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A Macromolecular Approach to Eradicate Multidrug Resistant Bacterial Infections While Mitigating Drug Resistance Onset

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A Macromolecular Approach to Eradicate Multidrug Resistant Bacterial Infections While Mitigating Drug Resistance Onset

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Nanomedicine and Biomaterials

Research > Nanomedicine and Biomaterials

Antiviral Polymers with Broad-Spectrum Activity, High Selectivity and Resistance Mitigation

Chuan Yang, Shujun Gao and Yi Yan Yang

Treatment of viral infections continues to be challenging due to the variance in viral structure (RNA, DNA, enveloped and non-enveloped viruses) and their ability to rapidly mutate and garner resistance. We have developed a general strategy to prevent viral infection using multi-functional macromolecules that were designed to have mannose moieties that compete with viruses for immune cells, and basic amine groups that block viral entry through electrostatic interactions and prevent viral replication by neutralizing the endosomal pH. These macromolecules effectively prevented dengue, influenza, Chikungunya, Enterovirus 71, Ebola, Marburg and herpes simplex infections at polymer concentrations as low as 0.2 mg/L with very high selectivity (> 5000) over mammalian cells. As the antiviral mechanism is based on non-specific supramolecular interactions between the amino acid residues and mannose/cationic moieties of the macromolecule, repeated use of the molecules did not induce drug resistance development. These macromolecules are being tested for in vivo efficacy.

CAR-Grafted Immune Cell Therapeutics for Cancer Immunotherapy

Jieming Zeng and Shu Wang

Chimeric antigen receptor (CAR)-modified immune cell therapy has achieved a significant advance in combating blood cancer and is highly promising for the treatment of solid tumors. Since CAR-grafted alpha beta T-cells concurrently express endogenous T cell receptors (TCRs) in the same T cells, uncontrolled graft-versus-host effects may be produced when used allogeneically. We aim to develop off-the-shelf, allogeneic CAR-grafted, anti-cancer cell therapeutics and focus on natural killer (NK) cells and gamma delta T-cells. Our goal is to translate the research findings in the laboratory into clinical products that can benefit patients.

Injectable Biodegradable Hydrogels for Drug Delivery and Tissue Engineering

Ki Hyun Bae, Atsushi Yamashita, Li Li, Shengyong Ng, Kun Liang, Joo Eun Chung and Motoichi Kurisawa

Hydrogels are soft materials with high water content. IBN researchers have developed a novel gel that can encapsulate therapeutic proteins, growth factors and cells for drug delivery and tissue regeneration. The hydrogels are biodegradable, made of non-toxic materials and can be injected into the body. They can regulate the rate of drug release in the body over a specific period, and reduce the need for frequent injections. These new materials show tremendous potential for improved treatment of cancer and neurological disorders. They can also be used as a scaffold to grow new tissues.

Macromolecular Antimicrobials to Combat Microbes

Chuan Yang, Shrinivas Venkataraman, Xin Ding, Shaoqiong Liu, Jeremy Tan, David Voo, Zhen Chang Liang, Eddy Tan, Shujun Gao, Yuan Yuan, Diane Lim, Hong Wu, Jackie Y. Ying, Yugen Zhang and Yi Yan Yang

The increasing prevalence of antibiotic-resistant infections, such as Methicillin-resistant Staphylococcus aureus (MRSA), has sparked off a pressing need for innovative antimicrobial treatments. IBN has developed a new class of antimicrobial polymers and peptides that can provide a new arsenal against superbugs. Most modern-day antibiotics act on specific molecular targets within the bacteria. While this yields therapeutic specificity, it also allows resistance development through mutation since the bacterial cell structure is generally preserved. The antimicrobial macromolecules are biodegradable and biocompatible, and have broad-spectrum antimicrobial activities against bacteria, yeast and fungi, to destroy multidrug-resistant microbes and prevent drug resistance development.

Polymeric Nanoparticles for Targeted Drug Delivery towards Cancer Cells and Cancer Stem Cells

Shaoqiong Liu, Ashlynn Lee, Chuan Yang, Shujun Gao and Yi Yan Yang

We aim to develop safe polymer-based nanocarriers with narrow size distribution, high drug loading capacity and in vivo stability to transport small molecular anti-cancer drugs to cancer cells and cancer stem cells that are responsible for tumor relapse and metastasis. Biodegradable polymer nanoparticles that can interact with the drugs have been synthesized. A number of platform technologies have been developed to deliver a variety of drugs, proteins and genes. In particular, the co-delivery of dual drugs has been demonstrated to effectively suppress tumor growth by eliminating both cancer cells and cancer stem cells. These co-delivery nanosized formulations have the potential to improve cancer therapy, and prevent relapse and metastasis.

