Dr. Lyu is a postdoctoral scholar in the Department of Neurosurgery at Stanford University. He obtained his PhD at Soochow University, China, where he gained training in Biomedical Engineering and led multidisciplinary research under the advice of Prof. Hong Chen. During his PhD, he worked as a visiting student researcher at Canary Center at Stanford for Early Cancer Detection where he gained training in microfluidics and cancer metastasis.
Under the guidance of Prof. Jon Park and Dr. Wonjae Lee, the overall goal of Dr. Lyu’s research is to develop an in vitro microphysiological model of ischaemic stroke and use it as a platform to systematically evaluate the neurorestorative potential of stem cell therapy.
Doctor of Philosophy, Soochow University, Biomedical Engineering (2017)
A neurovascular-unit-on-a-chip for the evaluation of the restorative potential of stem cell therapies for ischaemic stroke.
Nature biomedical engineering
The therapeutic efficacy of stem cells transplanted into an ischaemic brain depends primarily on the responses of the neurovascular unit. Here, we report the development and applicability of a functional neurovascular unit on a microfluidic chip as a microphysiological model of ischaemic stroke that recapitulates the function of the blood-brain barrier as well as interactions between therapeutic stem cells and host cells (human brain microvascular endothelial cells, pericytes, astrocytes, microglia and neurons). We used the model to track the infiltration of a number of candidate stem cells and to characterize the expression levels of genes associated with post-stroke pathologies. We observed that each type of stem cell showed unique neurorestorative effects, primarily by supporting endogenous recovery rather than through direct cell replacement, and that the recovery of synaptic activities is correlated with the recovery of the structural and functional integrity of the neurovascular unit rather than with the regeneration of neurons.
View details for DOI 10.1038/s41551-021-00744-7
View details for PubMedID 34385693
A versatile system to record cell-cell interactions.
Cell-cell interactions influence all aspects of development, homeostasis, and disease. In cancer, interactions between cancer cells and stromal cells play a major role in nearly every step of carcinogenesis. Thus, the ability to record cell-cell interactions would facilitate mechanistic delineation of the role of cancer microenvironment. Here, we describe GFP-based Touching Nexus (G-baToN) which relies upon nanobody-directed fluorescent protein transfer to enable sensitive and specific labeling of cells after cell-cell interactions. G-baToN is a generalizable system that enables physical contact-based labeling between various human and mouse cell types, including endothelial cell-pericyte, neuron-astrocyte, and diverse cancer-stromal cell pairs. A suite of orthogonal baToN tools enables reciprocal cell-cell labeling, interaction-dependent cargo transfer, and the identification of higher-order cell-cell interactions across a wide range of cell types. The ability to track physically interacting cells with these simple and sensitive systems will greatly accelerate our understanding of the outputs of cell-cell interactions in cancer as well as across many biological processes.
View details for DOI 10.7554/eLife.61080
View details for PubMedID 33025906
- Epithelial-to-Mesenchymal Transition (EMT) and Drug Response in Dynamic Bioengineered Lung Cancer Microenvironment ADVANCED BIOSYSTEMS 2019; 3 (1)
Sulfonate Groups and Saccharides as Essential Structural Elements in Heparin-Mimicking Polymers Used as Surface Modifiers: Optimization of Relative Contents for Antithrombogenic Properties
ACS APPLIED MATERIALS & INTERFACES
2018; 10 (1): 1440–49
Blood compatibility is a long sought-after goal in biomaterials research, but remains an elusive one, and in spite of extensive work in this area, there is still no definitive information on the relationship between material properties and blood responses such as coagulation and thrombus formation. Materials modified with heparin-mimicking polymers have shown promise and indeed may be seen as comparable to materials modified with heparin itself. In this work, heparin was conceptualized as consisting of two major structural elements: saccharide- and sulfonate-containing units, and polymers based on this concept were developed. Copolymers of 2-methacrylamido glucopyranose, containing saccharide groups, and sodium 4-vinylbenzenesulfonate, containing sulfonate groups, were graft-polymerized on vinyl-functionalized polyurethane (PU) surfaces by free radical polymerization. This graft polymerization method is simple, and the saccharide and sulfonate contents are tunable by regulating the feed ratio of the monomers. Homopolymer-grafted materials, containing only sulfonate or saccharide groups, showed different effects on cell-surface interactions including platelet adhesion, adhesion and proliferation of vascular endothelial cells, and adhesion and proliferation of smooth muscle cells. The copolymer-grafted materials showed effects due to both sulfonate and saccharide elements with respect to blood responses, and the optimum composition was obtained at a 2:1 ratio of sulfonate to saccharide units (material designated as PU-PS1M1). In cell adhesion experiments, this material showed the lowest platelet and human umbilical vein smooth muscle cell density and the highest human umbilical vein endothelial cell density. Among the materials investigated, PU-PS1M1 also had the longest plasma clotting time. This material was thus shown to be multifunctional with a combination of properties, suggesting thromboresistant behavior in blood contact.
