocompression bonding and the Pt metal sealing ring of the debris after the shear force test. The shear test is generally divided into three fracture modes: IMC mode, solder mode, and mixed IMC/solder mode. Fractures in the IMC mode generally occur in the IMC layer. As can be observed from the Figure 10, the shear test destroyed the bonding electrode and the sealing ring, and it can be seen that the fracture mode in the test is mainly the IMC

*Micromachines* **2022**, *13*, 1543 8 of 11

mode [25,26], indicating that the shear resistance is mainly due to the force exerted on the bonding electrode. This demonstrates that the bonding is effective. the force exerted on the bonding electrode. This demonstrates that the bonding is effective.

solder mode, and mixed IMC/solder mode. Fractures in the IMC mode generally occur in the IMC layer. As can be observed from the Figure 10, the shear test destroyed the bonding electrode and the sealing ring, and it can be seen that the fracture mode in the test is mainly the IMC mode [25,26], indicating that the shear resistance is mainly due to

**Figure 10.** Shear force test comparison image. (**a**) Top substrate. (**b**) Bottom substrate. **Figure 10.** Shear force test comparison image. (**a**) Top substrate. (**b**) Bottom substrate.

Of course, some metals do not perform well in shear tests. This may be caused by uneven sputtering during the coating process due to the influence of experimental fac-Of course, some metals do not perform well in shear tests. This may be caused by uneven sputtering during the coating process due to the influence of experimental factors.

#### *3.3. Hermeticity Detection*

tors.

*3.3. Hermeticity Detection*  According to the method defined by the inspection standard (GJB 548B-2005 method 1014.2), the purpose of the test is to determine the hermeticity of microelectronic and semiconductor device packages with internal cavities. The hermeticity test of the four groups of bonded pairs is carried out. First, a detailed inspection was carried out using the ZHP-30D helium mass spectrometer leak detector. The sample is kept under pressure of 4 × 10–5 Pa for 2 h, and the leakage rate is measured with the leak detector after taking it out. The actual leakage rate of the technically required samples is less than 2 × 10–3 Pa·cm3/s, that is, less than the specified leakage rate value (5 × 10–3 Pa·cm3/s). As Table 2 shown, the first group of samples through the experiment showed the minimum leakage rate measured to be 30 MPa/165 N, 350 °C, 1200 s: 3.3 × 10–4 Pa·cm3/s, the maximum leakage rate: 9.8 × 10–4 Pa·cm3/s, the average leakage rate: 6.55 × 10–4 Pa·cm3/s, which is less than the leakage rate value required by the specification. Similarly, the second group of samples showed the leakage rate measured under the bonding conditions of 50 MPa/275 N, 350 °C, 1200 s: 5.9 × 10–4 Pa·cm3/s, 3.3 × 10–5 Pa·cm3/s, average leakage rate: 3.115 × 10–4 Pa·cm3/s, which is less than the specified leakage rate value. The third group of samples: 80 MPa/550 N, 350 °C, the maximum leakage rate measured under the bonding condition of 1200 s: 2.77 × 10–5 Pa·cm3/s, the minimum leakage rate: 1.37 × 10–5 Pa·cm3/s, the average leakage rate: 1.81 × 10–5 Pa·cm3/s. The fourth group of samples: 100 MPa/550 N, 350 °C under the bonding conditions of 1200 s, the maximum leakage rate measured: 1.83 × 10–5 Pa·cm3/s, the minimum leakage rate: 1.29 × 10–5 Pa·cm3/s, average leakage rate: 1.48 × 10–5 Pa·cm3/s. In conclusion, the leakage rate values measured by the four groups of different bonding parameters are all within the range of the leakage rate values required by the specification. It can be inferred from Figure 11 that with the increase in the bonding pressure, the average air tightness of the samples will gradually increase, and the average air tightness of the successfully bonded samples can meet the According to the method defined by the inspection standard (GJB 548B-2005 method 1014.2), the purpose of the test is to determine the hermeticity of microelectronic and semiconductor device packages with internal cavities. The hermeticity test of the four groups of bonded pairs is carried out. First, a detailed inspection was carried out using the ZHP-30D helium mass spectrometer leak detector. The sample is kept under pressure of 4 × 10–5 Pa for 2 h, and the leakage rate is measured with the leak detector after taking it out. The actual leakage rate of the technically required samples is less than 2 × 10–3 Pa·cm3/s, that is, less than the specified leakage rate value (5 × 10–3 Pa·cm3/s). As Table 2 shown, the first group of samples through the experiment showed the minimum leakage rate measured to be 30 MPa/165 N, 350 ◦C, 1200 s: 3.3 × 10–4 Pa·cm3/s, the maximum leakage rate: 9.8 × 10–4 Pa·cm3/s, the average leakage rate: 6.55 × 10–4 Pa·cm3/s, which is less than the leakage rate value required by the specification. Similarly, the second group of samples showed the leakage rate measured under the bonding conditions of 50 MPa/275 N, 350 ◦C, 1200 s: 5.9 × 10–4 Pa·cm3/s, 3.3 × 10–5 Pa·cm3/s, average leakage rate: 3.115 × 10–4 Pa·cm3/s, which is less than the specified leakage rate value. The third group of samples: 80 MPa/550 N, 350 ◦C, the maximum leakage rate measured under the bonding condition of 1200 s: 2.77 × 10–5 Pa·cm3/s, the minimum leakage rate: 1.37 × 10–5 Pa·cm3/s, the average leakage rate: 1.81 × 10–5 Pa·cm3/s. The fourth group of samples: 100 MPa/550 N, 350 ◦C under the bonding conditions of 1200 s, the maximum leakage rate measured: 1.83 × 10–5 Pa·cm3/s, the minimum leakage rate: 1.29 × 10–5 Pa·cm3/s, average leakage rate: 1.48 × 10–5 Pa·cm3/s. In conclusion, the leakage rate values measured by the four groups of different bonding parameters are all within the range of the leakage rate values required by the specification. It can be inferred from Figure 11 that with the increase in the bonding pressure, the average air tightness of the samples will gradually increase, and the average air tightness of the successfully bonded samples can meet the packaging requirements.

