Gozde Durmus

All Publications

• The Hallmarks of Circulating Hybrid Cells. Results and problems in cell differentiation Patel, R. K., Parappilly, M., Rahman, S., Schwantes, I. R., Sewell, M., Giske, N. R., Whalen, R. M., Durmus, N. G., Wong, M. H. 2024; 71: 467-485

  Abstract

  While tumor metastases represent the primary driver of cancer-related mortality, our understanding of the mechanisms that underlie metastatic initiation and progression remains incomplete. Recent work identified a novel tumor-macrophage hybrid cell population, generated through the fusion between neoplastic and immune cells. These hybrid cells are detected in primary tumor tissue, peripheral blood, and in metastatic sites. In-depth analyses of hybrid cell biology indicate that they can exploit phenotypic properties of both parental tumor and immune cells, in order to intravasate into circulation, evade the immune response, and seed tumors at distant sites. Thus, it has become increasingly evident that the development and dissemination of tumor-immune hybrid cells play an intricate and fundamental role in the metastatic cascade and can provide invaluable information regarding tumor characteristics and patient prognostication. In this chapter, we review the current understanding of this novel hybrid cell population, the specific hallmarks of cancer that these cells exploit to promote cancer progression and metastasis, and discuss exciting new frontiers that remain to be explored.

  View details for DOI 10.1007/978-3-031-37936-9_21

  View details for PubMedID 37996690

  View details for PubMedCentralID 8923521

• Automated Image Analysis for Characterization of Circulating Tumor Cells and Clusters Sorted by Magnetic Levitation. Advanced biology Ogut, M. G., Ma, P., Gupta, R., Hoerner, C. R., Fan, A. C., El-Kaffas, A. N., Durmus, N. G. 2023: e2300109

  Abstract

  Magnetic levitation-based sorting technologies have revolutionized the detection and isolation of rare cells, including circulating tumor cells (CTCs) and circulating tumor cell clusters (CTCCs). Manual counting and quantification of these cells are prone to time-consuming processes, human error, and inter-observer variability, particularly challenging when heterogeneous cell types in 3D clusters are present. To overcome these challenges, we developed "Fastcount," an in-house MATLAB-based algorithm for precise, automated quantification and phenotypic characterization of CTCs and CTCCs, in both 2D and 3D. Fastcount is 120 times faster than manual counting and produces reliable results with a ±7.3% deviation compared to a trained laboratory technician. By analyzing 400 GB of fluorescence imaging data, we showed that Fastcount outperforms manual counting and commercial software when cells are aggregated in 3D or staining artifacts are present, delivering more accurate results. We further employed Fastcount for automated analysis of 3D image stacks obtained from CTCCs isolated from colorectal adenocarcinoma and renal cell carcinoma blood samples. Interestingly, we observed a highly heterogeneous spatial cellular composition within CTCCs, even among clusters from the same patient. Overall, Fastcount can be employed for various applications with lab-chip devices, such as CTC detection, CTCC analysis in 3D and cell detection in biosensors.

  View details for DOI 10.1002/adbi.202300109

  View details for PubMedID 37462226

• Levitational 3D Bioassembly and Density-Based Spatial Coding of Levitoids ADVANCED FUNCTIONAL MATERIALS Moncal, K., Yaman, S., Durmus, N. 2022

  View details for DOI 10.1002/adfm.202204092

  View details for Web of Science ID 000889975000001

• Size and density measurements of single sickle red blood cells using microfluidic magnetic levitation. Lab on a chip Goreke, U., Bode, A., Yaman, S., Gurkan, U. A., Durmus, N. G. 1800

  Abstract

  Single cells have unique biophysical signatures that can rapidly change during various disease states. For instance, cellular density is an inherent property differing between cell types. Characterizing changes in fundamental density properties down to the single-cell level can reveal sub-populations in pathological states. Here, we have developed a microfluidic, magnetic levitation-based assay (MagDense) that detects minute density differences of individual red blood cells (RBCs) down to 0.0001 g mL-1 resolution. This assay fractionates RBCs based on their density profiles in a non-ionic paramagnetic medium flowing in a capillary microchannel placed between magnets with same poles facing each other. Based on precisely measured levitation height and density of individual RBCs at their specific equilibrium state, we demonstrated that MagDense can accurately analyze the density of sickle hemoglobin (HbS)-containing RBCs and normal hemoglobin (HbA)-containing RBCs. In addition, the precise density and cell size measurements at the single cell level showed three different sub-populations of RBCs in blood samples from individuals with homozygous sickle cell disease receiving blood transfusions; where less dense, HbA-containing RBCs levitated higher, while the denser, HbS-containing RBCs levitated lower. We compared the mean RBC densities of sickle cell disease subjects with healthy controls and found distinctly separated bands of RBC density for each group denoting the likely range of cell densities seen in the blood samples. The high resolution of our method enabled measurement of deviation from the mean RBC density. Moreover, we introduced a new term as a measure of density dispersion, "RBC levitational density width, RLDW". Mean RBC density in sickle cell disease associated with hemoglobin from complete blood count (p = 0.032, linear regression) and RLDW associated with absolute reticulocyte count (ARC) and RBC distribution width (RDW) from complete blood count (p = 0.002 for ARC and p = 003 for RDW, linear regression). Our magnetic levitation-based assay enables rapid, accurate, density-based imaging, profiling and label-free monitoring of single RBCs. Our approach can be broadly applicable to investigate blood cell disorders and the effects of emerging pharmacological and curative therapies in patient outcomes.