View details for DOI 10.1021/acsami.7b16723
View details for Web of Science ID 000422814400157
View details for PubMedID 29231707
Deciphering the Role of Sulfonated Unit in Heparin-Mimicking Polymer to Promote Neural Differentiation of Embryonic Stem Cells
ACS APPLIED MATERIALS & INTERFACES
2017; 9 (34): 28209–21
Glycosaminoglycans (GAGs), especially heparin and heparan sulfate (HS), hold great potential for inducing the neural differentiation of embryonic stem cells (ESCs) and have brought new hope for the treatment of neurological diseases. However, the disadvantages of natural heparin/HS, such as difficulty in isolating them with a sufficient amount, highly heterogeneous structure, and the risk of immune responses, have limited their further therapeutic applications. Thus, there is a great demand for stable, controllable, and well-defined synthetic alternatives of heparin/HS with more effective biological functions. In this study, based upon a previously proposed unit-recombination strategy, several heparin-mimicking polymers were synthesized by integrating glucosamine-like 2-methacrylamido glucopyranose monomers (MAG) with three sulfonated units in different structural forms, and their effects on cell proliferation, the pluripotency, and the differentiation of ESCs were carefully studied. The results showed that all the copolymers had good cytocompatibility and displayed much better bioactivity in promoting the neural differentiation of ESCs as compared to natural heparin; copolymers with different sulfonated units exhibited different levels of promoting ability; among them, copolymer with 3-sulfopropyl acrylate (SPA) as a sulfonated unit was the most potent in promoting the neural differentiation of ESCs; the promoting effect is dependent on the molecular weight and concentration of P(MAG-co-SPA), with the highest levels occurring at the intermediate molecular weight and concentration. These results clearly demonstrated that the sulfonated unit in the copolymers played an important role in determining the promoting effect on ESCs' neural differentiation; SPA was identified as the most potent sulfonated unit for copolymer with the strongest promoting ability. The possible reason for sulfonated unit structure as a vital factor influencing the ability of the copolymers may be attributed to the difference in electrostatic and steric hindrance effect. The synthetic heparin-mimicking polymers obtained here can offer an effective alternative to heparin/HS and have great therapeutic potential for nervous system diseases.
View details for DOI 10.1021/acsami.7b08034
View details for Web of Science ID 000409395500010
View details for PubMedID 28783314
Intracellular Delivery Platform for "Recalcitrant" Cells: When Polymeric Carrier Marries Photoporation
ACS APPLIED MATERIALS & INTERFACES
2017; 9 (26): 21593–98
The intracellular delivery of exogenous macromolecules is of great interest for both fundamental biological research and clinical applications. Although traditional delivery systems based on either carrier mediation or membrane disruption have some advantages; however, they are generally limited with respect to delivery efficiency and cytotoxicity. Herein, a collaborative intracellular delivery platform with excellent comprehensive performance is developed using polyethylenimine of low molecular weight (LPEI) as a gene carrier in conjunction with a gold nanoparticle layer (GNPL) acting as a photoporation agent. In this system, the LPEI protects the plasmid DNA (pDNA) to avoid possible nuclease degradation, and the GNPL improves the delivery efficiency of the LPEI/pDNA complex to the cells. The collaboration of LPEI and GNPL is shown to give significantly higher transfection efficiencies for hard-to-transfect cells (88.5 ± 9.2% for mouse embryonic fibroblasts, 94.0 ± 6.3% for human umbilical vein endothelial cells) compared to existing techniques without compromising cell viability.