packaging requirements. **Table 2.** Case of leakage rate.

**Figure 11.** Influence of pressure on bonding leakage rate. **Figure 11.** Influence of pressure on bonding leakage rate.

#### *3.4. Failure Analysis*

**Table 2.** Case of leakage rate.

*3.4. Failure Analysis*  Owing to the high melting point and boiling point of Pt, the diffusion process is greatly restricted by temperature during the flip-chip welding process. Since the maximum welding temperature of flip-chip welding in the bulk silicon process does not exceed 400 °C, this work used a welding temperature of 250 °C–350 °C and a bonding pressure of 30 MPa–100 Mpa to explore the influence of different temperatures and pressures on welding failure rate. Bonding failure may be caused by a variety of reasons, and the failure may be manifested in that the top and bottom substrates do not adhere together or the tests such as shear force and air tightness cannot meet the test requirements. It was found that both the bonding pressure and the bonding temperature are positively correlated to the failure rate as shown in Figure 12. When the bonding temperature is 625 K and the bonding pressure is above 80 MPa, the failure rate is less than 0.4; under the same pressure conditions, when the temperature is less than 625 K, the failure rate is greater than 0.5. It shows that the failure rate is greatly affected by the bonding temperature, which should optimally be above 625 K. When the bonding pressure is less than 50 MPa, the failure rate of the bonding is more than 0.5, suggesting the Owing to the high melting point and boiling point of Pt, the diffusion process is greatly restricted by temperature during the flip-chip welding process. Since the maximum welding temperature of flip-chip welding in the bulk silicon process does not exceed 400 ◦C, this work used a welding temperature of 250 ◦C–350 ◦C and a bonding pressure of 30 MPa–100 Mpa to explore the influence of different temperatures and pressures on welding failure rate. Bonding failure may be caused by a variety of reasons, and the failure may be manifested in that the top and bottom substrates do not adhere together or the tests such as shear force and air tightness cannot meet the test requirements. It was found that both the bonding pressure and the bonding temperature are positively correlated to the failure rate as shown in Figure 12. When the bonding temperature is 625 K and the bonding pressure is above 80 MPa, the failure rate is less than 0.4; under the same pressure conditions, when the temperature is less than 625 K, the failure rate is greater than 0.5. It shows that the failure rate is greatly affected by the bonding temperature, which should optimally be above 625 K. When the bonding pressure is less than 50 MPa, the failure rate of the bonding is more than 0.5, suggesting the optimal bonding pressure of Pt–Pt bonding is more than 50 MPa. *Micromachines* **2022**, *13*, 1543 10 of 11

**Parameter Condition Minimum Leakage Rate Maximum Leakage Rate Average Leakage Rate**  Group 1 30 MPa/165 N 3.3 × 10–4 9.8 × 10–4 6.55 × 10–4 Group 2 50 MPa/275 N 3.3 × 10–5 5.9 × 10–4 3.115 × 10–4 Group 3 80 MPa/550 N 1.37 × 10–5 2.77 × 10–5 1.81 × 10–5 Group 4 100 MPa/550 N 1.29 × 10–5 1.83 × 10–5 1.48 × 10–5

**Figure 12.** Influence of temperature and pressure on welding failure rate. **Figure 12.** Influence of temperature and pressure on welding failure rate.

