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Fulltext Epidemiological and ES cell-based functional evaluation of BRCA2 variants identified in families with breast cancer

Sullivan T, Thirthagiri E, Chong CE, Stauffer S, Reid S, Southon E, et al.

Hum Mutat, 2021 Feb;42(2):200-212.
PMID: 33314489 DOI: 10.1002/humu.24154

The discovery of high-risk breast cancer susceptibility genes, such as Breast cancer associated gene 1 (BRCA1) and Breast cancer associated gene 2 (BRCA2) has led to accurate identification of individuals for risk management and targeted therapy. The rapid decline in sequencing costs has tremendously increased the number of individuals who are undergoing genetic testing world-wide. However, given the significant differences in population-specific variants, interpreting the results of these tests can be challenging especially for novel genetic variants in understudied populations. Here we report the characterization of novel variants in the Malaysian and Singaporean population that consist of different ethnic groups (Malays, Chinese, Indian, and other indigenous groups). We have evaluated the functional significance of 14 BRCA2 variants of uncertain clinical significance by using multiple in silico prediction tools and examined their frequency in a cohort of 7840 breast cancer cases and 7928 healthy controls. In addition, we have used a mouse embryonic stem cell (mESC)-based functional assay to assess the impact of these variants on BRCA2 function. We found these variants to be functionally indistinguishable from wild-type BRCA2. These variants could fully rescue the lethality of Brca2-null mESCs and exhibited no sensitivity to six different DNA damaging agents including a poly ADP ribose polymerase inhibitor. Our findings strongly suggest that all 14 evaluated variants are functionally neutral. Our findings should be valuable in risk assessment of individuals carrying these variants.
Fulltext Large scale multifactorial likelihood quantitative analysis of BRCA1 and BRCA2 variants: An ENIGMA resource to support clinical variant classification

Parsons MT, Tudini E, Li H, Hahnen E, Wappenschmidt B, Feliubadaló L, et al.

Hum Mutat, 2019 Sep;40(9):1557-1578.
PMID: 31131967 DOI: 10.1002/humu.23818

The multifactorial likelihood analysis method has demonstrated utility for quantitative assessment of variant pathogenicity for multiple cancer syndrome genes. Independent data types currently incorporated in the model for assessing BRCA1 and BRCA2 variants include clinically calibrated prior probability of pathogenicity based on variant location and bioinformatic prediction of variant effect, co-segregation, family cancer history profile, co-occurrence with a pathogenic variant in the same gene, breast tumor pathology, and case-control information. Research and clinical data for multifactorial likelihood analysis were collated for 1,395 BRCA1/2 predominantly intronic and missense variants, enabling classification based on posterior probability of pathogenicity for 734 variants: 447 variants were classified as (likely) benign, and 94 as (likely) pathogenic; and 248 classifications were new or considerably altered relative to ClinVar submissions. Classifications were compared with information not yet included in the likelihood model, and evidence strengths aligned to those recommended for ACMG/AMP classification codes. Altered mRNA splicing or function relative to known nonpathogenic variant controls were moderately to strongly predictive of variant pathogenicity. Variant absence in population datasets provided supporting evidence for variant pathogenicity. These findings have direct relevance for BRCA1 and BRCA2 variant evaluation, and justify the need for gene-specific calibration of evidence types used for variant classification.
Working principle and application of magnetic separation for biomedical diagnostic at high- and low-field gradients