  View details for DOI 10.1039/d1lc00686j

  View details for PubMedID 35094036

• Multiparametric biophysical profiling of red blood cells in malaria infection. Communications biology Deshmukh, S. S., Shakya, B., Chen, A., Durmus, N. G., Greenhouse, B., Egan, E. S., Demirci, U. 2021; 4 (1): 697

  Abstract

  Biophysical separation promises label-free, less-invasive methods to manipulate the diverse properties of live cells, such as density, magnetic susceptibility, and morphological characteristics. However, some cellular changes are so minute that they are undetectable by current methods. We developed a multiparametric cell-separation approach to profile cells with simultaneously changing density and magnetic susceptibility. We demonstrated this approach with the natural biophysical phenomenon of Plasmodium falciparum infection, which modifies its host erythrocyte by simultaneously decreasing density and increasing magnetic susceptibility. Current approaches have used these properties separately to isolate later-stage infected cells, but not in combination. We present biophysical separation of infected erythrocytes by balancing gravitational and magnetic forces to differentiate infected cell stages, including early stages for the first time, using magnetic levitation. We quantified height distributions of erythrocyte populations-27 ring-stage synchronized samples and 35 uninfected controls-and quantified their unique biophysical signatures. This platform can thus enable multidimensional biophysical measurements on unique cell types.

  View details for DOI 10.1038/s42003-021-02181-3

  View details for PubMedID 34103669

• Levitational Cell Cytometry for Forensics Advanced Biology Urey, D. Y., Chan, H., Durmus, N. 2021

  View details for DOI 10.1002/adbi.202000441

• CelLEVITAS: Label-free rapid sorting and enrichment of live cells via magnetic levitation Biorxiv Chin, E. K., Grant, C. A., Ogut, M. G., Cai, B., Durmus, N. 2020

  View details for DOI 10.1101/2020.07.27.223917

• Label-free imaging of exosomes using depth scanning correlation (DSC) interferometric microscopy Aygun, U., Ozkumur, A., Durmus, N., Demirci, U., Urey, H., Shaked, N. T., Hayden, O. SPIE-INT SOC OPTICAL ENGINEERING. 2020

  View details for DOI 10.1117/12.2543242

  View details for Web of Science ID 000558221300008

• Levitating Cells to Sort the Fit and the Fat. Advanced biosystems Puluca, N. n., Durmus, N. G., Lee, S. n., Belbachir, N. n., Galdos, F. X., Ogut, M. G., Gupta, R. n., Hirano, K. I., Krane, M. n., Lange, R. n., Wu, J. C., Wu, S. M., Demirci, U. n. 2020: e1900300

  Abstract

  Density is a core material property and varies between different cell types, mainly based on differences in their lipid content. Sorting based on density enables various biomedical applications such as multi-omics in precision medicine and regenerative repair in medicine. However, a significant challenge is sorting cells of the same type based on density differences. Here, a new method for real-time monitoring and sorting of single cells based on their inherent levitation profiles driven by their lipid content is reported. As a model system, human-induced pluripotent stem cell (hiPSC)-derived cardiomyocytes (CMs) from a patient with neutral lipid storage disease (NLSD) due to loss of function of adipose triglyceride lipase (ATGL) resulting in abnormal lipid storage in cardiac muscle are used. This levitation-based strategy detects subpopulations within ATGL-deficient hiPSC-CMs with heterogenous lipid content, equilibrating at different levitation heights due to small density differences. In addition, sorting of these differentially levitating subpopulations are monitored in real time. Using this approach, sorted healthy and diseased hiPSC-CMs maintain viability and function. Pixel-tracking technologies show differences in contraction between NLSD and healthy hiPSC-CMs. Overall, this is a unique approach to separate diseased cell populations based on their intracellular lipid content that cannot be achieved using traditional flow cytometry techniques.

  View details for DOI 10.1002/adbi.201900300

  View details for PubMedID 32352239

• MICROSCALE MAGNETIC LEVITATION FOR MULTIPLEXED ANALYSIS OF MALARIA-INFECTED BLOOD SAMPLES IN RESOURCE-LIMITED SETTINGS Deshmukh, S. S., Durmus, N., Greenhouse, B., Egan, E., Demirci, U. AMER SOC TROP MED & HYGIENE. 2019: 130–31

  View details for Web of Science ID 000507364502427

• A Novel On-Chip Method for Differential Extraction of Sperm in Forensic Cases ADVANCED SCIENCE Inci, F., Ozen, M. O., Saylan, Y., Miansari, M., Cimen, D., Dhara, R., Chinnasamy, T., Yuksekkaya, M., Filippini, C., Kumar, D., Calamak, S., Yesil, Y., Durmus, N., Duncan, G., Klevan, L., Demirci, U. 2018; 5 (9): 1800121

  Abstract

  One out of every six American women has been the victim of a sexual assault in their lifetime. However, the DNA casework backlog continues to increase outpacing the nation's capacity since DNA evidence processing in sexual assault casework remains a bottleneck due to laborious and time-consuming differential extraction of victim's and perpetrator's cells. Additionally, a significant amount (60-90%) of male DNA evidence may be lost with existing procedures. Here, a microfluidic method is developed that selectively captures sperm using a unique oligosaccharide sequence (Sialyl-LewisX), a major carbohydrate ligand for sperm-egg binding. This method is validated with forensic mock samples dating back to 2003, resulting in 70-92% sperm capture efficiency and a 60-92% reduction in epithelial fraction. Captured sperm are then lysed on-chip and sperm DNA is isolated. This method reduces assay-time from 8 h to 80 min, providing an inexpensive alternative to current differential extraction techniques, accelerating identification of suspects and advancing public safety.