View details for DOI 10.1021/acsami.7b06201
View details for Web of Science ID 000405159100002
View details for PubMedID 28632379
Synthetic Glycopolymers for Highly Efficient Differentiation of Embryonic Stem Cells into Neurons: Lipo- or Not?
ACS APPLIED MATERIALS & INTERFACES
2017; 9 (13): 11518–27
To realize the potential application of embryonic stem cells (ESCs) for the treatment of neurodegenerative diseases, it is a prerequisite to develop an effective strategy for the neural differentiation of ESCs so as to obtain adequate amount of neurons. Considering the efficacy of glycosaminoglycans (GAG) and their disadvantages (e.g., structure heterogeneity and impurity), GAG-mimicking glycopolymers (designed polymers containing functional units similar to natural GAG) with or without phospholipid groups were synthesized in the present work and their ability to promote neural differentiation of mouse ESCs (mESCs) was investigated. It was found that the lipid-anchored GAG-mimicking glycopolymers (lipo-pSGF) retained on the membrane of mESCs rather than being internalized by cells after 1 h of incubation. Besides, lipo-pSGF showed better activity in promoting neural differentiation. The expression of the neural-specific maker β3-tubulin in lipo-pSGF-treated cells was ∼3.8- and ∼1.9-fold higher compared to natural heparin- and pSGF-treated cells at day 14. The likely mechanism involved in lipo-pSGF-mediated neural differentiation was further investigated by analyzing its effect on fibroblast growth factor 2 (FGF2)-mediated extracellular signal-regulated kinases 1 and 2 (ERK1/2) signaling pathway which is important for neural differentiation of ESCs. Lipo-pSGF was found to efficiently bind FGF2 and enhance the phosphorylation of ERK1/2, thus promoting neural differentiation. These findings demonstrated that engineering of cell surface glycan using our synthetic lipo-glycopolymer is a highly efficient approach for neural differentiation of ESCs and this strategy can be applied for the regulation of other cellular activities mediated by cell membrane receptors.
View details for DOI 10.1021/acsami.7b01397
View details for Web of Science ID 000398764100023
View details for PubMedID 28287262
- Promoting neural differentiation of embryonic stem cells using beta-cyclodextrin sulfonate JOURNAL OF MATERIALS CHEMISTRY B 2017; 5 (10): 1896–1900
- A hemocompatible polyurethane surface having dual fibrinolytic and nitric oxide generating functions JOURNAL OF MATERIALS CHEMISTRY B 2017; 5 (5): 980–87
Glycosaminoglycans (GAGs) and GAG mimetics regulate the behavior of stem cell differentiation
COLLOIDS AND SURFACES B-BIOINTERFACES
2017; 150: 175–82
Glycosaminoglycans (GAGs) are linear sulfated polysaccharides that exist in most mammalian cells. By undergoing conjugation with various proteins, GAGs play important roles in a variety of bioactivities, including promoting stem cell differentiation. However, they have their own intrinsic disadvantages that limit their further applications for cell therapy and tissue engineering. Therefore, more and more GAG-mimetic materials have been studied as natural GAG analogs for emerging applications. This review explains the mechanism of how GAGs regulate stem cell differentiation and elaborates on the current progress of the applications of GAG-based materials on regulating stem cell differentiation. The types and applications of GAG-mimetic materials on regulating stem cell differentiation are introduced as well. Finally, the challenges and perspectives for GAGs and their mimetics in regulating stem cell differentiation are discussed.
