目的:分析骨髓增殖性肿瘤(MPN)患者不确定潜能的克隆性造血(CHIP)相关基因突变谱和临床特征,探讨CHIP相关基因与其心脑血管事件(CCE)的相关性及可能作用机制。方法:回顾性分析2019年8月-2022年7月首都医科大学附属北京安贞医院血液科收...目的:分析骨髓增殖性肿瘤(MPN)患者不确定潜能的克隆性造血(CHIP)相关基因突变谱和临床特征,探讨CHIP相关基因与其心脑血管事件(CCE)的相关性及可能作用机制。方法:回顾性分析2019年8月-2022年7月首都医科大学附属北京安贞医院血液科收治的73例MPN患者的临床资料和二代测序结果,采用Logistic回归分析CHIP相关基因、炎症细胞因子对MPN患者CCE的影响。结果:55例(75.3%)MPN患者检出CHIP相关基因,原发性血小板增多症(ET)和真性红细胞增多症(PV)患者CHIP相关基因各突变频率差异无统计学意义。CHIP相关基因突变以单基因形式为主,检出率从高至低依次为JAK2V617F(63.0%,46/73)、ASXL1(16.4%,12/73)、TET2(11.0%,8/73)、DNMT3A(9.6%,7/73)、SRSF2(6.9%,5/73)、SF3B1(4.1%,3/73)、TP53(1.4%,1/73)和PPMID(1.4%,1/73)。年龄>60岁患者CHIP相关基因检出率明显高于≤60岁者[91.7%(33/36)vs 59.5%(22/37)]。27例(37.0%)MPN患者伴CCE(MPN/CCE),2次CCE者5例,均为动脉事件。CCE组患者年龄(62.8±12.8 vs 53.9±15.8岁,P=0.015)、IL-1β水平(17.7±26.0vs 4.3±8.6,P=0.012)、IL-8水平(360.7±598.6 vs 108.3±317.0,P=0.045)、血栓形成史(29.6%vs 2.2%,P=0.020)和CHIP相关基因检出率(88.9%vs 67.4%,P=0.040)高于无CCE组。多因素Logistic回归分析结果显示,年龄(OR=0.917,95%CI:0.843-0.999,P=0.047)、血栓形成史(OR=34.148,95%CI:2.392-487.535,P=0.009)、任何1个CHIP相关基因突变(OR=16.065,95%CI:1.217-212.024,P=0.035)和IL-1β水平升高(OR=0.929,95%CI:0.870-0.992,P=0.027)均是MPN/CCE的独立危险因素;CHIP相关单基因突变与MPN/CCE无关,但DNMT3A(OR=88.717,95%CI:2.690-292.482,P=0.012)、ASXL1(OR=7.941,95%CI:1.045-60.353,P=0.045)突变是PV/CCE的独立危险因素。结论:MPN患者CHIP相关基因突变率高,尤其是60岁以上患者;高龄、血栓形成史、CHIP相关基因突变和IL-1β水平升高是MPN发生CCE的独立危险因素。DNMT3A、ASXL1单基因突变是PV患者CCE的独立危险因素。CHIP相关基因突变及炎症细胞因子IL-1β升高是MPN新的CCE危险因素。展开更多
Copper-based azide(Cu(N_(3))2 or CuN_(3),CA)chips synthesized by in-situ azide reaction and utilized in miniaturized explosive systems has become a hot research topic in recent years.However,the advantages of in-situ ...Copper-based azide(Cu(N_(3))2 or CuN_(3),CA)chips synthesized by in-situ azide reaction and utilized in miniaturized explosive systems has become a hot research topic in recent years.However,the advantages of in-situ synthesis method,including small size and low dosage,bring about difficulties in quantitative analysis and differences in ignition capabilities of CA chips.The aim of present work is to develop a simplified quantitative analysis method for accurate and safe analysis of components in CA chips to evaluate and investigate the corresponding ignition ability.In this work,Cu(N_(3))2 and CuN_(3)components in CA chips were separated through dissolution and distillation by utilizing the difference in solubility and corresponding content was obtained by measuring N_(3)-concentration through spectrophotometry.The spectrophotometry method was optimized by studying influencing factors and the recovery rate of different separation methods was studied,ensuring the accuracy and reproducibility of test results.The optimized method is linear in range from 1.0-25.0 mg/L,with a correlation coefficient R^(2)=0.9998,which meets the requirements of CA chips with a milligram-level content test.Compared with the existing ICP method,component analysis results of CA chips obtained by spectrophotometry are closer to real component content in samples and have satisfactory accuracy.Moreover,as its application in miniaturized explosive systems,the ignition ability of CA chips with different component contents for direct ink writing CL-20 and the corresponding mechanism was studied.This study provided a basis and idea for the design and performance evaluation of CA chips in miniaturized explosive systems.展开更多
On-demand droplet sorting is extensively applied for the efficient manipulation and genome-wide analysis of individual cells.However,state-of-the-art microfluidic chips for droplet sorting still suffer from low sortin...On-demand droplet sorting is extensively applied for the efficient manipulation and genome-wide analysis of individual cells.However,state-of-the-art microfluidic chips for droplet sorting still suffer from low sorting speeds,sample loss,and labor-intensive preparation procedures.Here,we demonstrate the development of a novel microfluidic chip that integrates droplet generation,on-demand electrostatic droplet charging,and high-throughput sorting.The charging electrode is a copper wire buried above the nozzle of the microchannel,and the