  View details for PubMedID 30250782

• A MAGNETIC LEVITATION PLATFORM FOR THE ISOLATION OF MATURE SPERM FROM TESE/TESA SAMPLES Durmus, G., Gupta, R., Badamjav, O., Reddy, V., Eisenberg, M. L., Behr, B., Demirci, U. ELSEVIER SCIENCE INC. 2018: E26–E27

  View details for Web of Science ID 000427891800035

• Monitoring Neutropenia for Cancer Patients at the Point of Care. Small methods Inan, H., Kingsley, J. L., Ozen, M. O., Tekin, H. C., Hoerner, C. R., Imae, Y., Metzner, T. J., Preiss, J. S., Durmus, N. G., Ozsoz, M., Wakelee, H., Fan, A. C., Tüzel, E., Demirci, U. 2017; 1 (9)

  Abstract

  Neutrophils have a critical role in regulating the immune system. The immune system is compromised during chemotherapy, increasing infection risks and imposing a need for regular monitoring of neutrophil counts. Although commercial hematology analyzers are currently used in clinical practice for neutrophil counts, they are only available in clinics and hospitals, use large blood volumes, and are not available at the point of care (POC). Additionally, phlebotomy and blood processing require trained personnel, where patients are often admitted to hospitals when the infections are at late stage due to lack of frequent monitoring. Here, a reliable method is presented that selectively captures and quantifies white blood cells (WBCs) and neutrophils from a finger prick volume of whole blood by integrating microfluidics with high-resolution imaging algorithms. The platform is compact, portable, and easy to use. It captures and quantifies WBCs and neutrophils with high efficiency (>95%) and specificity (>95%) with an overall 4.2% bias compared to standard testing. The results from a small cohort of patients (N = 11 healthy, N = 5 lung and kidney cancer) present a unique disposable cell counter, demonstrating the ability of this tool to monitor neutrophil and WBC counts within clinical or in resource-constrained environments.

  View details for DOI 10.1002/smtd.201700193

  View details for PubMedID 30740513

  View details for PubMedCentralID PMC6364993

• A Magnetic Levitation System to Study the Impact of Donor Gender, Age and Blood Storage Conditions on Red Blood Cell Density Profile Durmus, G., Tocchio, A., Howell, A., Sridhar, K., Acker, J. P., Demirci, U. WILEY. 2017: 32A

  View details for Web of Science ID 000409065000076

• Multifunctional, inexpensive, and reusable nanoparticle-printed biochip for cell manipulation and diagnosis. Proceedings of the National Academy of Sciences of the United States of America Esfandyarpour, R., DiDonato, M. J., Yang, Y., Durmus, N. G., Harris, J. S., Davis, R. W. 2017; 114 (8): E1306-E1315

  Abstract

  Isolation and characterization of rare cells and molecules from a heterogeneous population is of critical importance in diagnosis of common lethal diseases such as malaria, tuberculosis, HIV, and cancer. For the developing world, point-of-care (POC) diagnostics design must account for limited funds, modest public health infrastructure, and low power availability. To address these challenges, here we integrate microfluidics, electronics, and inkjet printing to build an ultra-low-cost, rapid, and miniaturized lab-on-a-chip (LOC) platform. This platform can perform label-free and rapid single-cell capture, efficient cellular manipulation, rare-cell isolation, selective analytical separation of biological species, sorting, concentration, positioning, enumeration, and characterization. The miniaturized format allows for small sample and reagent volumes. By keeping the electronics separate from microfluidic chips, the former can be reused and device lifetime is extended. Perhaps most notably, the device manufacturing is significantly less expensive, time-consuming, and complex than traditional LOC platforms, requiring only an inkjet printer rather than skilled personnel and clean-room facilities. Production only takes 20 min (vs. up to weeks) and $0.01-an unprecedented cost in clinical diagnostics. The platform works based on intrinsic physical characteristics of biomolecules (e.g., size and polarizability). We demonstrate biomedical applications and verify cell viability in our platform, whose multiplexing and integration of numerous steps and external analyses enhance its application in the clinic, including by nonspecialists. Through its massive cost reduction and usability we anticipate that our platform will enable greater access to diagnostic facilities in developed countries as well as POC diagnostics in resource-poor and developing countries.

  View details for DOI 10.1073/pnas.1621318114

  View details for PubMedID 28167769

• Monitoring Neutropenia for Cancer Patients at the Point of Care Small Methods Inan, H., et al 2017

  View details for DOI 10.1002/smtd.201700193

• Magnetically Guided Self-Assembly and Coding of 3D Living Architectures. Advanced materials (Deerfield Beach, Fla.) Tocchio, A. n., Durmus, N. G., Sridhar, K. n., Mani, V. n., Coskun, B. n., El Assal, R. n., Demirci, U. n. 2017

  Abstract

  In nature, cells self-assemble at the microscale into complex functional configurations. This mechanism is increasingly exploited to assemble biofidelic biological systems in vitro. However, precise coding of 3D multicellular living materials is challenging due to their architectural complexity and spatiotemporal heterogeneity. Therefore, there is an unmet need for an effective assembly method with deterministic control on the biomanufacturing of functional living systems, which can be used to model physiological and pathological behavior. Here, a universal system is presented for 3D assembly and coding of cells into complex living architectures. In this system, a gadolinium-based nonionic paramagnetic agent is used in conjunction with magnetic fields to levitate and assemble cells. Thus, living materials are fabricated with controlled geometry and organization and imaged in situ in real time, preserving viability and functional properties. The developed method provides an innovative direction to monitor and guide the reconfigurability of living materials temporally and spatially in 3D, which can enable the study of transient biological mechanisms. This platform offers broad applications in numerous fields, such as 3D bioprinting and bottom-up tissue engineering, as well as drug discovery, developmental biology, neuroscience, and cancer research.