#### **4. Conclusions 4. Conclusions**

ture.

**References**

https://doi.org/10.1126/science.1244358.

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2020JCJQZD043).

tation. *New J. Phys.* **2009**, *11*, 095012. https://doi.org/10.1088/1367-2630/11/9/095012.

**Data Availability Statement:** Not applicable.

Tech and Nano-Bionics, Chinese Academy of Sciences.

**Conflicts of Interest:** The authors declare no conflicts of interest.

1. Ghosh, S.; Nika, D.L.; Pokatilov, E.P.; Balandin, A. Heat conduction in graphene: Experimental study and theoretical interpre-

2. Wang, L.; Meric, I.; Huang, P.Y.; Gao, Q.; Gao, Y.; Tran, H.; Taniguchi, T.; Watanabe, K.; Campos, L.M.; Muller, D.A.; et al. One-dimensional electrical contact to a two-dimensional material. *Science* **2013**, *342*, 614–617.

The Pt–Pt metal interconnection used flip-chip hot-press packaging technology to achieve a relatively stable interconnection at a temperature of 350 °C and pressure above The Pt–Pt metal interconnection used flip-chip hot-press packaging technology to achieve a relatively stable interconnection at a temperature of 350 ◦C and pressure above

80 MPa. A series of experiments to evaluate its bonding performance was carried out. The thickness of the metal layer did not change significantly after bonding, and there

min, the shear resistance could reach up to 30 MPa. The shear experiment shows that the fractured interface is mostly on the silicon-metal layer, indicating that the interconnection interface after bonding is stable and does not easily fracture, indicating that the Pt– Pt metal bonding has a certain feasibility in packaging. The failure analysis experiment shows that the bonding pressure and temperature have an important influence on the failure rate, which is in line with the basic principle of metal welding. In addition, increasing the metal activity of the Pt metal interface may lower the requirements for bonding temperature and bonding pressure. Thus, these materials are considered worth exploring. We can plasma-treat the metal layer before bonding to improve the metal activity or find equipment that can increase the bonding temperature and bonding pressure to improve the quality of the bonding. In short, Pt–Pt metal bonding is a means of encapsulation that has great potential in the high-temperature environment in the fu-

**Author Contributions:** Data curation and writing—original draft, J.L.; conceptualization, methodology, project administration, writing—review and editing, J.W.; funding acquisition, supervision, M.L.; investigation and validation, H.Z. All authors have read and agreed to the published version

**Funding:** This research was funded by the "173" Projects of China (Grant No. 2021JCJQJJ0172,

**Acknowledgments:** The authors appreciate the facility assistance from Suzhou Institute of Nano-

80 MPa. A series of experiments to evaluate its bonding performance was carried out. The thickness of the metal layer did not change significantly after bonding, and there was no Pt overflow at the bonding interface. In the case of bonding force of 550 N for 20 min, the shear resistance could reach up to 30 MPa. The shear experiment shows that the fractured interface is mostly on the silicon-metal layer, indicating that the interconnection interface after bonding is stable and does not easily fracture, indicating that the Pt–Pt metal bonding has a certain feasibility in packaging. The failure analysis experiment shows that the bonding pressure and temperature have an important influence on the failure rate, which is in line with the basic principle of metal welding. In addition, increasing the metal activity of the Pt metal interface may lower the requirements for bonding temperature and bonding pressure. Thus, these materials are considered worth exploring. We can plasmatreat the metal layer before bonding to improve the metal activity or find equipment that can increase the bonding temperature and bonding pressure to improve the quality of the bonding. In short, Pt–Pt metal bonding is a means of encapsulation that has great potential in the high-temperature environment in the future.

**Author Contributions:** Data curation and writing—original draft, J.L.; conceptualization, methodology, project administration, writing— review and editing, J.W.; funding acquisition, supervision, M.L.; investigation and validation, H.Z. All authors have read and agreed to the published version of the manuscript.

**Funding:** This research was funded by the "173" Projects of China (Grant No. 2021JCJQJJ0172, 2020JCJQZD043).

**Data Availability Statement:** Not applicable.

**Acknowledgments:** The authors appreciate the facility assistance from Suzhou Institute of Nano-Tech and Nano-Bionics, Chinese Academy of Sciences.