Using Green Tea Nanocomplex to Fight Cancer

Joo Eun Chung, Kun Liang, Nunnarpas Yongvongsoontorn, Atsushi Yamashita, Ki Hyun Bae, Shengyong Ng, Lucky Swarnalatha Sasidharan, Min-Han Tan and Motoichi Kurisawa

Green tea has long been known for its anti-oxidant, anti-cancer, anti-aging and anti-microbial properties. IBN has taken the health benefits of green tea to the next level by using one of its key compounds, epigallocatechin gallate (EGCG), to develop micellar nanocomplexes for delivering anti-cancer protein drugs. The nanocarrier is formed by complexation of oligomerized EGCG with the protein drugs to form the core, followed by complexation of poly(ethylene glycol)–EGCG to form the shell. The micellar nanocomplexes protect the protein drugs from rapid proteolysis and renal clearance, while providing for tumor targeting. This green tea nanocarrier reduces tumor growth more effectively than using the drug by itself. We are also exploring the delivery of active ingredients in personal care and nutritional products using the micellar nanocomplexes.

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Tissue and Organoid Models

Research > Tissue and Organoid Models

Biomaterials for Cell Reprogramming

Hongfang Lu and Andrew Wan 

Cell plasticity refers to the ability of cells to be reprogrammed to other cell types, including stem cells. Our research efforts are focused on two fronts. First, we are trying to replace the more conventional cell reprogramming method, which typically involves genetic modification of cells, with transgene-free and xeno-free methods that dispense with the use of animal products. Through this, we hope to develop a safer source of cells for use in regenerative medicine. Our second research focus is on investigating the role of the cellular microenvironment in the reprogramming of cancer cells. We have shown that the extracellular matrix and 3D environment combine to influence the stemness of glioma cells, which is typically associated with the cells’ self-renewal and drug-resistance properties. This information would be useful in developing new cancer therapies.

Digital Livers: Quantitative Analysis of the Dynamic Processes of Liver Regeneration and Chronic Liver Diseases

Ziwei Song, Yu Yang and Hanry Yu 

We have developed optical imaging modalities to quantify cellular and extracellular changes in tissues. The instruments and machine-learning based image-processing/feature analysis algorithms developed are used to automate and improve pathological examinations related to (i) liver fibrosis, (ii) cholestasis and (iii) non-alcoholic fatty liver diseases. This helps to shed light on the etiology of the diseases quantitatively. We have developed a high-throughput tissue imaging platform to quantify tissue/cell and matrix features of big blocks of tissue in mice or the entire biopsy sample at molecular and cellular resolutions for 3D characterization of disease progression. We have spun off an award-winning company, HistoIndex Pte Ltd, from this project, and licensed key technologies to another start-up company, InvitroCue Pte Ltd, to create an impact in the digital pathology and telemedicine landscape. The team is also investigating the fundamental process of liver regeneration by quantifying and modeling the mechanical and biochemical regulation of the cellular hypertrophy.

Drug Testing Platforms: Development of Robust, Inexpensive, Scalable and Predictive Assays for Safety Testing of Drugs and Chemicals

Farah Tasnim, Xiaozhong Huang and Hanry Yu 

Cell-based assays for in vitro toxicity evaluation are attracting increasing attention from institutions and companies involved in the development of drugs and industrial chemicals. The major bottlenecks are the lack of stable human primary cells, and cell-culture models that recapitulate the in vivo physiological responses to the tested compounds. So far, only the sandwich culture of liver cells is accepted by the Federal Drug Administration (FDA) for routine hepatotoxicity testing of drugs. To improve the cell-based assays, we have developed (i) a scalable aligned substrate on optical media, (ii) two improved spheroid models for acute and chronic toxicity testing, respectively, (iii) a co-culture model for idiosyncratic toxicity, (iv) three perfusion-based models for improved sensitivity to detect metabolites, (v) a developmental toxin based on morphogenic migration of human stem cells, and (vi) stable and robust cell sources from human stem or progenitor cells. We are validating these established models for hepatotoxicity and teratogen testing of compounds, and improving the performance of these platforms for robustness, predictive fidelity, scalability and cost. We are also extending the applications of these models to sub-acute/chronic hepatotoxicity in order to better mimic “in vivo-like” conditions.