  View details for PubMedID 29215164

• Integrating Cell Phone Imaging with Magnetic Levitation (i-LEV) for Label-Free Blood Analysis at the Point-of-Living. Small Baday, M., Calamak, S., Durmus, N. G., Davis, R. W., Steinmetz, L. M., Demirci, U. 2016; 12 (9): 1222-1229

  Abstract

  There is an emerging need for portable, robust, inexpensive, and easy-to-use disease diagnosis and prognosis monitoring platforms to share health information at the point-of-living, including clinical and home settings. Recent advances in digital health technologies have improved early diagnosis, drug treatment, and personalized medicine. Smartphones with high-resolution cameras and high data processing power enable intriguing biomedical applications when integrated with diagnostic devices. Further, these devices have immense potential to contribute to public health in resource-limited settings where there is a particular need for portable, rapid, label-free, easy-to-use, and affordable biomedical devices to diagnose and continuously monitor patients for precision medicine, especially those suffering from rare diseases, such as sickle cell anemia, thalassemia, and chronic fatigue syndrome. Here, a magnetic levitation-based diagnosis system is presented in which different cell types (i.e., white and red blood cells) are levitated in a magnetic gradient and separated due to their unique densities. Moreover, an easy-to-use, smartphone incorporated levitation system for cell analysis is introduced. Using our portable imaging magnetic levitation (i-LEV) system, it is shown that white and red blood cells can be identified and cell numbers can be quantified without using any labels. In addition, cells levitated in i-LEV can be distinguished at single-cell resolution, potentially enabling diagnosis and monitoring, as well as clinical and research applications.

  View details for DOI 10.1002/smll.201501845

  View details for PubMedID 26523938

  View details for PubMedCentralID PMC4775401

• Multitarget, quantitative nanoplasmonic electrical field-enhanced resonating device (NE2RD) for diagnostics. Proceedings of the National Academy of Sciences of the United States of America Inci, F., Filippini, C., Baday, M., Ozen, M. O., Calamak, S., Durmus, N. G., Wang, S., Hanhauser, E., Hobbs, K. S., Juillard, F., Kuang, P. P., Vetter, M. L., Carocci, M., Yamamoto, H. S., Takagi, Y., Yildiz, U. H., Akin, D., Wesemann, D. R., Singhal, A., Yang, P. L., Nibert, M. L., Fichorova, R. N., Lau, D. T., Henrich, T. J., Kaye, K. M., Schachter, S. C., Kuritzkes, D. R., Steinmetz, L. M., Gambhir, S. S., Davis, R. W., Demirci, U. 2015; 112 (32): E4354-63

  Abstract

  Recent advances in biosensing technologies present great potential for medical diagnostics, thus improving clinical decisions. However, creating a label-free general sensing platform capable of detecting multiple biotargets in various clinical specimens over a wide dynamic range, without lengthy sample-processing steps, remains a considerable challenge. In practice, these barriers prevent broad applications in clinics and at patients' homes. Here, we demonstrate the nanoplasmonic electrical field-enhanced resonating device (NE(2)RD), which addresses all these impediments on a single platform. The NE(2)RD employs an immunodetection assay to capture biotargets, and precisely measures spectral color changes by their wavelength and extinction intensity shifts in nanoparticles without prior sample labeling or preprocessing. We present through multiple examples, a label-free, quantitative, portable, multitarget platform by rapidly detecting various protein biomarkers, drugs, protein allergens, bacteria, eukaryotic cells, and distinct viruses. The linear dynamic range of NE(2)RD is five orders of magnitude broader than ELISA, with a sensitivity down to 400 fg/mL This range and sensitivity are achieved by self-assembling gold nanoparticles to generate hot spots on a 3D-oriented substrate for ultrasensitive measurements. We demonstrate that this precise platform handles multiple clinical samples such as whole blood, serum, and saliva without sample preprocessing under diverse conditions of temperature, pH, and ionic strength. The NE(2)RD's broad dynamic range, detection limit, and portability integrated with a disposable fluidic chip have broad applications, potentially enabling the transition toward precision medicine at the point-of-care or primary care settings and at patients' homes.

  View details for DOI 10.1073/pnas.1510824112

  View details for PubMedID 26195743

  View details for PubMedCentralID PMC4538635

• Multitarget, quantitative nanoplasmonic electrical field-enhanced resonating device ((NERD)-R-2) for diagnostics PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Inci, F., Filippini, C., Baday, M., Ozen, M. O., Calamak, S., Durmus, N. G., Wang, S., Hanhauser, E., Hobbs, K. S., Juillard, F., Kuang, P. P., Vetter, M. L., Carocci, M., Yamamoto, H. S., Takagi, Y., Yildiz, U. H., Akin, D., Wesemann, D. R., Singhal, A., Yang, P. L., Nibert, M. L., Fichorova, R. N., Lau, D. T., Henrich, T. J., Kaye, K. M., Schachter, S. C., Kuritzkes, D. R., Steinmetz, L. M., Gambhir, S. S., Davis, R. W., Demirci, U. 2015; 112 (32): E4354-E4363

  Abstract

  Recent advances in biosensing technologies present great potential for medical diagnostics, thus improving clinical decisions. However, creating a label-free general sensing platform capable of detecting multiple biotargets in various clinical specimens over a wide dynamic range, without lengthy sample-processing steps, remains a considerable challenge. In practice, these barriers prevent broad applications in clinics and at patients' homes. Here, we demonstrate the nanoplasmonic electrical field-enhanced resonating device (NE(2)RD), which addresses all these impediments on a single platform. The NE(2)RD employs an immunodetection assay to capture biotargets, and precisely measures spectral color changes by their wavelength and extinction intensity shifts in nanoparticles without prior sample labeling or preprocessing. We present through multiple examples, a label-free, quantitative, portable, multitarget platform by rapidly detecting various protein biomarkers, drugs, protein allergens, bacteria, eukaryotic cells, and distinct viruses. The linear dynamic range of NE(2)RD is five orders of magnitude broader than ELISA, with a sensitivity down to 400 fg/mL This range and sensitivity are achieved by self-assembling gold nanoparticles to generate hot spots on a 3D-oriented substrate for ultrasensitive measurements. We demonstrate that this precise platform handles multiple clinical samples such as whole blood, serum, and saliva without sample preprocessing under diverse conditions of temperature, pH, and ionic strength. The NE(2)RD's broad dynamic range, detection limit, and portability integrated with a disposable fluidic chip have broad applications, potentially enabling the transition toward precision medicine at the point-of-care or primary care settings and at patients' homes.