Leong SS, Yeap SP, Lim J

Interface Focus, 2016 Dec 06;6(6):20160048.
PMID: 27920891

Magnetic separation is a versatile technique used in sample preparation for diagnostic purpose. For such application, an external magnetic field is applied to drive the separation of target entity (e.g. bacteria, viruses, parasites and cancer cells) from a complex raw sample in order to ease the subsequent task(s) for disease diagnosis. This separation process not only can be achieved via the utilization of high magnetic field gradient, but also, in most cases, low magnetic field gradient with magnitude less than 100 T m-1 is equally feasible. It is the aim of this review paper to summarize the usage of both high gradient magnetic separation and low gradient magnetic separation (LGMS) techniques in this area of research. It is noteworthy that effectiveness of the magnetic separation process not only determines the outcome of a diagnosis but also directly influences its accuracy as well as sensing time involved. Therefore, understanding the factors that simultaneously influence the efficiency of both magnetic separation process and target detection is necessary. Moreover, for LGMS, there are several important considerations that should be taken into account in order to ensure its successful implementation. Hence, this review paper aims to provide an overview to relate all this crucial information by linking the magnetic separation theory to biomedical diagnostic applications.
Variation of the platelet glycoprotein IIIa PI(A1/A2) allele frequencies in the three ethnic groups of Singapore

Lim J, Lal S, Ng KC, Ng KS, Saha N, Heng CK

Int J Cardiol, 2003 Aug;90(2-3):269-73.
PMID: 12957761

BACKGROUND: Polymorphisms of the glycoprotein IIIa receptor have been shown to be associated with differences in platelet aggregability. The PI(A2) variant of the polymorphism has been reported to be an inherited risk factor for acute coronary events. Although the allele frequency of this polymorphism is well documented in Caucasian populations, studies involving Asian Indians, Malays and Chinese are lacking. We studied 706 random male individuals to determine the genotypic distribution of this polymorphism in Singapore.
METHODS: Male subjects included in this study were drawn from those undergoing routine annual medical examinations offered by their employers. Venous blood was obtained from these patients after an overnight fast and from which genomic DNA was extracted. Genotyping was carried out by polymerase chain reaction (PCR) followed by digestion with restriction enzyme NciI. Personal and family medical history of the subjects were also taken.
RESULTS: The genotype distribution of the individuals studied was in accordance to a population at Hardy Weinberg equilibrium. The frequency of the PI(A2) allele was 0.1, 0.01 and 0.01 in the Indians, Malays and Chinese, respectively. The differences in frequencies of the PI(A2) variant are significant among different ethnic groups (P<0.001 for Indians vs. Chinese and Indians vs. Malays).
CONCLUSIONS: We observed a significantly higher frequency of the PI(A2) allele among Indians relative to the Chinese and Malays in Singapore. The effect of this genotype may partially explain the higher rate of ischaemic heart disease seen among Indians compared to the Chinese and Malay ethnic groups.
Fulltext Artificial intelligence-aided detection for prostate cancer with multimodal routine health check-up data: an Asian multi-center study

Song Z, Zhang W, Jiang Q, Deng L, Du L, Mou W, et al.

Int J Surg, 2023 Dec 01;109(12):3848-3860.
PMID: 37988414 DOI: 10.1097/JS9.0000000000000862

BACKGROUND: The early detection of high-grade prostate cancer (HGPCa) is of great importance. However, the current detection strategies result in a high rate of negative biopsies and high medical costs. In this study, the authors aimed to establish an Asian Prostate Cancer Artificial intelligence (APCA) score with no extra cost other than routine health check-ups to predict the risk of HGPCa.
PATIENTS AND METHODS: A total of 7476 patients with routine health check-up data who underwent prostate biopsies from January 2008 to December 2021 in eight referral centres in Asia were screened. After data pre-processing and cleaning, 5037 patients and 117 features were analyzed. Seven AI-based algorithms were tested for feature selection and seven AI-based algorithms were tested for classification, with the best combination applied for model construction. The APAC score was established in the CH cohort and validated in a multi-centre cohort and in each validation cohort to evaluate its generalizability in different Asian regions. The performance of the models was evaluated using area under the receiver operating characteristic curve (ROC), calibration plot, and decision curve analyses.
RESULTS: Eighteen features were involved in the APCA score predicting HGPCa, with some of these markers not previously used in prostate cancer diagnosis. The area under the curve (AUC) was 0.76 (95% CI:0.74-0.78) in the multi-centre validation cohort and the increment of AUC (APCA vs. PSA) was 0.16 (95% CI:0.13-0.20). The calibration plots yielded a high degree of coherence and the decision curve analysis yielded a higher net clinical benefit. Applying the APCA score could reduce unnecessary biopsies by 20.2% and 38.4%, at the risk of missing 5.0% and 10.0% of HGPCa cases in the multi-centre validation cohort, respectively.
CONCLUSIONS: The APCA score based on routine health check-ups could reduce unnecessary prostate biopsies without additional examinations in Asian populations. Further prospective population-based studies are warranted to confirm these results.
Report of the forth Asian Prostate Cancer (A-CaP) study meeting

Youl Lee J, Taniguchi T, Zhang K, Ng CF, Hakim L, Umbas R, et al.