Engineering Complex Tissues: Spatial and Temporal Control of Microenvironment

Zheng Liu (Justinian), Farah Tasnim and Hanry Yu 

Complex tissues with multiple cell types will be engineered by controlling cell-cell and cell-matrix interactions through (i) engineering inter-cellular linkers for 3D printing, (ii) engineering cellular response to the chemical and mechanical signals by developing ultra-soft macroporous sponges that are robust, transparent, degradable and enhancing compact spheroid formation, and (iii) fabricating relevant 3D microfluidics, micro-patterns and ultra-thin porous membranes incorporating mechanical compaction and multiple cell types for organ-on-a-chip applications, such as a liver cancer chip to aid chemotherapy testing. This project establishes the fundamental principles, toolboxes and devices to precision-engineer micro-tissue constructs of different cell types and inter-cellular tissue space (such as sinusoid and bile canaliculi in liver) for repeated dose testing of compounds that require mid-term (> 2-4 weeks) or long-term (up to 6 weeks) culture of micro-tissue constructs.

Fibrous Scaffolds for Tissue Engineering

Tze Chiun Lim, Chan Du, Yihua Loo, Wei Yang Seow, Benjamin Tai , Andrew Wan 

Tissue engineering requires the use of a framework or scaffold for cells to attach and grow. In addition, scaffolds may contain biological molecules, which control the rate of cell growth and propensity of stem cells to differentiate into cells of specific tissues and organs. Most of the current processes for the production of tissue scaffolds require high temperatures and organic solvents, which may denature the proteins and other biological molecules to be incorporated. In this project, we are fabricating scaffolds by encapsulating cells and the relevant biological molecules into fibers that are formed at the interface between two oppositely charged polyelectrolytes. These fibers are then combined to form 3D patterned tissue constructs.

New Alternative Methods for the Prediction of Chemical- and Nanomaterial-Induced Toxicities in Humans

Jacqueline Chuah, Faezah Hussain and Daniele Zink 

New alternative methods for toxicity prediction are required by the pharmaceutical, chemical, food and consumer care industries. Currently, there are no accepted alternative methods for the prediction of toxicities for human internal organs, such as the kidney and liver. We are developing robust screening platforms that predict toxicities to human internal organs with high sensitivity and accuracy (test balanced accuracy > 80%). Our methods include several novel technologies, such as the first in vitro assay that predicts nephrotoxicity in humans with high accuracy, the first stem cell-based predictive renal screening platforms, and the first predictive kidney-specific high-throughput platform. Our kidney-specific technologies have been awarded by the US Society of Toxicology (2015) and have won the Lush Prize (2016, Science category). The renal high-throughput platform is applied in collaboration with the US Environmental Protection Agency for the prediction of the human nephrotoxicity of ToxCast compounds. Our high-throughput technology is currently adapted for the prediction of other organ-specific toxicities. A liver-specific platform has been established, and a vasculature-specific platform is under development. Our methods can also be applied for the prediction of chemical- as well as nanomaterial-induced toxicities.

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Synthetic Xenobiology and Biosystems

Research > Synthetic Xenobiology and Biosystems

Antibody Engineering for Rapid Diagnostic Tests

Thai Leong Yap, Huajing Wang, Shin Yee Hong and William Sun 

Rapid tests for the detection of infectious diseases can provide diagnosis at the point-of-care setting, enabling speedy and proper patient management. Rapid diagnostics, such as the lateral flow strip, require high-quality antibodies. We use a variety of engineering methods to isolate antibodies specific for pathogen proteins. These antibodies can then be incorporated into suitable assay platforms for the development of diagnostic tests. Our efforts are focused on generating rapid tests for diagnosing infections prevalent in Southeast Asia, such as dengue fever and Zika.

Biomimetic Ultrashort Peptide Hydrogel Scaffolds for Tissue Engineering

Yihua Loo, Wei Yang Seow and Andrew Wan 

IBN researchers have designed a unique class of ultrashort peptides of only 3 to 7 aliphatic amino acids that self-assemble into nanofibrous hydrogels in aqueous conditions. These hydrogels are attractive materials for tissue scaffolds, as their microarchitecture resembles extracellular matrix in the body. The hydrogels also possess mechanical strength that far exceeds that of soft tissue in the human body, but can be tuned to the desired strength, enabling the biofabrication of 3D organotypic constructs for disease modeling or implantation. Harnessing their propensity for self-assembly and taking advantage of their mechanical rigidity, these peptides are of interest as bioinks for 3D bioprinting, injectable scaffolds for regenerative medicine, synthetic 3D matrices for stem cell culture, and wound dressing for burn treatment.

