In-Situ Transmission Electron Microscopy Studies on Advanced Materials for Micro- and Nano-Electronics

This PhD thesis was focused on the development of in-situ transmission electron microscopy (TEM) methodologies on advanced materials for micro- and nano-electronics. The first in-situ study was focused on time dependent dielectric breakdown (TDDB) degradation kinetics and failure mechanisms in Cu/low-k interconnect stacks. The second study investigated the stretching of patterned graphene ribbons for tuning the bandgap, and consequently the mechanical properties. In the in-situ TDDB study, the electric field was generated using a TEM holder and a source-measurement unit,while TEM imaging and electron spectroscopic imaging (ESI) were selected as techniques of choice to image the test structure and to detect possible Cu traces in the dielectrics during electrical testing. Three major TDDB-induced damage mechanisms in the “tip-to-tip” structures can occur during electrical tests. Cu migration into the low-k dielectric and SiO2 layer was only observed after forming a breach in the TaN/Ta barrier during the electricaltest. The final breakdown location depends on the complex interplay of the various steps in the degradation sequence, i.e. electronic damage,barrier material dissolution and breach, Cu diffusion and agglomeration. The experimental approach opens a novel opportunity to study the TDDB breakdown mechanism in the interconnect stacks of microelectronic products, and it could also be extended to other structures in active devices. The observed degradation mechanisms improve the understanding of reliability-limiting processes in integrated circuits and provide data for the selection of the model used for lifetime estimation. The mechanical response of patterned graphene ribbons under stretching was monitored in-situ in the TEM, and thecorresponding low-loss electron energy loss spectrum (EELS) was recorded as an attempt to reveal the tuning of the bandgap. Chemical vapor deposition (CVD) grown monolayer graphene was transferred onto a “push-to-pull” device by a modified poly (methyl methacrylate) (PMMA) method, and was patterned into ribbons by both focused ion beam (FIB) in a SEM/FIB tool and focused electron beam in a TEM. The elongation was confirmed to be about 3 % by more than 30 focused electron beam patterned graphene ribbons. To our knowledge, this experiment demonstrated here is the first one to directly measure the tensile failure strain of graphene ribbons. No bandgap opening in the in-situ stretched graphene ribbons was detected from the low-loss EELS spectrum even with an energy resolution of about 0.15 eV. Further improvement of the energy resolution may offer the possibility to directly detect the bandgap opening of strained graphene

Additional file 1: of Genomics of NSCLC patients both affirm PD-L1 expression and predict their clinical responses to anti-PD-1 immunotherapy

Table S1. Molecules with immunosuppressive functions used in simulation models to predict PD-1 drug responder status. (DOCX 55 kb

Additional file 6: of Genomics of NSCLC patients both affirm PD-L1 expression and predict their clinical responses to anti-PD-1 immunotherapy

Table S5. Analysis of the Discovery and Validation datasets was performed using Weka 3. The first number in each column represented the number of patient treatment responses correctly classified by the model. The second number represented the number of incorrectly classified patient treatment responses. The GOAL row at the bottom of each column described the number of correctly and incorrectly classified patients in the simulation models. The Test Set columns described the output from applying the model trained on the Discovery set to the Validation set. The “Test and Train” columns described test set accuracy (test set column) plus the training error (results obtained by applying the model to the training set, i.e. training error). (DOCX 19 kb

Additional file 8: of Genomics of NSCLC patients both affirm PD-L1 expression and predict their clinical responses to anti-PD-1 immunotherapy

Table S6. Comparisons of clinical and predicated responses and match scores. We used a cross-validation approach to assess the match scores in Table 1 of the PD-1 predicted responses against the PD-1 clinical responses in the Rizvi et al. 2015 Discovery dataset vs. the Validation dataset. We then pooled and re-partitioned the dataset into two new Training and Test datasets. We then used a similar cross-validation approach to assess the match scores of the PD-1 predicted responses vs. the PD-1 clinical responses. (DOCX 17 kb

Additional file 7: of Genomics of NSCLC patients both affirm PD-L1 expression and predict their clinical responses to anti-PD-1 immunotherapy

Figure S2. An example of the relationship between PD-L1 expression and predicted TGFB1 expression using Weka 3 algorithms for all patients in the dataset. Similar trends were seen when comparing the PD-L1 expression level to the other 13 predicted molecules. For this, the number of gene mutations identified for each patient ranged from 2 to 36 with a total of 264 unique genes between all patients. This categorical data was preprocessed and expanded into a gene vector of length 264 to represent each of the unique genes. For each gene in the vector, the data was represented in binary; a 1 was assigned if the patient had a mutation in this gene, a 0 otherwise. Two datasets, one including gene mutations (Molecules and Gene Mutations) and one without (Molecules), were both used to learn prediction models. The Discovery and Validation datasets were determined based on the split provided to allow for comparable results. The performance of a subset of these models on the testing and training sets for both Molecules and Molecules and Gene Mutations datasets are shown. The SMO support vector machine with a normalized polynomial kernel had the best performance when applied to the molecule dataset. This model correctly identified 24 out of 29 patients whereas the simulation models correctly identified 25 of 29. This was only a difference of one match between the two prediction methods. Still, several other methods, while not performing as well overall, were able to identify 9 patients in the test dataset accurately. This was near the computational simulation model prediction capability in which 10 patients were successfully identified in the test dataset. In general, adding the gene mutation data to the molecule data either maintained or decreased the performance of a model. (DOCX 4114 kb

Additional file 2: of Genomics of NSCLC patients both affirm PD-L1 expression and predict their clinical responses to anti-PD-1 immunotherapy

Table S2. Individual mutational profiles of patient drug responders (n = 11) and nonresponders (n = 18). (DOCX 19 kb

Additional file 4: of Genomics of NSCLC patients both affirm PD-L1 expression and predict their clinical responses to anti-PD-1 immunotherapy

Supplementary Materials and Methods (DOCX 109 kb

Additional file 5: of Genomics of NSCLC patients both affirm PD-L1 expression and predict their clinical responses to anti-PD-1 immunotherapy

Table S4. Creation of the dendritic cell infiltration index for the patient SA97V5-specific simulation model. Chemokines CCL11, CCL20, CCL2, CCL3, CCL4, CCL5, CCL7, CX3CL1, and CXCL14, capable of trafficking of dendritic cells into the tumor microenvironment, were used to create the index. Individual chemokine percent expression (with respect to non-tumorigenic baseline controls) was predicted and given weightage so as to normalize the total to 1. The index was then calculated to be the sum of each prediction % change * weightage. (DOCX 16 kb