Jpn J Clin Oncol, 2019 Jun 01;49(6):581-586.
PMID: 31141613 DOI: 10.1093/jjco/hyz053

The Asian Prostate Cancer (A-CaP) Study is an Asia-wide prospective registry study for surveying the treatment outcome of prostate cancer patients who have received a histopathological diagnosis. The study aims to clarify the clinical situation for prostate cancer in Asia and use the outcomes for the purposes of international comparison. Following the first meeting in Tokyo on December 2015, the second meeting in Seoul, Korea 2016, the third meeting in Chiang Mai, Thailand, on October 2017, the fourth meeting was held in Seoul, again on August 2018 with the participation of members and collaborators from 13 countries and regions. In the meeting, participating countries and regions presented the current status of data collection and the A-CaP office presented a preliminary analysis of the registered cases received from each country and region. Participants discussed ongoing challenges relating to data cleaning and data up-dating which is the next step of the A-CaP study following the data collection phase between 2016 and 2018. There was specific difference in term of the patient characteristics, and initial treatment pattern among East Asia, Southeast Asia and Turkey, and Jordan. Finally, a close relationship between prevalence of PSA test and disease stage of the patients at diagnosis in Japan and Malaysia was discussed.
Magnetophoresis of iron oxide nanoparticles at low field gradient: the role of shape anisotropy

Lim J, Yeap SP, Leow CH, Toh PY, Low SC

J Colloid Interface Sci, 2014 May 1;421:170-7.
PMID: 24594047 DOI: 10.1016/j.jcis.2014.01.044

Magnetophoresis of iron oxide magnetic nanoparticle (IOMNP) under low magnetic field gradient (<100 T/m) is significantly enhanced by particle shape anisotropy. This unique feature of magnetophoresis is influenced by the particle concentration and applied magnetic field gradient. By comparing the nanosphere and nanorod magnetophoresis at different concentration, we revealed the ability for these two species of particles to achieve the same separation rate by adjusting the field gradient. Under cooperative magnetophoresis, the nanorods would first go through self- and magnetic field induced aggregation followed by the alignment of the particle clusters formed with magnetic field. Time scale associated to these two processes is investigated to understand the kinetic behavior of nanorod separation under low field gradient. Surface functionalization of nanoparticles can be employed as an effective strategy to vary the temporal evolution of these two aggregation processes which subsequently influence the magnetophoretic separation time and rate.
Treatment of agro based industrial wastewater in sequencing batch reactor: performance evaluation and growth kinetics of aerobic biomass

Lim JX, Vadivelu VM

J Environ Manage, 2014 Dec 15;146:217-225.
PMID: 25173730 DOI: 10.1016/j.jenvman.2014.07.023

A sequencing batch reactor (SBR) with a working volume of 8 L and an exchange ratio of 25% was used to enrich biomass for the treatment of the anaerobically treated low pH palm oil mill effluent (POME). The influent concentration was stepwise increased from 5000 ± 500 mg COD/L to 11,500 ± 500 mg COD/L. The performance of the reactor was monitored at different organic loading rates (OLRs). It was found that approximately 90% of the COD content of the POME wastewater was successfully removed regardless of the OLR applied to the SBR. Cycle studies of the SBR show that the oxygen uptake by the biomass while there is no COD reduction may be due to the oxidation of the storage product by the biomass. Further, the growth kinetic parameters of the biomass were determined in batch experiments using respirometer. The maximum specific growth rate (μmax) was estimated to be 1.143 day(-1) while the half saturation constant (Ks) with respect to COD was determined to be 0.429 g COD/L. The decay coefficient (bD) and biomass yield (Y) were found to be 0.131 day(-1) and 0.272 mg biomass/mg COD consumed, respectively.
Fulltext Inherited mutations in BRCA1 and BRCA2 in an unselected multiethnic cohort of Asian patients with breast cancer and healthy controls from Malaysia

Wen WX, Allen J, Lai KN, Mariapun S, Hasan SN, Ng PS, et al.