**Conflicts of Interest:** The authors declare no conflict of interest.

#### **References**


*3.3. Chain Dynamics for σ* = *O*(*ε*2)

Here, we assume that the condition (48) holds. We distinguish the roots of the characteristic Equation (20) with real parts tending to zero as *ε* → 0. This equation's roots *λ* = *λ*(*k*) are calculated from the formula

$$\begin{split} \lambda + (r\_0 + \varepsilon^2 r\_1) \exp(-\lambda) &= d \left( \int\_{-\infty}^{\infty} F(s, \varepsilon) \exp(iks) ds - 1 \right) = \\ d(\cos(z) \exp(-\varepsilon^4 \sigma\_0^2 z^2) - 1), \end{split} \tag{63}$$

where *z* = *εk*. The vanishing of the right-hand side in (63) up to *O*(1) (as *ε* → 0) is responsible for the real parts of the roots tending to zero. Those numbers *k* = *k*(*ε*) satisfy this condition for which cos(*z*) ∼ 1. We introduce the notation to describe such numbers. We fix an arbitrary integer *n* and let *θn* = *θn*(*ε*) ∈ [0, 1) be the expression that complements the value 2*πnε*−1 to an integer. It appears that the function *θn*(*ε*) can be considered identically zero. The point is that the parameter *ε* introduced above is determined as *ε* = 2*π*(1 + 2*N*)−1. Therefore, 2*πnε*−1 = *n*(1 + 2*N*), which is an integer.

Then, the set of numbers *k*(*ε*) of the roots *λ*(*k*(*ε*)) consists of the values

$$k(\varepsilon) = 2\pi n \varepsilon^{-1} + m, \quad m, n = 0, \pm 1, \pm 2, \dots \tag{64}$$

in the considered case.

It is convenient to denote these roots by *λm*,*n*(*ε*). We obtain the asymptotic expression

$$\lambda\_{m,n}(\varepsilon) = i\frac{\pi}{2} - \varepsilon^2 \left(1 + i\frac{\pi}{2}\right)^{-1} \left(m^2 + 4\pi^2 \sigma\_0^2 n^2\right) + O(\varepsilon^4),$$

for them.

We follow the algorithm investigated above and introduce the formal series

$$\begin{split} u &= \varepsilon \left[ \exp \left( i \frac{\pi}{2} t \right) \sum\_{m = -\infty}^{\infty} \sum\_{n = -\infty}^{\infty} \xi\_{m, n}(\tau) \exp \left( i (2 \pi n \varepsilon^{-1} + m) x \right) + \\ &\varepsilon \left( -i \frac{\pi}{2} t \right) \sum\_{m = -\infty}^{\infty} \sum\_{n = -\infty}^{\infty} \bar{\xi}\_{m, n}(\tau) \exp \left( -i (2 \pi n \varepsilon^{-1} + m) x \right) \right] + \\ &\varepsilon^2 u\_2(t, \tau, x) + \varepsilon^3 u\_3(t, \tau, x) + \dots \,, \end{split} \tag{65}$$

where *τ* = *ε*2*t*, and the functions *uj*(*t*, *τ*, *x*) are periodic with respect to *t* and *x*.

Let *y* = 2*πε*−1*x* and

$$\xi(\tau, x, y) = \sum\_{m = -\infty}^{\infty} \sum\_{n = -\infty}^{\infty} \xi\_{m, n}(\tau) \exp(iny + imx).$$

Then, we can simplify expression (65)

$$u = \varepsilon \left[ \exp\left(i\frac{\pi}{2}t\right)\overline{\xi}(\tau, x, y) + \exp\left(-i\frac{\pi}{2}t\right)\overline{\xi}(\tau, x, y)\right] + \varepsilon^2 u\_2 + \varepsilon^3 u\_3 + \dots \tag{66}$$

We insert (66) into (15) and equate the coefficients at the same powers of *ε*. First, we determine *u*2(*τ*, *t*, *x*). Then, from the solvability condition of the equation with respect to *u*3, we obtain the expression for *ξ*(*τ*, *x*, *y*), determining:

$$\frac{\partial \tilde{\xi}}{\partial \tau} = \left(1 + i\frac{\pi}{2}\right)^{-1} \cdot \left(\frac{\partial^2 \tilde{\xi}}{\partial \mathbf{x}^2} + 4\pi^2 \sigma\_0^2 \frac{\partial^2 \tilde{\xi}}{\partial y^2}\right) + \lambda\_{10} \tilde{\xi} + g\tilde{\xi} |\tilde{\xi}|^2,\tag{67}$$

$$\xi(\mathbf{r}, \mathbf{x} + 2\pi, y) \equiv \xi(\mathbf{r}, \mathbf{x}, y + 2\pi) \equiv \xi(\mathbf{r}, \mathbf{x}, y),\tag{68}$$

where the coefficients *λ*10 and *g* are the same as in (52).