  View details for DOI 10.1073/pnas.1510824112

  View details for Web of Science ID 000359285100006

  View details for PubMedID 26195743

  View details for PubMedCentralID PMC4538635

• Magnetic levitation of single cells. Proceedings of the National Academy of Sciences of the United States of America Durmus, N. G., Tekin, H. C., Guven, S., Sridhar, K., Arslan Yildiz, A., Calibasi, G., Ghiran, I., Davis, R. W., Steinmetz, L. M., Demirci, U. 2015; 112 (28): E3661-8

  Abstract

  Several cellular events cause permanent or transient changes in inherent magnetic and density properties of cells. Characterizing these changes in cell populations is crucial to understand cellular heterogeneity in cancer, immune response, infectious diseases, drug resistance, and evolution. Although magnetic levitation has previously been used for macroscale objects, its use in life sciences has been hindered by the inability to levitate microscale objects and by the toxicity of metal salts previously applied for levitation. Here, we use magnetic levitation principles for biological characterization and monitoring of cells and cellular events. We demonstrate that each cell type (i.e., cancer, blood, bacteria, and yeast) has a characteristic levitation profile, which we distinguish at an unprecedented resolution of 1 × 10(-4) g⋅mL(-1). We have identified unique differences in levitation and density blueprints between breast, esophageal, colorectal, and nonsmall cell lung cancer cell lines, as well as heterogeneity within these seemingly homogenous cell populations. Furthermore, we demonstrate that changes in cellular density and levitation profiles can be monitored in real time at single-cell resolution, allowing quantification of heterogeneous temporal responses of each cell to environmental stressors. These data establish density as a powerful biomarker for investigating living systems and their responses. Thereby, our method enables rapid, density-based imaging and profiling of single cells with intriguing applications, such as label-free identification and monitoring of heterogeneous biological changes under various physiological conditions, including antibiotic or cancer treatment in personalized medicine.

  View details for DOI 10.1073/pnas.1509250112

  View details for PubMedID 26124131

  View details for PubMedCentralID PMC4507238

• Magnetic levitation of single cells. Proceedings of the National Academy of Sciences of the United States of America Durmus, N. G., Tekin, H. C., Guven, S., Sridhar, K., Arslan Yildiz, A., Calibasi, G., Ghiran, I., Davis, R. W., Steinmetz, L. M., Demirci, U. 2015; 112 (28): E3661-8

  View details for DOI 10.1073/pnas.1509250112

  View details for PubMedID 26124131

• Portable Microfluidic Integrated Plasmonic Platform for Pathogen Detection SCIENTIFIC REPORTS Tokel, O., Yildiz, U. H., Inci, F., Durmus, N. G., Ekiz, O. O., Turker, B., Cetin, C., Rao, S., Sridhar, K., Natarajan, N., Shafiee, H., Dana, A., Demirci, U. 2015; 5

  Abstract

  Timely detection of infectious agents is critical in early diagnosis and treatment of infectious diseases. Conventional pathogen detection methods, such as enzyme linked immunosorbent assay (ELISA), culturing or polymerase chain reaction (PCR) require long assay times, and complex and expensive instruments, which are not adaptable to point-of-care (POC) needs at resource-constrained as well as primary care settings. Therefore, there is an unmet need to develop simple, rapid, and accurate methods for detection of pathogens at the POC. Here, we present a portable, multiplex, inexpensive microfluidic-integrated surface plasmon resonance (SPR) platform that detects and quantifies bacteria, i.e., Escherichia coli (E. coli) and Staphylococcus aureus (S. aureus) rapidly. The platform presented reliable capture and detection of E. coli at concentrations ranging from ~10(5) to 3.2 × 10(7) CFUs/mL in phosphate buffered saline (PBS) and peritoneal dialysis (PD) fluid. The multiplexing and specificity capability of the platform was also tested with S. aureus samples. The presented platform technology could potentially be applicable to capture and detect other pathogens at the POC and primary care settings.

  View details for DOI 10.1038/srep09152

  View details for Web of Science ID 000351699600001

  View details for PubMedID 25801042

  View details for PubMedCentralID PMC4371189

• Paper and flexible substrates as materials for biosensing platforms to detect multiple biotargets. Scientific reports Shafiee, H., Asghar, W., Inci, F., Yuksekkaya, M., Jahangir, M., Zhang, M. H., Durmus, N. G., Gurkan, U. A., Kuritzkes, D. R., Demirci, U. 2015; 5: 8719-?

  Abstract

  The need for sensitive, robust, portable, and inexpensive biosensing platforms is of significant interest in clinical applications for disease diagnosis and treatment monitoring at the point-of-care (POC) settings. Rapid, accurate POC diagnostic assays play a crucial role in developing countries, where there are limited laboratory infrastructure, trained personnel, and financial support. However, current diagnostic assays commonly require long assay time, sophisticated infrastructure and expensive reagents that are not compatible with resource-constrained settings. Although paper and flexible material-based platform technologies provide alternative approaches to develop POC diagnostic assays for broad applications in medicine, they have technical challenges integrating to different detection modalities. Here, we address the limited capability of current paper and flexible material-based platforms by integrating cellulose paper and flexible polyester films as diagnostic biosensing materials with various detection modalities through the development and validation of new widely applicable electrical and optical sensing mechanisms using antibodies and peptides. By incorporating these different detection modalities, we present selective and accurate capture and detection of multiple biotargets including viruses (Human Immunodeficieny Virus-1), bacteria (Escherichia coli and Staphylococcus aureus), and cells (CD4(+) T lymphocytes) from fingerprick volume equivalent of multiple biological specimens such as whole blood, plasma, and peritoneal dialysis effluent with clinically relevant detection and sensitivity.

