Shona Pek, Wu Hong, and Jackie Y. Ying

We have developed several methods of synthesizing nanocomposite biomaterials with controllable microstructure and composition. This enables us to incorporate and deliver substances such as drugs, proteins, growth factors, cells and organic dyes via membrane or scaffold platforms. For example, we have developed microspheres for sustained and/or delayed release of small drugs and growth factors. We have also developed transparent microemulsion-based membranes with tunable properties as the world’s first photochromic contact lenses.

Joo Eun Chung, Motoichi Kurisawa, Susi Tan and Jackie Y. Ying

This research aims to develop smart and safe polymer-based carriers to target small molecular anticancer drugs specifically to tumor cells. Novel core-shell polymer nanoparticles are synthesized from functional biodegradable polymers with well-defined molecular weights and functionalities. The nanoparticles have nanosize and a narrow size distribution, and are tailored for high loading of various types of drug molecules. The shell of the nanoparticles contains biological ligands that can specifically recognize receptors over-expressed on cancer cell surfaces. These nanoparticles provide a platform for controlled delivery of a variety of anticancer drugs.

Shona Pek, Shujun Gao, Shariff Arshad and Jackie Y. Ying

Large amounts of lost bone are usually replaced by a variety of grafts or permanent alloy implants. The aim of this project is to create a composite bone scaffold material that has sufficient strength to support patients' lifestyles, and bioactivity to promote cell attachment and proliferation. This scaffold would be resorbable by natural tissue, with tunable mechanical properties and degradation rates. Two research challenges are the introduction of macroporosity and mechanical strength for load-bearing applications. IBN's research strategy involves creating a nanocomposite foam of collagen fibers and apatite nanocrystals. Preliminary in vitro studies with MC3T3 osteoblast cells indicate excellent cell attachment and proliferation on this scaffold. Ectopic in vivo implantation on SCID mice shows evidence of bone, tissue and blood vessel formation in the scaffold material. In addition, in vivo implantation of this scaffold material into critical-sized defects in the femur of Wistar rat and the tibia of Yorkshire-Landrace pigs resulted in successful healing and functioning of the defect areas without the need for an external supporting cast.

Yar Oo Zay, Farah Tasnim, Ming Ni, Karthikeyan Kandasamy, Rensheng Deng, Mohammed Shahrudin Bin Ibrahim, Jackie Y. Ying and Daniele Zink

Artificial kidneys are widely used to treat patients suffering from renal failure but are unable to replicate many of the physiological functions of the kidney. As such, this treatment is associated with high rates of morbidity and mortality. IBN’s bioartificial kidney incorporates a layer of human kidney cells on specially designed hollow fiber membranes. The cells can perform the metabolic, transport and endocrinologic functions of the kidney, which are lacking in conventional treatment. IBN is also developing a device that delivers the growth factor bone morphogenetic protein-7 to kidney patients. We are now seeking industrial collaborations to commercialize our bioartifical kidney project.

Yao Li, Began Gopalan, Yong Yeow Lee, Jackie Y. Ying and Daniele Zink

The lack of predictive toxicity screening technologies is a major cause of failure for current drug and cosmetic development. The kidney is a major target organ for drug-induced toxic effects, and validated or approved in vitro assays for the prediction of nephrotoxicity are not available. We are developing screening technologies for the prediction of nephrotoxicity in humans based on our expertise in kidney tissue engineering and stem cell technology. Our two-dimensional (2D) and 3D in vitro models are based on human primary renal cells or human stem cell-derived cells with similar properties. Results obtained with larger numbers of clinically well-characterized drugs showed that nephrotoxicants can be identified with high sensitivity and specificity. Currently the technology is adapted to IBN’s DropArray™ platform for high-content screening. In addition, we will explore the suitability of our renal models for nanotoxicology. Co-culture models and tissue-like models for studying the invasion of renal and other tissues by nanoparticles are also being developed.

Benjamin Tai, Shona Pek, Karthikeyan Narayanan, Chan Du, James Hsieh, Meng Fatt Leong, Jerry Toh, Hongfang Lu, Andrew Wan and Jackie Y. Ying

Tissue engineering requires the use of a structural framework to support the adhesion and growth of cells. In addition to acting as a structural template, scaffolds provide the opportunity for the presentation of biological molecules that regulate the proliferation and differentiation of cells into tissue structures. This is especially important in conjunction with the use of stem and progenitor cells. Most of the current processes for the production of tissue scaffolds are incompatible with the incorporation of biological molecules, specifically proteins, due to the severity of conditions involving the use of high temperatures and organic solvents. We are developing procedures for making scaffolds by polyelectrolyte complexation, which is inherently more suitable for the presentation of biologics due to the milder, aqueous-based synthesis. The characteristics of these scaffolds are optimized to capitalize on the activity of various biological factors with respect to tissue development. By culturing differentiated embryonic and mesenchymal stem cells on these scaffolds, we are working towards therapies for liver failure and diabetes Type I. Another important effort in our group is the development of 3D matrices, to more closely mimic the natural environment of the cell for in vitro models.