Ideologically, the basic results of this subsection repeat Theorems 5 and 6. We cite an analogue of Theorem 5 as an example.

**Theorem 7.** *Let ξ*0(*τ*, *x*, *y*) *be the bounded solution of the boundary value problem* (67)*,* (68) *as τ* → ∞*. Then, the function*

$$\begin{split} u\_0(t, \mathbf{x}, \boldsymbol{\varepsilon}) &= 1 + \varepsilon \Big[ \exp \left( i \frac{\boldsymbol{\pi}}{2} t \right) \mathbb{f}\_0(\boldsymbol{\varepsilon}^2 t, \mathbf{x}, 2\boldsymbol{\pi}^{-1} \mathbf{x}) + \\ & \quad \exp \left( -i \frac{\boldsymbol{\pi}}{2} t \right) \mathbb{f}\_0(\boldsymbol{\varepsilon}^2 t, \mathbf{x}, 2\boldsymbol{\pi} \boldsymbol{\varepsilon}^{-1} \mathbf{x}) \Big] + \varepsilon^2 \mu\_2 \end{split} \tag{69}$$

*satisfies the boundary value problem* (15) *up to O*(*ε*3)*.*

The boundary value problems (61) and (67), (68) have been numerically investigated by many authors (see, for example, [30]). It has been shown that complicated and irregular oscillations are typical for such boundary value problems, especially for (67), (68). The formulas (60) and (66), which couple these boundary value problem solutions with the boundary value problem (15) solutions, allow us to formulate the same conclusion about the solutions of (15).


*Methodological Considerations*

Research in construction has challenges with loss to follow up due to the dynamic nature of construction with workers coming and going on worksites as the construction job requires specific trades during the timeline of the study [18,36]. The issue of poor follow-up rates can lead to bias; however, usually towards the null [62]. This is predominately due to the itinerant nature of construction workers [18]. This resulted in our analyses at FU2 being underpowered for some of our outcomes (such as pain and injury) where the effect size was similar to FU1. Similar findings have been found in related interventions [63].

Another challenge was the success of integrating the injury prevention and health promotion activities in this environment. Integration was achieved by linking the two programs by name and key messaging in the planning and implementation phases. In addition, messaging around Health Week included training on both injury prevention and health promotion giving workers the tools to improve their working conditions, as well as giving them control for their health. The ergonomics program prior to Health Week did have health messaging but without any specific health promotion activities.

One limitation was that our intervention depended on the participation of the general contractor safety managers, whose involvement and dedication to the study varied across sites and between general contractors. This aspect of the intervention was by design, as we considered it important for integration and sustainability into current company processes, that the ergonomics inspections were performed by the safety managers. Giving the safety managers latitude to decide how invested they were in the program allowed us to assess the feasibility of the intervention being adopted without the aid of study staff. This would ensure that our observations were realistic and representative of barriers and facilitators to the intervention's delivery by non-study staff.

Further, this study involved worksites in commercial construction only. Thus, the results may not be generalizable to other types of construction (i.e., residential or industrial). However, commercial construction accounts for a large portion of U.S. construction activities, and represents an important area for injury prevention research. Similarly, the construction workforce in the Boston metropolitan area may not be representative of commercial construction workers in other parts of the country or world, where work practices, demographics, and union membership differ.

Despite these limitations, our study had several strengths, most notably the study design and the wide variety of general contractors and sites recruited into the study. The cluster randomized control trial design is a novel approach in commercial construction. Typically, approaches to improve the health and safety of construction workers have often focused on the individual worker, targeting workers when they are enrolled in apprentice programs [64,65], targeting workers through social media campaigns via posters at worksites and/or brochures sent to union members [66,67], and engineering controls for specific tasks [68]. However, best practice involves system-level approaches that comprehensively address workplace systems relevant to the control of hazards and worker safety, health, and well-being [20]. This study was fortunate to be able to recruit five major general contractors operating in the Boston metropolitan area and gain access to ten different construction sites for the purpose of evaluating the ARM intervention. Furthermore, delivering the intervention through mid-level managers (through a combination of the general contractor safety managers and subcontractor foremen) was a strength of the study. This focused intervention efforts on those who were in the best positions to make changes to the conditions of work.