deflecting electrode is the phosphate buffered saline in the microchannel,which greatly simplifies the structure and fabrication process of the chip.Moreover,this chip is capable of high-frequency droplet generation and sorting,with a frequency of 11.757 kHz in the drop state.The chip completes the selective charging process via electrostatic induction during droplet generation.On-demand charged microdroplets can arbitrarilymove to specific exit channels in a three-dimensional(3D)-deflected electric field,which can be controlled according to user requirements,and the flux of droplet deflection is thereby significantly enhanced.Furthermore,a lossless modification strategy is presented to improve the accuracy of droplet deflection or harvest rate from 97.49% to 99.38% by monitoring the frequency of droplet generation in real time and feeding it back to the charging signal.This chip has great potential for quantitative processing and analysis of single cells for elucidating cell-to-cell variations.展开更多
CHIP(carboxyl terminus of Hsc70-interacting protein)又称STUB1(STIP1 homology and U-box containing protein 1),是一种分子伴侣结合蛋白,具有E3泛素连接酶活性.研究表明,CHIP蛋白在细胞体内通过蛋白质量控制系统调控细胞代谢、分...CHIP(carboxyl terminus of Hsc70-interacting protein)又称STUB1(STIP1 homology and U-box containing protein 1),是一种分子伴侣结合蛋白,具有E3泛素连接酶活性.研究表明,CHIP蛋白在细胞体内通过蛋白质量控制系统调控细胞代谢、分化、增殖、迁移和肿瘤发生发展等多种生理病理过程.本文对CHIP在癌症及多种常见疾病中的作用进行综述,以期为临床治疗和药物开发提供潜在突破点.展开更多
Trace amines(TAs)are metabolically related to catecholamine and associated with cancer and neurological disorders.Comprehensive measurement of TAs is essential for understanding pathological processes and providing pr...Trace amines(TAs)are metabolically related to catecholamine and associated with cancer and neurological disorders.Comprehensive measurement of TAs is essential for understanding pathological processes and providing proper drug intervention.However,the trace amounts and chemical instability of TAs challenge quantification.Here,diisopropyl phosphite coupled with chip two-dimensional(2D)liquid chromatography tandem triple-quadrupole mass spectrometry(LC-QQQ/MS)was developed to simultaneously determine TAs and associated metabolites.The results showed that the sensitivities of TAs increased up to 5520 times compared with those using nonderivatized LC-QQQ/MS.This sensitive method was utilized to investigate their alterations in hepatoma cells after treatment with sorafenib.The significantly altered TAs and associated metabolites suggested that phenylalanine and tyrosine metabolic pathways were related to sorafenib treatment in Hep3B cells.This sensitive method has great potential to elucidate the mechanism and diagnose diseases considering that an increasing number of physiological functions of TAs have been discovered in recent decades.展开更多
Spiking neural networks(SNNs)utilize brain-like spatiotemporal spike encoding for simulating brain functions.Photonic SNN offers an ultrahigh speed and power efficiency platform for implementing high-performance neuro...Spiking neural networks(SNNs)utilize brain-like spatiotemporal spike encoding for simulating brain functions.Photonic SNN offers an ultrahigh speed and power efficiency platform for implementing high-performance neuromorphic computing.Here,we proposed a multi-synaptic photonic SNN,combining the modified remote supervised learning with delayweight co-training to achieve pattern classification.The impact of multi-synaptic connections and the robustness of the network were investigated through numerical simulations.In addition,the collaborative computing of algorithm and hardware was demonstrated based on a fabricated integrated distributed feedback laser with a saturable absorber(DFB-SA),where 10 different noisy digital patterns were successfully classified.A functional photonic SNN that far exceeds the scale limit of hardware integration was achieved based on time-division multiplexing,demonstrating the capability of hardware-algorithm co-computation.展开更多