James T. M. Hsieh, Karthikeyan Narayanan, Meng Fatt Leong, Jerry Toh, Andrew Wan and Jackie Y. Ying

It has been discovered that cells behave differently in a flat layer than in complex, three-dimensional tissue. Cell studies in 3D may be more physiologically relevant as the 3D environment more closely resembles living tissue. However, few existing methods have been able to provide the required degree of control to spatially pattern cells in 3D. IBN is developing various new bioartificial devices using the 2-photon stereolithography laser system. These new devices are designed to closely resemble the natural cell architecture by incorporating biochemical cues onto material surfaces. In addition, these miniaturized devices are made from biodegradable materials, thus offering the potential for implantation.

Ming Ni, Karthikeyan Narayanan, Karthikeyan Kandasamy, Yar Oo Zay, Andrew Wan, Jackie Y. Ying and Daniele Zink

Clinical applications of human stem cells require large cell numbers and cell growth under chemically defined conditions. Appropriate in vitro culture systems should include synthetic substrates that support stem cell growth in combination with media that do not contain any components purified from humans or animals. Large-scale applications of expensive materials, such as peptide-based substrates, are cost-prohibitive. We are developing cost-effective and fully synthetic coatings that can be applied to flat synthetic substrates and microcarriers. Large-scale expansion of human embryonic stem cells (hESCs), induced pluripotent stem cells (hiPSCs) and mesenchymal stem cells (hMSCs) on these substrates is addressed by using serum- and xeno-free media. The results reveal that on our current substrates, different types of human stem cells can be propagated for at least 10 passages without karyotypic changes, while maintaining their cell type-specific properties in terms of self-renewal and potency.

Nandanan Erathodiyil, Yong Wang, Karthikeyan Narayanan and Jackie Y. Ying

Cell separation has become an essential tool for a wide variety of biomedical applications. It is important to attain the cell populations of interest in high purity from mixed cell populations for use in therapeutics and diagnostics. Antibodies can serve as molecules targeting specific membrane proteins on certain cell types. Our approach in cell separation utilizes targeting ligands with magnetic nanoparticles and quantum dots. For example, we have used glucosamine in the separation of insulin-secreting beta cells. The differential binding affinity of Glut2 towards glucosamine is employed to target and separate insulin-secreting beta cells from a mixed population of cells. Cell sorting was achieved by magnetic cell manipulation or FACS. We are currently developing a variety of small molecules to target other cell types such as neurons.

Kwong Joo Leck, Jun Hui Soh, Somenath Roy, Jackie Y. Ying and Charlotte Hauser

G-protein coupled receptors (GPCRs) belong to one of the most important protein classes responsible for signaling. GPCRs are able to signal through several G-protein pathways and through G-protein-independent pathways mostly in a ligand-specific manner. They are directly involved in a variety of physiological processes such as sensing, learning and memory, but they are also coupled to body functions such as cardiac, urinary, gastrointestinal and endocrine functions. Therefore, GPCRs are one of the most attractive classes of receptors for drug design and are direct targets of more than 50% of clinically prescribed medicine. We are interested in GPCRs for the development of biosensors to design medical and environmental diagnostic devices. Our focus is on (1) human serotonin receptors (2) odorant receptors from zebrafish and (3) Wnt receptors, Frizzleds (FZDs). We are experienced in expression and characterization of proteins, and in particular membrane proteins. Our goal is to provide more detailed structural knowledge of the GPCRs for the design of ultrasensitive devices and to screen for novel drugs.

Xiaojun Chen, Yanbing Zu, Hua Wang, Somenath Roy, Yanfen Peng, Jun Hui Soh and Jackie Y. Ying

Ultrasensitive detection of DNA down to femtomolar concentration provides promising applications in the diagnosis of genetic and infectious diseases, forensic investigation, and environmental monitoring. This project aims to develop novel amplification schemes to realize PCR-free detection of nucleic acids. In order to achieve this objective, we are developing signal amplification strategies by functionalizing catalytic nanoparticles, optical nanoparticles, enzymes and DNAzymes for the electrical/electrochemical detection of nucleic acids. In particular, the combination of specific recognition of aptamer and amplification power of DNAzyme opens new perspective for ultrasensitive detection of biomolecules. The biosensors are integrated with microfluidic systems as compact and portable devices for point-of-care applications.

Somenath Roy, Yanbing Zu, Hua Wang and Jackie Y. Ying

The rapid growth of molecular diagnostics and therapeutics demands more accurate, robust and cost-effective techniques for nucleic acid analysis. Our group is focused on the development of new and improved diagnostic and drug screening tools. We are developing functionalized gold nanoprobes that allow for the accurate and cost-effective DNA analysis for genotyping and DNA-based pathogen detection. We are also establishing a microfluidic array with a flow convection-induced assay for point-of-care quantification of the expression levels of specific miRNAs linked to diseases such as cancer, preeclampsia, diabetes, cardiovascular and autoimmune diseases. Using electrobiochemical biosensors, we are investigating drug-induced cleavage or intercalation of DNAs/RNAs for point-of-care drug screening.