The ergonomics inspection and communication protocol provided a method to identify broad areas for improving ergonomics in the dynamic construction work environment. It is important to understand the challenges and successes of intervention delivery in order to inform and improve future worksite-based interventions. It appears that the largest barriers to the success of the intervention were the inability of subcontractors to make changes to their worksite and the variability in the involvement and dedication to the study across different worksites and general contractors. These are real-world, as well as research study challenges. Subcontractors did not have the systems in place, or the available tools, to assist in changing their working conditions. Competing safety and production priorities also influenced the level of management commitment to the study. Additionally, construction safety research may have broader implications for an increasing number of industries that are becoming as dynamic and variable as construction, as more services once housed in a single facility are outsourced to multiple employers [17].


9Prevention in English, http://www.everydayhealth.com/cold-and-flu-pictures/ ways-to-prevent-colds-and-flu.aspx; prevention in Italian, http://www.abcsalute. it/blog/influenza-americana-inverno-2014-cose-e-come-curarla/; vaccine in English, http://www.everydayhealth.com/drugs/influenza-virus-vaccine-livetrivalent-http://www.webcitation.org/6buN57wQn; vaccine in Italian, http://www. farmacoecura.it/influenza/influenza-2008-2009-vaccino-prevenzione/)

on the HON website, may limit its diffusion. In addition, at list in our search, it is not displayed by websites from government agencies, public healthcare services or Universities.

# News

The impact on news websites deserves more discussion. First of all, they give a more "balanced" view and this is the class of websites that is more likely to describe both EBM and non-EBM approaches, in both languages (**Figure 5**) and to describe the influenza vaccine in a "neutral" way (with the caveat discussed below). This has also been noted in a Dutch qualitative study similarly reported that news websites are more objective and non-judgmental while a critical view of vaccination was more common in social media (35). On the other hand, journalism websites are not very well represented among those recommending the vaccine when searching for preventative strategies.

The textual analysis of the journalistic websites shows that, for the past winter, they all gave the same type of news, different in the two languages. This is probably due to the fact that newspapers are nowadays understaffed and tend to just re-post press releases rather than having articles written by their own scientific journalists. English websites mainly reported data from government agencies describing the low efficacy of that year's vaccine. Although most newspapers reminded the reader that, despite the concerns reported, the government still recommended vaccination for those at risk, the titles had a negative tone (Sky News: "flu jab found to work in just 3% of cases"10; Daily Mail, "Flu jab is a waste of time for 97% of patients"11).

The news websites in Italian were even more peculiar. On 28th of November, 2014, all main newspapers published in the front-page headline that three elderly people died within 2 days from having been vaccinated (e.g., il Corriere della Sera and il Giornale12) and panic ensued. The health authorities suspended two batches of vaccine and the number of "suspicious deaths" reached 13, as reported in the front page of il Sole 24 Ore.13 The emergency did not last long and a week later newspapers reported (with much less emphasis) that the health authorities have concluded that those deaths were not associated with the vaccine, which was confirmed on 3 December 2014 by the Pharmacovigilance Risk Assessment Committee of the European Medicines Agency (EMA).14

As early as the 29th of November, Dr. Cirielli, president of the Società Italiana di Medicina Generale (Simg) noted that every day in Italy 1,600 over-65s die; as the uptake rate for the influenza vaccine in that population is over 50%, 400 people die every day "after having been vaccinated."15 Thus, it would require a highly powered study to attribute three deaths to the vaccination.

It is nuclear what have sensitized the public opinion to report those deaths. One interesting coincidence is that three days earlier, the 25th of November, most newspapers reported that judge Di Leo of the Tribunale del Lavoro di Milano (employment tribunal), based on an 18-page report from forensic doctor Alberto Tornatore, concluded that a hexavalent vaccine (against, among others, *Haemophilus influenzae*) had probably caused autism in a child and sentenced the Italian government to pay monthly compensation.16

Thus, in each language, a language-specific "bad news" made up a very significant portion of the journalistic websites on the influenza vaccine. There was a small overlap between the two SERP on vaccine in that two Italian websites reported the data of low efficacy released by the CDC17 and two websites in English reported the news of the suspected accident in Italy.18

Many studies have investigated the quality of health information available on the web, often with a preconception that either the uncontrolled nature of the web will allow posting of low quality information, misinformation or disinformation. In this perspective, the layperson not being able to discriminate between low-quality and high-quality sites, there is a concern that the use of the Internet by the patient may cause harm by promoting potentially unsafe treatments (36), although others found little evidence of this in the medical literature (37).