  View details for DOI 10.1038/srep08719

  View details for PubMedID 25743880

  View details for PubMedCentralID PMC4351531

• Paper and flexible substrates as materials for biosensing platforms to detect multiple biotargets. Scientific reports Shafiee, H., Asghar, W., Inci, F., Yuksekkaya, M., Jahangir, M., Zhang, M. H., Durmus, N. G., Gurkan, U. A., Kuritzkes, D. R., Demirci, U. 2015; 5: 8719-?

  Abstract

  The need for sensitive, robust, portable, and inexpensive biosensing platforms is of significant interest in clinical applications for disease diagnosis and treatment monitoring at the point-of-care (POC) settings. Rapid, accurate POC diagnostic assays play a crucial role in developing countries, where there are limited laboratory infrastructure, trained personnel, and financial support. However, current diagnostic assays commonly require long assay time, sophisticated infrastructure and expensive reagents that are not compatible with resource-constrained settings. Although paper and flexible material-based platform technologies provide alternative approaches to develop POC diagnostic assays for broad applications in medicine, they have technical challenges integrating to different detection modalities. Here, we address the limited capability of current paper and flexible material-based platforms by integrating cellulose paper and flexible polyester films as diagnostic biosensing materials with various detection modalities through the development and validation of new widely applicable electrical and optical sensing mechanisms using antibodies and peptides. By incorporating these different detection modalities, we present selective and accurate capture and detection of multiple biotargets including viruses (Human Immunodeficieny Virus-1), bacteria (Escherichia coli and Staphylococcus aureus), and cells (CD4(+) T lymphocytes) from fingerprick volume equivalent of multiple biological specimens such as whole blood, plasma, and peritoneal dialysis effluent with clinically relevant detection and sensitivity.

  View details for DOI 10.1038/srep08719

  View details for PubMedID 25743880

  View details for PubMedCentralID PMC4351531

• Enhanced Efficacy of Superparamagnetic Iron Oxide Nanoparticles Against Antibiotic-Resistant Biofilms in the Presence of Metabolites ADVANCED MATERIALS Durmus, N. G., Taylor, E. N., Kummer, K. M., Webster, T. J. 2013; 25 (40): 5706-?

  Abstract

  Antibiotic resistance and the lack of new antibacterial agents cause major challenges for the treatment of infections. Here, we describe a simple, broad-spectrum, and low-cost dual-sided approach which uses superparamagnetic iron oxide particles (SPION) in combination with fructose metabolites as an alternative to existing antibacterial strategies. This strategy offers further improved efficacy of SPION against persistent gram-positive and gram-negative bacteria infections by manipulating the biofilm metabolic microenvironment and outperforms vancomycin (the antibiotic of last resort), creating a new nanotechnology-driven approach.

  View details for DOI 10.1002/adma.201302627

  View details for Web of Science ID 000330773400002

  View details for PubMedID 23963848

• Effects of different sterilization techniques and varying anodized TiO2 nanotube dimensions on bacteria growth JOURNAL OF BIOMEDICAL MATERIALS RESEARCH PART B-APPLIED BIOMATERIALS Kummer, K. M., Taylor, E. N., Durmas, N. G., Tarquinio, K. M., Ercan, B., Webster, T. J. 2013; 101B (5): 677-688

  View details for DOI 10.1002/jbm.b.32870

  View details for Web of Science ID 000320131500001

• BIOPRINTING Functional droplet networks NATURE MATERIALS Durmus, N. G., Tasoglu, S., Demirci, U. 2013; 12 (6): 478-479

  View details for DOI 10.1038/nmat3665

  View details for Web of Science ID 000319402200013

  View details for PubMedID 23695742

• Eradicating Antibiotic-Resistant Biofilms with Silver-Conjugated Superparamagnetic Iron Oxide Nanoparticles ADVANCED HEALTHCARE MATERIALS Durmus, N. G., Webster, T. J. 2013; 2 (1): 165-171

  Abstract

  Concerns about antibiotic-resistant microorganisms, such as methicillin-resistant Staphylococcus aureus (MRSA), is causing a resurgence in the search for novel strategies which can eradicate infections without the use of antibiotics. In this study, the unique magnetic and antibacterial properties of superparamagnetic iron oxide nanoparticles (SPION) and silver have been combined through the design of silver-conjugated SPION. For the first time, it is demonstrated that MRSA biofilms can be eradicated by silver-conjugated SPION without resorting to the use of antibiotics. A significant decrease in biofilm mass, which corresponds to a seven orders of magnitude decrease in viability, is observed when MRSA biofilms are treated with 1 mg/mL of silver-conjugated SPION (p < 0.01). Moreover, SPION anti-biofilm efficacy is further improved in the presence of an external magnetic field. The anti-biofilm property of silver-conjugated SPION treatment is due to the significant increases in intracellular or membrane-bound iron (p < 0.001), sulfur (p < 0.05), and silver (p < 0.001) concentrations, thus increases in SPION uptake within the biofilms. For this reason, this study demonstrates for the first time that silver-conjugated SPION could be used as a targeted antibacterial therapy to the infection site. Thus, this novel infection eradication strategy holds great promise to be an alternative to the antibiotic of last resort, vancomycin, which bacteria have already started to develop a resistance towards.