J Med Genet, 2018 02;55(2):97-103.
PMID: 28993434 DOI: 10.1136/jmedgenet-2017-104947

BACKGROUND: Genetic testing for BRCA1 and BRCA2 is offered typically to selected women based on age of onset and family history of cancer. However, current internationally accepted genetic testing referral guidelines are built mostly on data from cancer genetics clinics in women of European descent. To evaluate the appropriateness of such guidelines in Asians, we have determined the prevalence of germ line variants in an unselected cohort of Asian patients with breast cancer and healthy controls.
METHODS: Germ line DNA from a hospital-based study of 2575 unselected patients with breast cancer and 2809 healthy controls were subjected to amplicon-based targeted sequencing of exonic and proximal splice site junction regions of BRCA1 and BRCA2 using the Fluidigm Access Array system, with sequencing conducted on a Illumina HiSeq2500 platform. Variant calling was performed with GATK UnifiedGenotyper and were validated by Sanger sequencing.
RESULTS: Fifty-five (2.1%) BRCA1 and 66 (2.6%) BRCA2 deleterious mutations were identified among patients with breast cancer and five (0.18%) BRCA1 and six (0.21%) BRCA2 mutations among controls. One thousand one hundred and eighty-six (46%) patients and 97 (80%) carriers fulfilled the National Comprehensive Cancer Network guidelines for genetic testing.
CONCLUSION: Five per cent of unselected Asian patients with breast cancer carry deleterious variants in BRCA1 or BRCA2. While current referral guidelines identified the majority of carriers, one in two patients would be referred for genetic services. Given that such services are largely unavailable in majority of low-resource settings in Asia, our study highlights the need for more efficient guidelines to identify at-risk individuals in Asia.
Oncologist-led BRCA counselling improves access to cancer genetic testing in middle-income Asian country, with no significant impact on psychosocial outcomes

Yoon SY, Wong SW, Lim J, Ahmad S, Mariapun S, Padmanabhan H, et al.

J Med Genet, 2022 Mar;59(3):220-229.
PMID: 33526602 DOI: 10.1136/jmedgenet-2020-107416

BACKGROUND: Identifying patients with BRCA mutations is clinically important to inform on the potential response to treatment and for risk management of patients and their relatives. However, traditional referral routes may not meet clinical needs, and therefore, mainstreaming cancer genetics has been shown to be effective in some high-income and high health-literacy settings. To date, no study has reported on the feasibility of mainstreaming in low-income and middle-income settings, where the service considerations and health literacy could detrimentally affect the feasibility of mainstreaming.
METHODS: The Mainstreaming Genetic Counselling for Ovarian Cancer Patients (MaGiC) study is a prospective, two-arm observational study comparing oncologist-led and genetics-led counselling. This study included 790 multiethnic patients with ovarian cancer from 23 sites in Malaysia. We compared the impact of different method of delivery of genetic counselling on the uptake of genetic testing and assessed the feasibility, knowledge and satisfaction of patients with ovarian cancer.
RESULTS: Oncologists were satisfied with the mainstreaming experience, with 95% indicating a desire to incorporate testing into their clinical practice. The uptake of genetic testing was similar in the mainstreaming and genetics arm (80% and 79%, respectively). Patient satisfaction was high, whereas decision conflict and psychological impact were low in both arms of the study. Notably, decisional conflict, although lower than threshold, was higher for the mainstreaming group compared with the genetics arm. Overall, 13.5% of patients had a pathogenic variant in BRCA1 or BRCA2, and there was no difference between psychosocial measures for carriers in both arms.
CONCLUSION: The MaGiC study demonstrates that mainstreaming cancer genetics is feasible in low-resource and middle-resource Asian setting and increased coverage for genetic testing.
The use of intrapartum fetal pulse oximetry in the presence of fetal cardiac arrhythmia due to a cardiac tumour