View details for DOI 10.1016/j.colsurfb.2016.11.022
View details for Web of Science ID 000393726900021
View details for PubMedID 27914254
- A Universal Platform for Macromolecular Delivery into Cells Using Gold Nanoparticle Layers via the Photoporation Effect ADVANCED FUNCTIONAL MATERIALS 2016; 26 (32): 5787–95
Interactions of biomaterial surfaces with proteins and cells
Polymeric Biomaterials for Tissue Regeneration
Springer. 2016: 103–121
View details for DOI https://doi.org/10.1007/978-981-10-2293-7_5
- Bioinspired Blood Compatible Surface Having Combined Fibrinolytic and Vascular Endothelium-Like Properties via a Sequential Coimmobilization Strategy ADVANCED FUNCTIONAL MATERIALS 2015; 25 (32): 5206–13
A theranostic prodrug delivery system based on Pt(IV) conjugated nano-graphene oxide with synergistic effect to enhance the therapeutic efficacy of Pt drug
2015; 51: 12–21
Due to their high NIR-optical absorption and high specific surface area, graphene oxide and graphene oxide-based nanocomposites have great potential in both drug delivery and photothermal therapy. In the work reported herein we successfully integrate a Pt(IV) complex (c,c,t-[Pt(NH3)2Cl2(OH)2]), PEGylated nano-graphene oxide (PEG-NGO), and a cell apoptosis sensor into a single platform to generate a multifunctional nanocomposite (PEG-NGO-Pt) which shows potential for targeted drug delivery and combined photothermal-chemotherapy under near infrared laser irradiation (NIR), and real-time monitoring of its therapeutic efficacy. Non-invasive imaging using a fluorescent probe immobilized on the GO shows an enhanced therapeutic effect of PEG-NGO-Pt in cancer treatment via apoptosis and cell death. Due to the enhanced cytotoxicity of cisplatin and the highly specific tumor targeting of PEG-NGO-Pt at elevated temperatures, this nanocomposite displays a synergistic effect in improving the therapeutic efficacy of the Pt drug with complete destruction of tumors, no tumor recurrence and minimal systemic toxicity in comparison with chemotherapy or photothermal treatment alone, highlighting the advantageous effects of integrating Pt(IV) with GO for anticancer treatment.
View details for DOI 10.1016/j.biomaterials.2015.01.074
View details for Web of Science ID 000351796700002
View details for PubMedID 25770993
- Efficient cancer cell capturing SiNWAs prepared via surface-initiated SET-LRP and click chemistry POLYMER CHEMISTRY 2015; 6 (19): 3708–15
A new avenue to the synthesis of GAG-mimicking polymers highly promoting neural differentiation of embryonic stem cells
2015; 51 (84): 15434–37
A new strategy for the fabrication of glycosaminoglycan (GAG) analogs was proposed by copolymerizing the sulfonated unit and the glyco unit, 'splitted' from the sulfated saccharide building blocks of GAGs. The synthetic polymers can promote cell proliferation and neural differentiation of embryonic stem cells with the effects even better than those of heparin.
View details for DOI 10.1039/c5cc06944k
View details for Web of Science ID 000363167600020
View details for PubMedID 26344781
6-O-Sulfated Chitosan Promoting the Neural Differentiation of Mouse Embryonic Stem Cells
ACS APPLIED MATERIALS & INTERFACES
2014; 6 (22): 20043–50
Embryonic stem cells (ESCs) can be induced to differentiate into nerve cells, endowing them with potential applications in the treatment of neurological diseases and neural repair. In this work, we report for the first time that sulfated chitosan can promote the neural differentiation of ESCs. As a type of sulfated glycosaminoglycan analog, sulfated chitosan with well-defined sulfation sites and a controlled degree of sulfation (DS) were prepared through simple procedures and the influence of sulfated glycosaminoglycan on neural differentiation of ESCs was investigated. Compared with other sulfation sites, 6-O-sulfated chitosan showed the most optimal effects. By monitoring the expression level of neural differentiation markers using immunofluorescence staining and PCR, it was found that neural differentiation was better enhanced by increasing the DS of 6-O-sulfated chitosan. However, increasing the DS by introducing another sulfation site in addition to the 6-O site to chitosan did not promote neural differentiation as much as 6-O-sulfated chitosan, indicating that compared with DS, the sulfation site is more important. Additionally, the optimal concentration and incubation time of 6-O-sulfated chitosan were investigated. Together, our results indicate that the sulfate site and the molecular structure in a sulfated polysaccharide are very important for inducing the differentiation of ESCs. Our findings may help to highlight the role of sulfated polysaccharide in inducing the neural differentiation of ESCs.