Guolin Xu, Saravana Kumar, Rensheng Deng, Min-Han Tan and Jackie Y. Ying

Our Lab-on-a-Cartridge system can extract DNA and RNA automatically from tissue or body fluid samples and detect the presence of up to 100 target genes within two hours. The capability of the cartridge to rapidly and accurately detect diseases in a self-contained environment makes it a superior platform for typing and sub-typing infectious diseases such as influenza. Since our system is able to process tissue sample directly, it may also be used to detect diseases such as cancer at the early stage from tumor tissue.

Yong Yeow Lee, Jianhao Bai and Jackie Y. Ying

This research aims to develop a fully integrated, automated diagnostic platform for point-of-care applications. Using this technology, we miniaturize and simplify standard enzyme-linked immunosorbent assays (ELISAs) into lateral flow assays (LFAs) for performing in vitro diagnostic tests. We envision that this technology allows the analysis of multiple analytes from a single finger prick of blood. The results can be interpreted semi-quantitatively by the naked eye. Applications for this technology include screening of cancer, infectious diseases and other diseases.

Yugen Zhang, Michael Reithofer, Liuqun Gu, Dingyi Yu, Siti Nurhanna Riduan, Mei Xuan Tan, and Jackie Y. Ying

Green chemistry is the design of chemical products and processes that reduce or eliminate the use and generation of hazardous substances. To achieve this target, we are interested in the development of novel green and environmentally friendly technology for organic synthesis and the pharmaceuticals industry. Our research is focused on metal-free organo catalysis, sustainable resources (e.g. using CO₂ as C1 resource), and environmentally benign catalysis (e.g. non-toxic, inexpensive iron catalysts and water-mediated reactions). We are also interested in the development of alternative and renewable energy resources and technologies through the use of novel catalyst systems. This includes creating highly efficient and highly selective catalyst systems for the dehydration of biomass into chemicals, fuels and materials. We are also working on transforming greenhouse gases such as carbon dioxide into useful chemicals or fuels such as methanol.

Jinhua Yang, Xianfeng Yang, Xiaojun Chen and Jackie Y. Ying

Fuel cells and batteries based on nanocomposite materials have attracted significant attention. Our research is focused on the synthesis of a variety of inorganic nanostructures with designed compositions and morphologies for fuel cell and battery applications. These novel materials possess excellent catalytic activity, and are promising for use in highly efficient and low-cost fuel cell and battery systems.

Yugen Zhang, Ting Lu, Liuqun Gu, Siti Nurhanna Riduan, Leng Leng Chng, Nandanan Erathodiyil and Jackie Y. Ying

Heterogeneous catalysis has many advantages over homogeneous catalysis. However, there are certain limitations on current protocols for producing heterogeneous catalysts via the immobilization of homogeneous catalysts onto inorganic or organic solid supports. This project aims to develop a new type of supported catalysts based on mesoporous silica and polymers, and organic-inorganic nanocomposites. This research will focus on the development of new materials and new chemistry. Organocatalysts, organometallic catalysts or biocatalysts will be investigated. The aim of this study is to build new catalyst support platforms to develop highly efficient catalyst systems. The target heterogeneous catalysts will allow for the synthesis of pharmaceuticals with superb activity, excellent enantioselectivity and recyclability. They will also enhance efficiency in the production of pharmaceuticals and specialty chemicals.

Nandanan Erathodiyil, Nor Lizawati Ibrahim, Yong Wang, Leng Leng Chng and Jackie Y. Ying

The reproducible growth and differentiation of pluripotent stem cells are one of the frontiers in modern tissue engineering and regenerative medicine. Of prime importance is the development of functional scaffolds that present the appropriate chemical, physical and biological cues so that they can interact effectively with living cells and encourage the development of new tissues. The heterogeneity of animal-derived cell culture substrates leads to variability in the responses of cultured cells, and the carryover of pathogens or immunogens complicates the use of human cells in therapeutic applications. The ideal scaffold should be biocompatible, non-immunogenic, pathogen-free, biochemically defined and support the regeneration of specific tissue types. We are developing chemically well-defined synthetic functional substrates that support embryonic stem cell passage or differentiation, with the aim of overcoming the disadvantages of current cell culture substrates. These synthetic polymer-based materials would offer great versatility in controlling chemical structure, molecular weight, mechanical strength and specific functions to mimic cellular environments. They are safe, versatile and may replace complex biological matrices of animal origin for applications in cell culture, tissue engineering, drug delivery, biosensors and regenerative medicine.