  View details for DOI 10.1002/adhm.201200215

  View details for Web of Science ID 000315121900015

  View details for PubMedID 23184367

• Short communication: carboxylate functionalized superparamagnetic iron oxide nanoparticles (SPION) for the reduction of S. aureus growth post biofilm formation INTERNATIONAL JOURNAL OF NANOMEDICINE Leuba, K. D., Durmus, N. G., Taylor, E. N., Webster, T. J. 2013; 8: 731-736

  Abstract

  Biofilms formed by antibiotic resistant Staphylococcus aureus (S. aureus) continue to be a problem for medical devices. Antibiotic resistant bacteria (such as S. aureus) often complicate the treatment and healing of the patient, yet, medical devices are needed to heal such patients. Therefore, methods to treat these Biofilms once formed on medical devices are badly needed. Due to their small size and magnetic properties, superparamagnetic iron oxide nanoparticles (SPION) may be one possible material to penetrate Biofilms and kill or slow the growth of bacteria. In this study, SPION were functionalized with amine, carboxylate, and isocyanate functional groups to further improve their efficacy to disrupt the growth of S. aureus Biofilms. Without the use of antibiotics, results showed that SPION functionalized with carboxylate groups (followed by isocyanate then amine functional groups then unfunctionalized SPION) significantly disrupted Biofilms and retarded the growth of S. aureus compared to untreated Biofilms (by over 35% after 24 hours).

  View details for DOI 10.2147/IJN.S38256

  View details for Web of Science ID 000317922700066

  View details for PubMedID 23450111

• Superparamagnetic Iron Oxide Nanoparticles (SPION) for the Treatment of Antibiotic-Resistant Biofilms SMALL Taylor, E. N., Kummer, K. M., Durmus, N. G., Leuba, K., Tarquinio, K. M., Webster, T. J. 2012; 8 (19): 3016-3027

  Abstract

  Bacterial infections caused by antibiotic-resistant strains are of deep concern due to an increasing prevalence, and are a major cause of morbidity in the United States of America. In particular, medical device failures, and thus human lives, are greatly impacted by infections, where the treatments required are further complicated by the tendency of pathogenic bacteria, such as Staphylococcus aureus, to produce antibiotic resistant biofilms. In this study, a panel of relevant antibiotics used clinically including penicillin, oxacillin, gentamicin, streptomycin, and vancomycin are tested, and although antibiotics are effective against free-floating planktonic S. aureus, either no change in biofilm function is observed, or, more frequently, biofilm function is enhanced. As an alternative, superparamagnetic iron oxide nanoparticles (SPION) are synthesized through a two-step process with dimercaptosuccinic acid as a chelator, followed by the conjugation of metals including iron, zinc, and silver; thus, the antibacterial properties of the metals are coupled to the superparamagnetic properties of SPION. SPION might be the ideal antibacterial treatment, with a superior ability to decrease multiple bacterial functions, target infections in a magnetic field, and had activity better than antibiotics or metal salts alone, as is required for the treatment of medical device infections for which no treatment exists today.

  View details for DOI 10.1002/smll.201200575

  View details for Web of Science ID 000309454800014

  View details for PubMedID 22777831

• Nanostructured titanium: the ideal material for improving orthopedic implant efficacy? NANOMEDICINE Durmus, N. G., Webster, T. J. 2012; 7 (6): 791-793

  View details for DOI 10.2217/NNM.12.53

  View details for Web of Science ID 000305713400001

  View details for PubMedID 22734635

• Fructose-enhanced reduction of bacterial growth on nanorough surfaces INTERNATIONAL JOURNAL OF NANOMEDICINE Durmus, N. G., Taylor, E. N., Inci, F., Kummer, K. M., Tarquinio, K. M., Webster, T. J. 2012; 7: 537-545

  Abstract

  Patients on mechanical ventilators for extended periods of time often face the risk of developing ventilator-associated pneumonia. During the ventilation process, patients incapable of breathing are intubated with polyvinyl chloride (PVC) endotracheal tubes (ETTs). PVC ETTs provide surfaces where bacteria can attach and proliferate from the contaminated oropharyngeal space to the sterile bronchoalveolar area. To overcome this problem, ETTs can be coated with antimicrobial agents. However, such coatings may easily delaminate during use. Recently, it has been shown that changes in material topography at the nanometer level can provide antibacterial properties. In addition, some metabolites, such as fructose, have been found to increase the efficiency of antibiotics used to treat Staphylococcus aureus (S. aureus) infections. In this study, we combined the antibacterial effect of nanorough ETT topographies with sugar metabolites to decrease bacterial growth and biofilm formation on ETTs. We present for the first time that the presence of fructose on the nanorough surfaces decreases the number of planktonic S. aureus bacteria in the solution and biofilm formation on the surface after 24 hours. We thus envision that this method has the potential to impact the future of surface engineering of biomaterials leading to more successful clinical outcomes in terms of longer ETT lifetimes, minimized infections, and decreased antibiotic usage; all of which can decrease the presence of antibiotic resistant bacteria in the clinical setting.