View details for DOI 10.1021/am505628g
View details for Web of Science ID 000345721400072
View details for PubMedID 25300532
Stimulation of Gene Transfection by Silicon Nanowire Arrays Modified with Polyethylenimine
ACS APPLIED MATERIALS & INTERFACES
2014; 6 (16): 14391–98
In this work, a novel gene delivery strategy was proposed based on silicon nanowire arrays modified with high-molecular-weight 25 kDa branched polyethylenimine (SN-PEI). Both the plasmid DNA (pDNA) binding capacity and the in vitro gene transfection efficiency of silicon nanowire arrays (SiNWAs) were significantly enhanced after modification with high-molecular-weight bPEI. Moreover, the transfection efficiency was substantially further increased by the introduction of free pDNA/PEI complexes formed by low-molecular-weight branched PEI (bPEI, 2 kDa). Additionally, factors affecting the in vitro transfection efficiency of the novel gene delivery system were investigated in detail, and the transfection efficiency was optimized on SN-PEI with a bPEI grafting time of 3 h, an incubation time of 10 min for tethered pDNA/PEI complexes consisting of high-molecular-weight bPEI grafted onto SiNWAs, and with an N/P ratio of 80 for free pDNA/PEI complexes made of low-molecular-weight bPEI. Together, our results indicate that high-molecular-weight bPEI modified SiNWAs can serve as an efficient platform for gene delivery.
View details for DOI 10.1021/am5036626
View details for Web of Science ID 000341122000130
View details for PubMedID 25032791
Maintaining the pluripotency of mouse embryonic stem cells on gold nanoparticle layers with nanoscale but not microscale surface roughness
2014; 6 (12): 6959–69
Efficient control of the self-renewal and pluripotency maintenance of embryonic stem cell (ESC) is a prerequisite for translating stem cell technologies to clinical applications. Surface topography is one of the most important factors that regulates cell behaviors. In the present study, micro/nano topographical structures composed of a gold nanoparticle layer (GNPL) with nano-, sub-micro-, and microscale surface roughnesses were used to study the roles of these structures in regulating the behaviors of mouse ESCs (mESCs) under feeder-free conditions. The distinctive results from Oct-4 immunofluorescence staining and quantitative real-time polymerase chain reaction (qPCR) demonstrate that nanoscale and low sub-microscale surface roughnesses (Rq less than 392 nm) are conducive to the long-term maintenance of mESC pluripotency, while high sub-microscale and microscale surface roughnesses (Rq greater than 573 nm) result in a significant loss of mESC pluripotency and a faster undirectional differentiation, particularly in long-term culture. Moreover, the likely signalling cascades engaged in the topological sensing of mESCs were investigated and their role in affecting the maintenance of the long-term cell pluripotency was discussed by analyzing the expression of proteins related to E-cadherin mediated cell-cell adhesions and integrin-mediated focal adhesions (FAs). Additionally, the conclusions from MTT, cell morphology staining and alkaline phosphatase (ALP) activity assays show that the surface roughness can provide a potent regulatory signal for various mESC behaviors, including cell attachment, proliferation and osteoinduction.
View details for DOI 10.1039/c4nr01540a
View details for Web of Science ID 000337143900089
View details for PubMedID 24839204
Fast and green synthesis of smart glyco-surface via aqueous single electron transfer-living radical polymerization
Macromolecular Chemistry Physics
View details for DOI 10.1002/macp.201400227
- Enzyme-triggered supramolecular self-assembly of platinum prodrug with enhanced tumor-selective accumulation and reduced systemic toxicity JOURNAL OF MATERIALS CHEMISTRY B 2014; 2 (47): 8303–9
- Incorporation of tyrosine phosphate into tetraphenylethylene affords an amphiphilic molecule for alkaline phosphatase detection, hydrogelation and calcium mineralization JOURNAL OF MATERIALS CHEMISTRY B 2013; 1 (41): 5550–56