In this work,an automated microfluidic chip that uses negative pressure to sample and analyze solutions with high temporal resolution was developed.The chip has a T-shaped channel for mixing the sample with a fluoresc...In this work,an automated microfluidic chip that uses negative pressure to sample and analyze solutions with high temporal resolution was developed.The chip has a T-shaped channel for mixing the sample with a fluorescent indicator,a flow-focusing channel for generating droplets in oil,and a long storage channel for incubating and detecting the droplets.By monitoring the fluorescence intensity of the droplets,the device could detect changes in solution accurately over time.The chip can generate droplets at frequencies of up to 42 Hz with a mixing ratio of 1:1 and a temporal resolution of 3–6 s.It had excellent linearity in detecting fluorescein solution in the concentration range 1–5μM.This droplet microfluidic chip provides several advantages over traditional methods,including high temporal resolution,stable droplet generation,and faster flow rates.This approach could be applied to monitoring calcium ions with a dynamic range from 102 to 107 nM and a detection limit of 10 nM.展开更多
Emodin is an effective component of rhubarb with positive pharmacological effects on human health.However,it is also toxic to different cells or tissues to varying degrees.The effects of emodin on glomerular endotheli...Emodin is an effective component of rhubarb with positive pharmacological effects on human health.However,it is also toxic to different cells or tissues to varying degrees.The effects of emodin on glomerular endothelial cells(GECs)remain to be tested,and the documented works were always performed in vitro and hardly reflect the real physiological situation.To study the effects of emodin on GECs in a biomimetic environment,we utilized a microfluidic chip to assess the physiological reaction of human renal glomerular endothelial cells to various concentrations of emodin in this work.The results showed that emodin caused cytotoxicity,impaired glomerular filtration barrier integrity to macromolecules,and increased barrier permeability in a dose-dependent manner.With the increase in emodin concentration,the concentration of the pro-inflammatory cytokine tumor necrosis factor-α,interleukin(IL)-6,transforming growth factor-β1,and monocyte chemoattractant protein(MCP-1)increased while the production of inflammatory cytokine IL-6 first increased and then decreased with the increase in emodin concentration.Our findings shed new light on emodin-induced nephrotoxicity and provide insights for the application of microfluidic chip devices to reveal drug-cell interactions.展开更多
Diabetes mellitus is a global health problem resulting from islet dysfunction or insulin resistance.The mechanisms of islet dysfunction are still under investigation.Islet hormone secretion is the main function of isl...Diabetes mellitus is a global health problem resulting from islet dysfunction or insulin resistance.The mechanisms of islet dysfunction are still under investigation.Islet hormone secretion is the main function of islets,and serves an important role in the homeostasis of blood glucose.Elucidating the detailed mechanism of islet hormone secretome distortion can provide clues for the treatment of diabetes.Therefore,it is crucial to develop accurate,real-time,laborsaving,high-throughput,automated,and cost-effective techniques for the sensing of islet secretome.Microfluidic chips,an elegant platform that combines biology,engineering,computer science,and biomaterials,have attracted tremendous interest from scientists in the field of diabetes worldwide.These tiny devices are miniatures of traditional experimental systems with more advantages of timesaving,reagent-minimization,automation,high-throughput,and online detection.These features of microfluidic chips meet the demands of islet secretome analysis and a variety of chips have been designed in the past 20 years.In this review,we present a brief introduction of microfluidic chips,and three microfluidic chipsbased islet hormone sensing techniques.We focus mainly on the theory of these techniques,and provide detailed examples based on these theories with the hope of providing some insights into the design of future chips or whole detection systems.展开更多