  View details for DOI 10.2147/IJN.S27957

  View details for Web of Science ID 000302710600001

  View details for PubMedID 22334783

• Microengineering methods for cell-based microarrays and high-throughput drug-screening applications BIOFABRICATION Xu, F., Wu, J., Wang, S., Durmus, N. G., Gurkan, U. A., Demirci, U. 2011; 3 (3)

  Abstract

  Screening for effective therapeutic agents from millions of drug candidates is costly, time consuming, and often faces concerns due to the extensive use of animals. To improve cost effectiveness, and to minimize animal testing in pharmaceutical research, in vitro monolayer cell microarrays with multiwell plate assays have been developed. Integration of cell microarrays with microfluidic systems has facilitated automated and controlled component loading, significantly reducing the consumption of the candidate compounds and the target cells. Even though these methods significantly increased the throughput compared to conventional in vitro testing systems and in vivo animal models, the cost associated with these platforms remains prohibitively high. Besides, there is a need for three-dimensional (3D) cell-based drug-screening models which can mimic the in vivo microenvironment and the functionality of the native tissues. Here, we present the state-of-the-art microengineering approaches that can be used to develop 3D cell-based drug-screening assays. We highlight the 3D in vitro cell culture systems with live cell-based arrays, microfluidic cell culture systems, and their application to high-throughput drug screening. We conclude that among the emerging microengineering approaches, bioprinting holds great potential to provide repeatable 3D cell-based constructs with high temporal, spatial control and versatility.

  View details for DOI 10.1088/1758-5082/3/3/034101

  View details for Web of Science ID 000294955200003

  View details for PubMedID 21725152

• Living Bacterial Sacrificial Porogens to Engineer Decellularized Porous Scaffolds PLOS ONE Xu, F., Sridharan, B., Durmus, N. G., Wang, S., Yavuz, A. S., Gurkan, U. A., Demirci, U. 2011; 6 (4)

  Abstract

  Decellularization and cellularization of organs have emerged as disruptive methods in tissue engineering and regenerative medicine. Porous hydrogel scaffolds have widespread applications in tissue engineering, regenerative medicine and drug discovery as viable tissue mimics. However, the existing hydrogel fabrication techniques suffer from limited control over pore interconnectivity, density and size, which leads to inefficient nutrient and oxygen transport to cells embedded in the scaffolds. Here, we demonstrated an innovative approach to develop a new platform for tissue engineered constructs using live bacteria as sacrificial porogens. E.coli were patterned and cultured in an interconnected three-dimensional (3D) hydrogel network. The growing bacteria created interconnected micropores and microchannels. Then, the scafold was decellularized, and bacteria were eliminated from the scaffold through lysing and washing steps. This 3D porous network method combined with bioprinting has the potential to be broadly applicable and compatible with tissue specific applications allowing seeding of stem cells and other cell types.

  View details for DOI 10.1371/journal.pone.0019344

  View details for Web of Science ID 000290020700050

  View details for PubMedID 21552485

• Microporous Cell-Laden Hydrogels for Engineered Tissue Constructs BIOTECHNOLOGY AND BIOENGINEERING Park, J. H., Chung, B. G., Lee, W. G., Kim, J., Brigham, M. D., Shim, J., Lee, S., Hwang, C. M., Durmus, N. G., Demirci, U., Khademhosseini, A. 2010; 106 (1): 138-148

  Abstract

  In this article, we describe an approach to generate microporous cell-laden hydrogels for fabricating biomimetic tissue engineered constructs. Micropores at different length scales were fabricated in cell-laden hydrogels by micromolding fluidic channels and leaching sucrose crystals. Microengineered channels were created within cell-laden hydrogel precursors containing agarose solution mixed with sucrose crystals. The rapid cooling of the agarose solution was used to gel the solution and form micropores in place of the sucrose crystals. The sucrose leaching process generated homogeneously distributed micropores within the gels, while enabling the direct immobilization of cells within the gels. We also characterized the physical, mechanical, and biological properties (i.e., microporosity, diffusivity, and cell viability) of cell-laden agarose gels as a function of engineered porosity. The microporosity was controlled from 0% to 40% and the diffusivity of molecules in the porous agarose gels increased as compared to controls. Furthermore, the viability of human hepatic carcinoma cells that were cultured in microporous agarose gels corresponded to the diffusion profile generated away from the microchannels. Based on their enhanced diffusive properties, microporous cell-laden hydrogels containing a microengineered fluidic channel can be a useful tool for generating tissue structures for regenerative medicine and drug discovery applications.

  View details for DOI 10.1002/bit.22667

  View details for Web of Science ID 000276844500014

  View details for PubMedID 20091766

• Engineered 3D tissue models for cell-laden microfluidic channels ANALYTICAL AND BIOANALYTICAL CHEMISTRY Song, Y. S., Lin, R. L., Montesano, G., Durmus, N. G., Lee, G., Yoo, S., Kayaalp, E., Haeggstrom, E., Khademhosseini, A., Demirci, U. 2009; 395 (1): 185-193

  Abstract

  Delivery of nutrients and oxygen within three-dimensional (3D) tissue constructs is important to maintain cell viability. We built 3D cell-laden hydrogels to validate a new tissue perfusion model that takes into account nutrition consumption. The model system was analyzed by simulating theoretical nutrient diffusion into cell-laden hydrogels. We carried out a parametric study considering different microchannel sizes and inter-channel separation in the hydrogel. We hypothesized that nutrient consumption needs to be taken into account when optimizing the perfusion channel size and separation. We validated the hypothesis by experiments. We fabricated circular microchannels (r = 400 microm) in 3D cell-laden hydrogel constructs (R = 7.5 mm, volume = 5 ml). These channels were positioned either individually or in parallel within hydrogels to increase nutrient and oxygen transport as a way to improve cell viability. We quantified the spatial distribution of viable cells within 3D hydrogel scaffolds without channels and with single- and dual-perfusion microfluidic channels. We investigated quantitatively the cell viability as a function of radial distance from the channels using experimental data and mathematical modeling of diffusion profiles. Our simulations show that a large-channel radius as well as a large channel to channel distance diffuse nutrients farther through a 3D hydrogel. This is important since our results reveal that there is a close correlation between nutrient profiles and cell viability across the hydrogel.

  View details for DOI 10.1007/s00216-009-2935-1

  View details for Web of Science ID 000268866800021

  View details for PubMedID 19629459