Raman S, Lim JM, Hanifullah K, Omar A

J Obstet Gynaecol, 1999 Mar;19(2):200-1.
PMID: 15512273
Fulltext A Perspective Review on the Role of Nanomedicine in the Modulation of TNF-TNFR2 Axis in Breast Cancer Immunotherapy

Al-Hatamleh MAI, Ahmad S, Boer JC, Lim J, Chen X, Plebanski M, et al.

J Oncol, 2019;2019:6313242.
PMID: 31239840 DOI: 10.1155/2019/6313242

In the past decade, nanomedicine research has provided us with highly useful agents (nanoparticles) delivering therapeutic drugs to target cancer cells. The present review highlights nanomedicine applications for breast cancer immunotherapy. Recent studies have suggested that tumour necrosis factor (TNF) and its receptor 2 (TNFR2) expressed on breast cancer cells have important functional consequences. This cytokine/receptor interaction is also critical for promoting highly immune-suppressive phenotypes by regulatory T cells (Tregs). This review generally provides a background for nanoparticles as potential drug delivery agents for immunomodulators and further discusses in depth the potential of TNF antagonists delivery to modulate TNF-TNFR2 interactions and inhibit breast cancer progression.
Electrosteric stabilization and its role in cooperative magnetophoresis of colloidal magnetic nanoparticles

Yeap SP, Ahmad AL, Ooi BS, Lim J

Langmuir, 2012 Oct 23;28(42):14878-91.
PMID: 23025323 DOI: 10.1021/la303169g

A detailed study on the conflicting role that colloid stability plays in magnetophoresis is presented. Magnetic iron oxide particles (MIOPs) that were sterically stabilized via surface modification with poly(sodium 4-styrene sulfonate) of different molecular weights (i.e., 70 and 1000 kDa) were employed as our model system. Both sedimentation kinetics and quartz crystal microbalance with dissipation (QCM-D) measurements suggested that PSS 70 kDa is a better stabilizer as compared to PSS 1000 kDa. This observation is mostly attributed to the bridging flocculation of PSS 1000 kDa decorated MIOPs originated from the extended polymeric conformation layer. Later, a lab-scale high gradient magnetic separation (HGMS) device was designed to study the magnetophoretic collection of MIOPs. Our experimental results revealed that the more colloidally stable the MIOP suspension is, the harder it is to be magnetically isolated by HGMS. At 50 mg/L, naked MIOPs without coating can be easily captured by HGMS at separation efficiency up to 96.9 ± 2.6%. However, the degree of separation dropped quite drastically to 83.1 ± 1.2% and 67.7 ± 4.6%, for MIOPs with PSS 1000k and PSS 70k coating, respectively. This observation clearly implies that polyelectrolyte coating that was usually employed to electrosterically stabilize a colloidal system in turn compromises the magnetic isolation efficiency. By artificially destroying the colloidal stability of the MIOPs with ionic strength increment, the ability for HGMS to recover the most stable suspension (i.e., PSS 70k-coated MIOPs) increased to >86% at 100 mM monovalent ion (Na(+)) or at 10 mM divalent ion (Ca(2+)). This observation has verified the conflicting role of colloidal stability in magnetophoretic separation.
Unified View of Magnetic Nanoparticle Separation under Magnetophoresis

Leong SS, Ahmad Z, Low SC, Camacho J, Faraudo J, Lim J

Langmuir, 2020 07 21;36(28):8033-8055.
PMID: 32551702 DOI: 10.1021/acs.langmuir.0c00839