Flip chip die-to-wafer bonding faces challenges for industry adoption due to a variety of technical gaps or process integration factors that are not fully developed to high volume manufacturing(HVM)maturity.In this pa...Flip chip die-to-wafer bonding faces challenges for industry adoption due to a variety of technical gaps or process integration factors that are not fully developed to high volume manufacturing(HVM)maturity.In this paper,flip-chip and wire bonding are compared,then flip-chip bonding techniques are compared to examine advantages for scaling and speed.Specific recent 3-year trends in flip-chip die-to-wafer bonding are reviewed to address the key gaps and challenges to HVM adoption.Finally,some thoughts on the care needed by the packaging technology for successful HVM introduction are reviewed.展开更多
文摘目的:分析骨髓增殖性肿瘤(MPN)患者不确定潜能的克隆性造血(CHIP)相关基因突变谱和临床特征,探讨CHIP相关基因与其心脑血管事件(CCE)的相关性及可能作用机制。方法:回顾性分析2019年8月-2022年7月首都医科大学附属北京安贞医院血液科收治的73例MPN患者的临床资料和二代测序结果,采用Logistic回归分析CHIP相关基因、炎症细胞因子对MPN患者CCE的影响。结果:55例(75.3%)MPN患者检出CHIP相关基因,原发性血小板增多症(ET)和真性红细胞增多症(PV)患者CHIP相关基因各突变频率差异无统计学意义。CHIP相关基因突变以单基因形式为主,检出率从高至低依次为JAK2V617F(63.0%,46/73)、ASXL1(16.4%,12/73)、TET2(11.0%,8/73)、DNMT3A(9.6%,7/73)、SRSF2(6.9%,5/73)、SF3B1(4.1%,3/73)、TP53(1.4%,1/73)和PPMID(1.4%,1/73)。年龄>60岁患者CHIP相关基因检出率明显高于≤60岁者[91.7%(33/36)vs 59.5%(22/37)]。27例(37.0%)MPN患者伴CCE(MPN/CCE),2次CCE者5例,均为动脉事件。CCE组患者年龄(62.8±12.8 vs 53.9±15.8岁,P=0.015)、IL-1β水平(17.7±26.0vs 4.3±8.6,P=0.012)、IL-8水平(360.7±598.6 vs 108.3±317.0,P=0.045)、血栓形成史(29.6%vs 2.2%,P=0.020)和CHIP相关基因检出率(88.9%vs 67.4%,P=0.040)高于无CCE组。多因素Logistic回归分析结果显示,年龄(OR=0.917,95%CI:0.843-0.999,P=0.047)、血栓形成史(OR=34.148,95%CI:2.392-487.535,P=0.009)、任何1个CHIP相关基因突变(OR=16.065,95%CI:1.217-212.024,P=0.035)和IL-1β水平升高(OR=0.929,95%CI:0.870-0.992,P=0.027)均是MPN/CCE的独立危险因素;CHIP相关单基因突变与MPN/CCE无关,但DNMT3A(OR=88.717,95%CI:2.690-292.482,P=0.012)、ASXL1(OR=7.941,95%CI:1.045-60.353,P=0.045)突变是PV/CCE的独立危险因素。结论:MPN患者CHIP相关基因突变率高,尤其是60岁以上患者;高龄、血栓形成史、CHIP相关基因突变和IL-1β水平升高是MPN发生CCE的独立危险因素。DNMT3A、ASXL1单基因突变是PV患者CCE的独立危险因素。CHIP相关基因突变及炎症细胞因子IL-1β升高是MPN新的CCE危险因素。
基金the financial support provided by the National Natural Science Foundation of China(Grant No.11872013).
文摘Copper-based azide(Cu(N_(3))2 or CuN_(3),CA)chips synthesized by in-situ azide reaction and utilized in miniaturized explosive systems has become a hot research topic in recent years.However,the advantages of in-situ synthesis method,including small size and low dosage,bring about difficulties in quantitative analysis and differences in ignition capabilities of CA chips.The aim of present work is to develop a simplified quantitative analysis method for accurate and safe analysis of components in CA chips to evaluate and investigate the corresponding ignition ability.In this work,Cu(N_(3))2 and CuN_(3)components in CA chips were separated through dissolution and distillation by utilizing the difference in solubility and corresponding content was obtained by measuring N_(3)-concentration through spectrophotometry.The spectrophotometry method was optimized by studying influencing factors and the recovery rate of different separation methods was studied,ensuring the accuracy and reproducibility of test results.The optimized method is linear in range from 1.0-25.0 mg/L,with a correlation coefficient R^(2)=0.9998,which meets the requirements of CA chips with a milligram-level content test.Compared with the existing ICP method,component analysis results of CA chips obtained by spectrophotometry are closer to real component content in samples and have satisfactory accuracy.Moreover,as its application in miniaturized explosive systems,the ignition ability of CA chips with different component contents for direct ink writing CL-20 and the corresponding mechanism was studied.This study provided a basis and idea for the design and performance evaluation of CA chips in miniaturized explosive systems.