Chemically Modified Glycomimetics as Molecular Scaffolds

Song-Gil Lee, Teck Chuan Lim and Su Seong Lee 

Although carbohydrates mediate important biological processes in the human body, their structural complexity and diversity have hindered efforts to understand their defined biological roles. Synthetic access to carbohydrate molecules of defined structure, in combination with biological studies, could provide unique tools for a systematic examination of structure-activity relationships. We are interested in developing structurally well-defined carbohydrate mimetics via synthetic approaches. These synthetic carbohydrate mimetics would pave the way for the development of carbohydrate-based drugs, vaccines, adjuvants, as well as novel biomaterials.

Circulating Tumor Cell Isolation for Non-Invasive Cancer Diagnosis and Prognosis

Min Hu, Jamie Mong, Jun-Li Shi, Min-Han Tan and Jackie Y. Ying 

Circulating tumor cells (CTCs) are cells that detach from a primary tumor and travel in the bloodstream to other locations, leading to the spread of tumor in the body. Catching and analyzing CTCs can further our understanding of cancer metastasis and enhance the treatment of cancer patients. However, CTCs are very rare compared to the large number of blood cells in the body, and there is a lack of universal cancer cell biomarkers to distinguish them from other circulating cells. Based on size and deformability selection, IBN’s microsieve devices enable the effective isolation of circulating tumor cells from patients’ blood samples in minutes without the use of costly reagents and complex instruments. The microsieve technology permits a simple workflow, with rapid separation and cell characterization on the same device. Intact and viable isolated CTCs can be easily eluted for molecular diagnosis, drug screening and assay development.

Development of Peptides with High Binding Affinity and High Specificity for Diagnostic and Therapeutic Applications

Joo-Eun Jee, Yong Siang Ong and Su Seong Lee 

Currently, antibodies are widely used for detecting protein biomarkers, but their high cost and chemical instability are major issues. Using synthetic peptides, IBN is developing high-affinity, highly specific capture agents for biomarkers of infectious diseases, such as dengue and Zika. The protein capture agents can be produced by screening bead-based D-peptide libraries in a high-throughput platform. Compared to antibodies, these synthetic peptides are highly stable and inexpensive, making them ideal as protein capture agents for in vitro diagnostic devices, immunohistochemistry and flow cytometry. These peptides can also be used for therapeutic purposes.

Genetic Alphabet Expansion using Unnatural Base Pair Systems

Michiko Kimoto, Itaru Okamoto, Kiyofumi Hamashima, Ken-ichiro Matsunaga and Ichiro Hirao 

The genetic information flow of the central dogma relies on only four nucleobases, which in turn constrains the Darwinian evolution of nucleic acids and proteins as functional molecules. IBN is developing a genetic alphabet expansion technology of DNA by creating extra base pairs, called unnatural base pairs. The unnatural base pairs exhibit high fidelity and efficiency in replication and/or transcription as a third base pair. The unnatural base pair systems can be used in a wide variety of biotechnology applications, such as PCR detection and aptamer generation.

High-Affinity DNA Aptamer Generation

Michiko Kimoto, Itaru Okamoto, Kiyofumi Hamashima, Nur-Afidah Binte Mohamed Suhaimi, Ken-ichiro Matsunaga and Ichiro Hirao 

IBN has successfully generated high-affinity DNA aptamers that bind to target proteins and cells by a new evolutionary engineering method called ExSELEX (genetic alphabet Expansion for Systematic Evolution of Ligands by EXponential enrichment) using our unnatural base pair technology. We have also created another technology, called mini-hairpin, to stabilize high-affinity DNA aptamers against heat and nucleases. We are developing diagnostic and therapeutic methods using these new technologies for cancer and infectious diseases.