# CONCLUSION AND LIMITATIONS

In drawing conclusions, one should be aware of the limitation of this study. Search results vary with time; different search terms or health topics will give different results; searching from a different location (as defined by the IP address) will give different results. Although some findings were in agreement with previous studies from our group performed in the last three years across different searches (such as commercial websites ranking lower and having a lower JAMA score), other findings may not be generalized.

The other finding that would be worth confirming further is that most websites returned are not "standalone websites" but are in fact documents and publications from professional organizations,

10http://news.sky.com/story/1422308/flu-jab-found-to-work-in-just-3-percentof-cases (archived in: http://www.webcitation.org/6bvdaI4M9)

11http://www.dailymail.co.uk/news/article-2941896/Flu-jab-waste-time-97 patients-Vaccine-developed-year-ago-no-longer-matches-virus-mutated-much. html (archived in: http://www.webcitation.org/6Z9hZ28b2

12http://archiviostorico.corriere.it/2014/novembre/28/Vaccini\_morti\_sospette\_ caos\_co\_0\_20141128\_e7fda2a2-76d2-11e4-b904-b99b9498524a.shtml (archived in: http://www.webcitation.org/6bsuHeVY2); http://www.ilgiornale.it/news/ politica/serie-morti-vaccino-panico-regioni-nel-caos-1071444.html (archived in: http://www.webcitation.org/6bsugIYSo)

13http://www.ilsole24ore.com/art/notizie/2014-11-29/vaccini-antinfluenzalimorti-sospette-salgono-12-ministro-lorenzin-primi-test-negativi-220813. shtml?uuid=AbiFgtJC (archived in: http://www.webcitation.org/6bsusggIm)

14http://www.ema.europa.eu/ema/index.jsp?curl=pages/news\_and\_events/ news/2014/12/news\_detail\_002228.jsp&mid=WC0b01ac058004d5c1; http:// www.webcitation.org/6bu31e9mg (archived in: http://www.webcitation. org/6bvfp65Vq)

15http://www.quotidianosanita.it/scienza-e-farmaci/articolo.php?articolo\_ id=24648; archived in: http://www.webcitation.org/6bu3d4t4R

16http://www.repubblica.it/salute/medicina/2014/11/25/news/il\_tribunale\_ bimbo\_autistico\_per\_colpa\_del\_vaccino-101357013/ (archived in: http://www. webcitation.org/6bswRLubo)

17http://www.assis.it/cdc-questanno-il-vaccino-antinfluenzale-e-pressocheinefficace/ (archived in: http://www.webcitation.org/6bssq8yTV); http://www. terranuova.it/Medicina-Naturale/Vaccino-antinfluenzale-ora-si-scopre-che-eanche-inefficace (archived in: http://www.webcitation.org/6bstEgxJV)

18http://time.com/3610872/italy-flu-vaccine-deaths/ (archived in: http://www. webcitation.org/6bstODqvC); http://blogs.wsj.com/pharmalot/2014/12/01/ italy-investigates-novartis-flu-vaccine-after-12-deaths-are-reported/ (archived in: http://www.webcitation.org/6bstTpbD1)

newspapers, government agencies, and commercial companies. If this was generalized, then the idea is that the Internet is a source of uncontrolled information where anyone can make any statement.

Another important finding was that, for relatively hot topics, Google returns a high proportion of journalistic websites from TV channels or print journals. This raises the interesting theoretical point on whether "newsworthiness" should be considered an indicator of IQ like trustworthiness or if it is a confounder, as well as the role of journalist as the gatekeeper. When we discuss health IQ, we think of information as "knowledge obtained from investigation, study, or instruction" but the word also defines "intelligence or news" (Merriam-Webster Online Dictionary). It is not clear whether the ways we assess IQ are the same for the two definitions of "information." Also, we do not know which ones of the top 10 websites a user will actually read and whether they will give the same weight to an article in the press or a different type of information. This would be an important follow up of this study.

It would be important to know whether the different pattern in Italian vs. English is observed with other search terms, and to what extent this happens with other non-English languages. It is also curious that only "bad news" received so much attention. An earlier study on news on medical research in the press had concluded that "Newspapers underreported randomized trials,

# REFERENCES

1. Jefferson T, Di Pietrantonj C, Rivetti A, Bawazeer GA, Al-Ansary LA, Ferroni E. Vaccines for preventing influenza in healthy adults. *Cochrane Database Syst Rev* (2010) **7**:CD001269. doi:10.1002/14651858.CD001269.pub4

emphasized bad news from observational studies, and ignored research from developing countries" (38).