基金The authors acknowledge the financial support from the NationalNatural Science Foundation ofChina(No.52275562)the Technology Innovation Fund of Huazhong University of Science and Technology(No.2022JYCXJJ015).
文摘On-demand droplet sorting is extensively applied for the efficient manipulation and genome-wide analysis of individual cells.However,state-of-the-art microfluidic chips for droplet sorting still suffer from low sorting speeds,sample loss,and labor-intensive preparation procedures.Here,we demonstrate the development of a novel microfluidic chip that integrates droplet generation,on-demand electrostatic droplet charging,and high-throughput sorting.The charging electrode is a copper wire buried above the nozzle of the microchannel,and the deflecting electrode is the phosphate buffered saline in the microchannel,which greatly simplifies the structure and fabrication process of the chip.Moreover,this chip is capable of high-frequency droplet generation and sorting,with a frequency of 11.757 kHz in the drop state.The chip completes the selective charging process via electrostatic induction during droplet generation.On-demand charged microdroplets can arbitrarilymove to specific exit channels in a three-dimensional(3D)-deflected electric field,which can be controlled according to user requirements,and the flux of droplet deflection is thereby significantly enhanced.Furthermore,a lossless modification strategy is presented to improve the accuracy of droplet deflection or harvest rate from 97.49% to 99.38% by monitoring the frequency of droplet generation in real time and feeding it back to the charging signal.This chip has great potential for quantitative processing and analysis of single cells for elucidating cell-to-cell variations.
文摘CHIP(carboxyl terminus of Hsc70-interacting protein)又称STUB1(STIP1 homology and U-box containing protein 1),是一种分子伴侣结合蛋白,具有E3泛素连接酶活性.研究表明,CHIP蛋白在细胞体内通过蛋白质量控制系统调控细胞代谢、分化、增殖、迁移和肿瘤发生发展等多种生理病理过程.本文对CHIP在癌症及多种常见疾病中的作用进行综述,以期为临床治疗和药物开发提供潜在突破点.
基金supported by the Science and Technology Development Fund,Macao,China(Grant No.:FDCT0044/2018/AFJ).
文摘Trace amines(TAs)are metabolically related to catecholamine and associated with cancer and neurological disorders.Comprehensive measurement of TAs is essential for understanding pathological processes and providing proper drug intervention.However,the trace amounts and chemical instability of TAs challenge quantification.Here,diisopropyl phosphite coupled with chip two-dimensional(2D)liquid chromatography tandem triple-quadrupole mass spectrometry(LC-QQQ/MS)was developed to simultaneously determine TAs and associated metabolites.The results showed that the sensitivities of TAs increased up to 5520 times compared with those using nonderivatized LC-QQQ/MS.This sensitive method was utilized to investigate their alterations in hepatoma cells after treatment with sorafenib.The significantly altered TAs and associated metabolites suggested that phenylalanine and tyrosine metabolic pathways were related to sorafenib treatment in Hep3B cells.This sensitive method has great potential to elucidate the mechanism and diagnose diseases considering that an increasing number of physiological functions of TAs have been discovered in recent decades.
基金supports from the National Key Research and Development Program of China (Nos.2021YFB2801900,2021YFB2801901,2021YFB2801902,2021YFB2801903,2021YFB2801904)the National Outstanding Youth Science Fund Project of National Natural Science Foundation of China (No.62022062)+1 种基金the National Natural Science Foundation of China (No.61974177)the Fundamental Research Funds for the Central Universities (No.QTZX23041).
文摘Spiking neural networks(SNNs)utilize brain-like spatiotemporal spike encoding for simulating brain functions.Photonic SNN offers an ultrahigh speed and power efficiency platform for implementing high-performance neuromorphic computing.Here,we proposed a multi-synaptic photonic SNN,combining the modified remote supervised learning with delayweight co-training to achieve pattern classification.The impact of multi-synaptic connections and the robustness of the network were investigated through numerical simulations.In addition,the collaborative computing of algorithm and hardware was demonstrated based on a fabricated integrated distributed feedback laser with a saturable absorber(DFB-SA),where 10 different noisy digital patterns were successfully classified.A functional photonic SNN that far exceeds the scale limit of hardware integration was achieved based on time-division multiplexing,demonstrating the capability of hardware-algorithm co-computation.