Peptide Tags for Live Cell Imaging

Joo-Eun Jee and Su Seong Lee 

A universal tagging method for fluorescence probes is important for imaging complex biological events through live cell imaging. The current tagging methods employing fluorescence proteins, such as green fluorescent protein, have some disadvantages, including interference of the bulky fluorescence tags in the physiological activities of the target proteins. Many research groups have been developing smaller probes to overcome this problem. In this project, we aim to develop small peptide tags that can bind strongly and selectively to a specific fluorescence dye. The identified peptide tags can be genetically incorporated into target proteins and bind specifically to the fluorescent dyes for imaging purpose. In particular, we are targeting intracellular imaging using fluorescence dyes with cell-penetrating ability.

Practical Assays Predicting Diagnosis, Drug Response and Prognosis in Oncology

Michelle Pek, Jamie Mong, Jun Li Shi and Min-Han Tan 

We focus on developing practical assays that will be deployed in the clinic. We are interested in developing working assays for predicting outcomes in lung, breast, renal and colorectal cancers, as well as for adverse drug reactions in non-oncological settings. To support assay development, we work with patient-derived material and create customized animal models.

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Green and Safe Biomaterials

Research > Green and Safe Biomaterials

Eco-Friendly Antimicrobial Materials and Antimicrobial Resistance Mitigation

Yuan Yuan, Diane Lim and Yugen Zhang 

Antimicrobial resistance (AMR) is one of the most critical challenges in our modern society. The overuse of antibiotics, including its use in non-therapeutic applications, such as agriculture and environmental disinfection, represents one of the main causes of antimicrobial resistance. IBN has developed a series of novel non-resistant, eco-friendly antimicrobial oligomers and polymers with broad-spectrum antimicrobial activities against bacteria, yeast and fungi. These have synergistic effect with small molecular antibiotics and prevent drug resistance development. Our novel antimicrobial materials will self-destruct after treatment, leaving no active residue that can lead to secondary environmental contamination. This is especially meaningful in the context of agricultural applications, topical use and environmental disinfection.

Green Synthesis, Care Chemicals and Functional Materials

Xiukai Li, Jinquan Wang, Diane Lim, Siew Ping Teong, Wei Lun Toh and Yugen Zhang 

IBN’s green synthesis research involves the use of sustainable resources for the environmentally friendly synthesis and investigation of green and benign chemical processes for the specialty chemicals industry. IBN researchers are developing green and safe chemicals for consumer care, healthcare and the food and nutrition industries. IBN is also creating functional materials for a broad range of applications including environmental, healthcare and medical applications.

Inorganic Nanomaterials for Antimicrobial Applications

Guangshun Yi, Siti Nurhanna Riduan, Yuan Yuan, Xiukai Li, Siew Ping Teong and Yugen Zhang 

IBN has developed inorganic and non-toxic antimicrobial materials specifically for surface disinfection and consumer care applications. Our antimicrobial technologies kill microbes either by physically rupturing their cell membranes or by a radical killing mechanism, which prevents the microbes from developing drug resistance and mutating into superbugs. Our nanomaterials are inexpensive to produce, environmentally friendly and safe. They are effective against a wide range of microbes and would be a powerful weapon against superbugs.

Phase-Selective Organogelators for Oil Spill Treatment

Changliang Ren and Huaqiang Zeng 

Marine oil spills can cause devastating and lasting damage to the environment and ecosystem, and are difficult to clean up using currently available oil-control techniques. We are developing cost-effective organogelators that can phase-selectively congeal oil from oily water, and allow easy separation of the gelled oil from water. It is made up of small organic molecules that can instantly self-assemble into nanofibers to form a 3D net that traps the oil molecules into clumps that can be skimmed off the water surface. This is a novel solution to clean up polluted water caused by oil spills.

Water Channel-Based Biomimetic Membranes for Water Desalination

Jie Shen, Feng Chen, Changliang Ren, Arundhati Roy and Huaqiang Zeng 

Commercial use of water-transporting aquaporins has been explored for wastewater reclamation and re-use as well as seawater desalination. However, significant challenges associated with manipulating channel proteins in terms of complexity, stability, scalability and activity reconstitution still remain. An alternative strategy is to design small molecule-based synthetic water channels that can mimic aquaporins in functionality for various water purification applications. Towards this goal, we are developing synthetic water channel-based membranes to desalinate seawater with higher salt rejection rates at much lower pressures than the current seawater reverse osmosis technology. These novel biomimetic membranes could form the basis for the next generation of water purification technology with less energy consumption and better performance. In addition, the low production cost of the membranes makes it attractive for other potential applications, such as pharmaceutical separations, artificial skin and kidney.