As suggested in the peer review process, we performed a search on the prevention of influenza comparing different search terms. In English, we searched for "preventing the flu" and "influenza prevention"; in Italian for "prevenire l'influenza," "prevenzione influenza" and "prevenzione antinfluenzale" and analyzed the top 10 websites. We investigated: (1) the percentage of commercial websites and (2) the orientation (EBM vs. non-EBM). The results are shown in **Figure 11** (raw data are available in the Supplementary Material as Data Sheet S3 in Supplementary Material). Because this search was performed several months later, it cannot be compared to the ones above. However, the results confirm the main messages of the study, that is, that a search in Italian gives more visibility to commercial websites and to non-EBM websites than those in English. In fact, a search in Italian for "prevenire l'influenza" (which is a less formal language than without the other search terms without the article) returns no government websites and is more oriented toward non-EBM terminology as compared to the results with other search terms. This probably should suggest government agencies to ensure that informal language as it may well be that official government in Italian are written in a more technical language than their correspondent texts in English and should carefully consider this point when performing search engine optimization. The results also suggest performing future research on the impact of the language style on the quality of health information returned by Google.

Finally, it is important to monitor the impact of web health information on public health. The output of search engines can affect knowledge and attitude about vaccination significantly, (39) and thus might impact on the uptake of vaccination (40). It would be interesting to have a follow-up epidemiological study to assess how the health information available in the press has influenced the vaccine uptake in the next year.

# AUTHOR CONTRIBUTIONS

PG, AM: designed research, analysed the data, and wrote paper. RE: designed research, wrote paper.

# FUNDING

Supported by the Brighton & Sussex Medical School.

# SUPPLEMENTARY MATERIAL

The Supplementary Material for this article can be found online at http://journal.frontiersin.org/article/10.3389/ fimmu.2015.00616.

*Cochrane Database Syst Rev* (2011) **6**:CD006207. doi:10.1002/14651858. CD006207.pub4

**Conflict of Interest Statement:** The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

*Copyright © 2015 Maki, Evans and Ghezzi. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.*

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Acknowledgements

4. Result discussion and conclusions

Specimen JIC

164 Contact and Fracture Mechanics

(4 � 2 � 20 mm3

kJ/m2

(UC = Unloading Compliance; MS = Multiple specimen method)

1 T-CT 598,3 3,0 UC 0.16 T-CT 345,2 7,0 UC CVN 573,1 10,0 MS KLST 513,6 14,0 MS

Table 8. Summarization of average values of fracture toughness results, material AISI 304.

); unloading compliance method of measurement.

Specimen O.16 T-CT KLST (4 � 2 � 20 mm3

JIC kJ/m2 31,9 2,5 85,7 9,1

Table 9. Comparison of fracture toughness results; material AM Ti6Al4V; geometry, 0.16 T-CT vs. KLST

test preparation, execution and assessment.

point-bend specimens of cross section 2 � 4 mm2

The chapter presented here gives basic overview on issues related to small-size specimen testing in the field of the fracture mechanics tests. Some theoretical background and the relation between values obtained on small- and full-sized specimens for all regimes of the fracture behavior ranging from the lower shelf behavior up to the upper shelf region are shown. Some possibilities on how to resolve the size issue influence of the fracture toughness parameters and the reasons for differences obtained during the evaluation in the first chapter part were presented. An overview of size requirements for a valid value determination of the fracture toughness is also given. The subsequent experimental part is demonstrating results of the fracture toughness determination for three materials covering transition and upper shelf region behavior. As an important part of the fracture toughness tests are tensile properties determination. The chapter is dealing with miniature specimen testing; thus mini tensile tests are presented here for the basic property determination that is necessary for fracture toughness

Avg. St. dev. Avg. St. dev.

Testing in the transition region and evaluation with the use of the Master Curve approach yielded very good result comparability between miniaturized and full-size specimens for the material investigated. Testing program spanning over five specimens' geometries agrees very well with published results and confirms reliable result determination in this region even with the use of the miniaturized specimens including 4-mm-thick mini-CT specimens and three-

crack extension was investigated for stainless steel and Ti-alloy produced by the additive manufacturing process. In the case of the stainless steel, four specimens' geometries were

. The upper shelf behavior with the stable

Number of specimens Specimen

)

This chapter was created with support of the projects TH02020448S service life assessment with the use of miniaturized test specimens, 2017–2020, and Development of West-Bohemian Centre of Materials and Metallurgy No. LO1412, financed by the MEYS of the Czech Rep.