基金We acknowledge support from the equipment research and development projects of the Chinese Academy of Sciences,“On-chip integrated optical biochemical detection key technology research and development team,”E11YTB1001.
文摘In this work,an automated microfluidic chip that uses negative pressure to sample and analyze solutions with high temporal resolution was developed.The chip has a T-shaped channel for mixing the sample with a fluorescent indicator,a flow-focusing channel for generating droplets in oil,and a long storage channel for incubating and detecting the droplets.By monitoring the fluorescence intensity of the droplets,the device could detect changes in solution accurately over time.The chip can generate droplets at frequencies of up to 42 Hz with a mixing ratio of 1:1 and a temporal resolution of 3–6 s.It had excellent linearity in detecting fluorescein solution in the concentration range 1–5μM.This droplet microfluidic chip provides several advantages over traditional methods,including high temporal resolution,stable droplet generation,and faster flow rates.This approach could be applied to monitoring calcium ions with a dynamic range from 102 to 107 nM and a detection limit of 10 nM.
基金This work was supported by the National Key R&D Program of China(Project No.2018YFC1602103)Ministry of Science and Technology of China.
文摘Emodin is an effective component of rhubarb with positive pharmacological effects on human health.However,it is also toxic to different cells or tissues to varying degrees.The effects of emodin on glomerular endothelial cells(GECs)remain to be tested,and the documented works were always performed in vitro and hardly reflect the real physiological situation.To study the effects of emodin on GECs in a biomimetic environment,we utilized a microfluidic chip to assess the physiological reaction of human renal glomerular endothelial cells to various concentrations of emodin in this work.The results showed that emodin caused cytotoxicity,impaired glomerular filtration barrier integrity to macromolecules,and increased barrier permeability in a dose-dependent manner.With the increase in emodin concentration,the concentration of the pro-inflammatory cytokine tumor necrosis factor-α,interleukin(IL)-6,transforming growth factor-β1,and monocyte chemoattractant protein(MCP-1)increased while the production of inflammatory cytokine IL-6 first increased and then decreased with the increase in emodin concentration.Our findings shed new light on emodin-induced nephrotoxicity and provide insights for the application of microfluidic chip devices to reveal drug-cell interactions.
基金Supported by the Project of Suzhou Hospital of Anhui Medical University,No.2020A1Natural Science Project of North Anhui Health Vocational College,No.WZK201907.
文摘Diabetes mellitus is a global health problem resulting from islet dysfunction or insulin resistance.The mechanisms of islet dysfunction are still under investigation.Islet hormone secretion is the main function of islets,and serves an important role in the homeostasis of blood glucose.Elucidating the detailed mechanism of islet hormone secretome distortion can provide clues for the treatment of diabetes.Therefore,it is crucial to develop accurate,real-time,laborsaving,high-throughput,automated,and cost-effective techniques for the sensing of islet secretome.Microfluidic chips,an elegant platform that combines biology,engineering,computer science,and biomaterials,have attracted tremendous interest from scientists in the field of diabetes worldwide.These tiny devices are miniatures of traditional experimental systems with more advantages of timesaving,reagent-minimization,automation,high-throughput,and online detection.These features of microfluidic chips meet the demands of islet secretome analysis and a variety of chips have been designed in the past 20 years.In this review,we present a brief introduction of microfluidic chips,and three microfluidic chipsbased islet hormone sensing techniques.We focus mainly on the theory of these techniques,and provide detailed examples based on these theories with the hope of providing some insights into the design of future chips or whole detection systems.
文摘Flip chip die-to-wafer bonding faces challenges for industry adoption due to a variety of technical gaps or process integration factors that are not fully developed to high volume manufacturing(HVM)maturity.In this paper,flip-chip and wire bonding are compared,then flip-chip bonding techniques are compared to examine advantages for scaling and speed.Specific recent 3-year trends in flip-chip die-to-wafer bonding are reviewed to address the key gaps and challenges to HVM adoption.Finally,some thoughts on the care needed by the packaging technology for successful HVM introduction are reviewed.