The migration process of magnetic nanoparticles and colloids in solution under the influence of magnetic field gradients, which is also known as magnetophoresis, is an essential step in the separation technology used in various biomedical and engineering applications. Many works have demonstrated that in specific situations, separation can be performed easily with the weak magnetic field gradients created by permanent magnets, a process known as low-gradient magnetic separation (LGMS). Due to the level of complexity involved, it is not possible to understand the observed kinetics of LGMS within the classical view of magnetophoresis. Our experimental and theoretical investigations in the last years unravelled the existence of two novel physical effects that speed up the magnetophoresis kinetics and explain the observed feasibility of LGMS. Those two effects are (i) cooperative magnetophoresis (due to the cooperative motion of strongly interacting particles) and (ii) magnetophoresis-induced convection (fluid dynamics instability originating from inhomogeneous magnetic gradients). In this feature article, we present a unified view of magnetophoresis based on the extensive research done on these effects. We present the physical basis of each effect and also propose a classification of magnetophoresis into four distinct regimes. This classification is based on the range of values of two dimensionless quantities, namely, aggregation parameter N* and magnetic Grashof number Grm, which include all of the dependency of LGMS on various physical parameters (such as particle properties, thermodynamic parameters, fluid properties, and magnetic field properties). This analysis provides a holistic view of the classification of transport mechanisms in LGMS, which could be particularly useful in the design of magnetic separators for engineering applications.
Magnetophoresis of Magnetic Pickering Emulsions Under Low Field Gradient: Macroscopic and Microscopic Motion

Tham FK, Ng WM, Leong SS, Yeap SP, Low SC, Lee HL, et al.

Langmuir, 2021 Jan 26.
PMID: 33496594 DOI: 10.1021/acs.langmuir.0c03153

Monodispersed iron oxide nanoparticles (IONPs) coated with polystyrenesulfonate (PSS) and cetrimonium bromide (CTAB) have been used to stabilize magnetic Pickering emulsions (MPEs). Magnetophoresis of MPEs under the influence of a low gradient magnetic field (∇B < 100 T/m) was investigated at the macroscopic and microscopic scale. At the macroscopic scale, for the case of pH 7, the MPE achieved a magnetophoretic velocity of 70.9 μm/s under the influence of ∇B at 93.8 T/m. The magnetic separation efficiency of the MPE at 90% was achieved within 30 min for pH 3, 7, and 10. At pH 10, the colloidal stability of the MPE was the lowest compared to that for pH 3 and 7. Thus, MPE at pH 10 required the shortest time for achieving the highest separation efficiency, as the MPE experienced cooperative magnetophoresis at alkaline pH. The creaming rate of the MPE at all conditions was still lower compared to magnetophoresis and was negligible in influencing its separation kinetics profiles. At the microscopic scale, the migration pathways of the MPEs (with diameters between 2.5 and 7.5 μm) undergoing magnetophoresis at ∇B ∼ 13.0 T/m were recorded by an optical microscope. From these experiments, and taking into consideration the MPE size distribution from the dynamic light scattering (DLS) measurement, we determined the averaged microscopic magnetophoretic velocity to be 7.8 ± 5.5 μm/s. By making noncooperative magnetophoresis assumptions (with negligible interactions between the MPEs along their migration pathways), the calculated velocity of individual MPEs was 9.8 μm/s. Such a value was within the percentage error of the experimental result of 7.8 ± 5.5 μm/s. This finding allows for an easy and quick estimation of the magnetophoretic velocity of MPEs at the microscale by using macroscopic separation kinetics data.
The Transport Behavior of a Biflagellated Microswimmer before and after Cargo Loading

Teng XJ, Ng WM, Chong WH, Chan DJC, Mohamud R, Ooi BS, et al.

Langmuir, 2021 08 03;37(30):9192-9201.
PMID: 34255525 DOI: 10.1021/acs.langmuir.1c01345

The changes in the transport behavior of a microswimmer before and after cargo loading are crucial to understanding and control of the motion of a biohybrid microbot. In this work, we show the change in swimming behavior of biflagellated microalgae Chlamydomonas reinhardtii picking up a 4.5 μm polystyrene microbead upon collision. The microswimmer changed from linear forward motion into helical motion upon the attachment of the cargo and swam with a decreased swimming velocity. We revealed the helical motion of the microswimmer upon cargo loading due to suppression of flagella by image analysis of magnified time-lapse images of C. reinhardtii with one microbead attached at the anterior end (between the flagella). Furthered suppression on the flagellum imposed by the loading of the second cargo has led to increased oscillation per displacement traveled and decreased swimming velocity. Moreover, the microswimmer with a microbead attached at the posterior end swam with swimming velocity close to free swimming microalgae and did not exhibit helical swimming behavior. The experimental results and analysis showed that the loading location of the cargo has a great influence over the swimming behavior of the microswimmer. Furthermore, the work balance calculation and mathematical analysis based on Lighthill's model are well consistent with our experimental findings.
Artificial Magnetotaxis of Microbot: Magnetophoresis versus Self-Swimming

Ng WM, Che HX, Guo C, Liu C, Low SC, Chieh Chan DJ, et al.

Langmuir, 2018 07 10;34(27):7971-7980.
PMID: 29882671 DOI: 10.1021/acs.langmuir.8b01210

An artificial magnetotactic microbot was created by integrating the microalgal cell with magnetic microbead for its potential application as biomotor in microscale environment. Here, we demonstrate the remote magnetotactic control of the microbot under a low gradient magnetic field (<100 T/m). We characterize the kinematic behavior of the microbots carrying magnetic microbeads of two different sizes, with diameter of 2 and 4.5 μm, in the absence and presence of magnetic field. In the absence of magnetic field, we observed the microbot showed a helical motion as a result of the misalignment between the thrust force and the symmetry axis after the attachment. The microbot bound with a larger magnetic microbead moved with higher translational velocity but rotated slower about its axis of rotation. The viscous force was balanced by the thrust force of the microbot, resulting in a randomized swimming behavior of the microbot at its terminal velocity. Meanwhile, under the influence of a low gradient magnetic field, we demonstrated that the directional control of the microbot was based on following principles: (1) magnetophoretic force was insignificant on influencing its perpendicular motion and (2) its parallel motion was dependent on both self-swimming and magnetophoresis, in which this cooperative effect was a function of separation distance from the magnet. As the microbot approached the magnet, the magnetophoretic force suppressed its self-swimming behavior, leading to a positive magnetotaxis of the microbot toward the source of magnetic field. Our experimental results and kinematic analysis revealed the contribution of mass density variation of particle-and-cell system on influencing its dynamical behavior.
Sedimentation Kinetics of Magnetic Nanoparticle Clusters: Iron Oxide Nanospheres vs Nanorods

Ng WM, Katiyar A, Mathivanan V, Teng XJ, Leong S, Low S, et al.

Langmuir, 2020 May 19;36(19):5085-5095.
PMID: 32338911 DOI: 10.1021/acs.langmuir.0c00135

A detailed study of the sedimentation kinetics of iron oxide nanoparticle (IONP) clusters composed of nanospheres and nanorods is presented. Measurements were performed to determine the absorbance of an IONP suspension undergoing sedimentation over time by using a UV-vis spectrophotometer with simultaneous monitoring of the hydrodynamic diameter of the clusters formed with dynamic light scattering (DLS). Mathematical analysis based on Happel's spherical and cylindrical models was conducted to reveal the relationship between the settling velocity of the IONP clusters and their packing density. For the case of IONP clusters composed of rodlike particles, two distinctive phases of sedimentation were recorded, with the occurrence of rapid sedimentation at the beginning of the process (phase I) followed by a slower settling rate (phase II). In sedimentation phase II, even though the nanorod clusters had a hydrodynamic size of >500 nm, which was much larger than that of the nanosphere clusters (∼200 nm), their settling velocity of 0.0038 mm/min was still slower than that of the nanosphere clusters. Such observations were mainly a result of the packing density differences between the formed clusters; due to the end-to-end particle interactions of nanorods, the nanorod clusters were less tightly packed and more permeable. In addition to the mathematical analysis, quartz crystal microbalance with dissipation (QCM-D) was employed to measure the "softness" of the IONP clusters formed, and this physical property can be further related to their packing density. This study illustrated that for a rapidly aggregating system, such as magnetic IONPs, not only do the particle shape and size uniformity contribute to the physical properties of the particle clusters formed but also the nature of the aggregation, either end-to-end and/or side-to-side, should be carefully considered when designing a colloidally stable IONP suspension.
Low-Gradient Magnetophoresis of Nanospheres and Nanorods through a Single Layer of Paper

Law JKC, Ng WM, Chong WH, Li Q, Zhang L, Khoerunnisa F, et al.

Langmuir, 2023 Apr 11;39(14):4904-4916.
PMID: 36992604 DOI: 10.1021/acs.langmuir.2c03164

The possible magnetophoretic migration of iron oxide nanoparticles through the cellulosic matrix within a single layer of paper is challenging with its underlying mechanism remained unclear. Even with the recent advancements of theoretical understanding on magnetophoresis, mainly driven by cooperative and hydrodynamics phenomena, the contributions of these two mechanisms on possible penetration of magnetic nanoparticles through cellulosic matrix of paper have yet been proven. Here, by using iron oxide nanoparticles (IONPs), both nanospheres and nanorods, we have investigated the migration kinetics of these nanoparticles through grade 4 Whatman filter paper with a particle retention of 20-25 μm. By performing droplet tracking experiments, the real-time stained area growth of the particle droplet on the filter paper, under the influences of a grade N40 NdFeB magnet, were recorded. Our results show that the spatial and temporal expansion of the IONP stain is biased toward the magnet and such an effect is dependent on (i) particle concentration and (ii) particle shape. The kinetics data were first analyzed by treating it as a radial wicking fluid, and later the IONP distribution within the cellulosic matrix was investigated by optical microscopy. The macroscopic flow front velocities of the stained area ranged from 259 μm/s to 16 040 μm/s. Moreover, the microscopic magnetophoretic velocity of nanorod cluster was also successfully measured as ∼214 μm/s. Findings in this work have indirectly revealed the strong influence of cooperative magnetophoresis and the engineering feasibility of paper-based magnetophoretic technology by taking advantage of magnetoshape anisotropy effect of the particles.
Exploring the Impact of Surface Functionalization on the Reaction, Magnetophoretic, and Collective Transport Behavior of Nanoscale Zerovalent Iron

Ng WM, Chong WH, Abdullah AZ, Lim J

Langmuir, 2023 Dec 05;39(48):17270-17285.
PMID: 37976676 DOI: 10.1021/acs.langmuir.3c02358

This study provides a systematic analysis of the transport and magnetophoretic behavior of nanoscale zerovalent iron (nZVI) particles, both bare and surface functionalized by poly(ethylene glycol) (PEG) and carboxymethyl cellulose (CMC), after undergoing a chemical reaction. Here, a simple and well-investigated chemical reaction of methyl orange (MO) degradation by nZVI was used as a model reaction system, and the sand column transport and low-gradient magnetophoretic profiles of the nanoparticles were measured before and after the reaction. The results were compared over time and analyzed in the context of extended Derjaguin-Landau-Verwey-Overbeek (DLVO) theory to understand the particle interactions involved. The colloidal stability of both bare and functionalized nZVI particles was enhanced after the reaction due to the consumption of metallic Fe content, resulting in a significant drop in their magnetic properties. As a result, they exhibited improved mobility across the sand column and a slower magnetophoretic collection rate compared to the unreacted particles. Here, the colloidal filtration theory (CFT) was employed to analyze the transport behavior of nZVI particles across the packed sand column. It has been observed that the surface properties of the reacted functionalized particles changed, possibly due to the entrapment of degraded products within the polymer adlayer. Moreover, quartz crystal microbalance with dissipation (QCM-D) measurements were performed to reveal the viscoelastic contribution of the adlayer formed by both bare and functionalized nZVI particles after the reaction on influencing their transport behavior across the sand column. Finally, we proposed the implementation of a high-gradient magnetic trap (HGMT) to reduce the transport distance of the colloidally stable CMC-nZVI, both before and after the reaction. This study sheds light on the behavioral changes of iron nanoparticles after the reaction and highlights environmental concerns regarding the presence of reacted nanoparticles.

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