Instructor, Cardiovascular Institute
Honors & Awards
Progenitor Cell Biology Consortium (PCBC) Jump Start Award, National Institute of Health (NIH), National Heart, Lung, and Blood Institute (NHLBI) (2016 – 2017)
Pathway to Independence Award (K99/R00), National Institute of Health (NIH), National Heart, Lung, and Blood Institute (NHLBI) (2016-2021)
Two-Photon and Super-Resolution Microscopy Pilot Grant, Stanford University Neuroscience Microscopy Service (January 2016)
Dr. Gerald Hatch Doctoral Fellowship Award, McGill University (2008)
Provosts Graduate Fellowship, McGill University (2009)
McGill Engineering Doctoral Award (MEDA), McGill University (2007-2010)
Oak Foundation Cardiovascular Award, Stanford School of Medicine (March 2011-2013)
Cardiovascular Institute (CVI) Young Investigator Award in Basic Sciences 2012, Stanford University School of Medicine (September 2012)
Cardiovascular Institute (CVI) Seed Grant Award, Stanford University School of Medicine (December 2012)
EMBO Fellowship, Institute for Stem Cell Therapy (I-STEM), France, European Molecular Biology Organization (EMBO) (May-June 2013)
Cardiovascular Institute (CVI) Travel Award, Stanford School of Medicine (July 2013)
Boards, Advisory Committees, Professional Organizations
Professional Member, American Heart Association (AHA) (2011 - Present)
Member, Canadian Biomaterials Society (CBS) (2008 - 2011)
Secretary/Treasurer Officer, Society for Biomaterials (2011 - 2013)
Member, Tissue Engineering and Regenerative Medicine International Society (TERMIS) (2011 - Present)
PhD, McGill University, Biomaterials for Tissue Engineering (2011)
Masters, Sharif University of Technology, Materials Sci and Eng (2006)
Bachelor, Sharif University of Technology, Materials Sci and Tech (2003)
Current Research and Scholarly Interests
My research in Dr. Sean Wu's lab at Stanford Cardiovascular Institute is focused on employing various bioengineering approaches to design and develop engineered cardiac constructs that can mimic structure and function of native adult mammalian heart tissue/organ. I use newly emerging 3D bioprinting technique to fabricate biomimetic tissue constructs consisting of an spectrum of hard and soft biomaterials, and tri-lineage hiPSC-derived cardiac cells including cardiomyocytes, endothelial cells, and smooth muscle cells.
Epicardial FSTL1 reconstitution regenerates the adult mammalian heart.
2015; 525 (7570): 479-485
The elucidation of factors that activate the regeneration of the adult mammalian heart is of major scientific and therapeutic importance. Here we found that epicardial cells contain a potent cardiogenic activity identified as follistatin-like 1 (Fstl1). Epicardial Fstl1 declines following myocardial infarction and is replaced by myocardial expression. Myocardial Fstl1 does not promote regeneration, either basally or upon transgenic overexpression. Application of the human Fstl1 protein (FSTL1) via an epicardial patch stimulates cell cycle entry and division of pre-existing cardiomyocytes, improving cardiac function and survival in mouse and swine models of myocardial infarction. The data suggest that the loss of epicardial FSTL1 is a maladaptive response to injury, and that its restoration would be an effective way to reverse myocardial death and remodelling following myocardial infarction in humans.
View details for DOI 10.1038/nature15372
View details for PubMedID 26375005
- Protein Corona Influences Cell-Biomaterial Interactions in Nanostructured Tissue Engineering Scaffolds ADVANCED FUNCTIONAL MATERIALS 2015; 25 (28): 4379-4389
Micropatterned nanostructures: a bioengineered approach to mass-produce functional myocardial grafts.
2015; 26 (6): 060501-?
Cell-based therapies are a recently established path for treating a wide range of human disease. Tissue engineering of contractile heart muscle for replacement therapy is among the most exciting and important of these efforts. However, current in vitro techniques of cultivating functional mature cardiac grafts have only been moderately successful due to the poor capability of traditional two-dimensional cell culture systems to recapitulate necessary in vivo conditions. In this issue, Kiefer et al  introduce a laser-patterned nanostructured substrate (Al/Al2O3 nanowires) for efficient maintenance of oriented human cardiomyocytes, with great potential to open new roads to mass-production of contractile myocardial grafts for cardiovascular tissue engineering.
View details for DOI 10.1088/0957-4484/26/6/060501
View details for PubMedID 25611345
- Nanoparticles-induced inflammatory cytokines in human plasma concentration manner: an ignored factor at the nanobio-interface JOURNAL OF THE IRANIAN CHEMICAL SOCIETY 2015; 12 (2): 317-323
[Pyr-1]-Apelin-13 delivery via nano-liposomal encapsulation attenuates pressure overload-induced cardiac dysfunction
2015; 37: 289-298
Nanoparticle-mediated sustained delivery of therapeutics is one of the highly effective and increasingly utilized applications of nanomedicine. Here, we report the development and application of a drug delivery system consisting of polyethylene glycol (PEG)-conjugated liposomal nanoparticles as an efficient in vivo delivery approach for [Pyr1]-apelin-13 polypeptide. Apelin is an adipokine that regulates a variety of biological functions including cardiac hypertrophy and hypertrophy-induced heart failure. The clinical use of apelin has been greatly impaired by its remarkably short half-life in circulation. Here, we investigate whether [Pyr1]-apelin-13 encapsulation in liposome nanocarriers, conjugated with PEG polymer on their surface, can prolong apelin stability in the blood stream and potentiate apelin beneficial effects in cardiac function. Atomic force microscopy and dynamic light scattering were used to assess the structure and size distribution of drug-laden nanoparticles. [Pyr1]-apelin-13 encapsulation in PEGylated liposomal nanocarriers resulted in sustained and extended drug release both in vitro and in vivo. Moreover, intraperitoneal injection of [Pyr1]-apelin-13 nanocarriers in a mouse model of pressure-overload induced heart failure demonstrated a sustainable long-term effect of [Pyr1]-apelin-13 in preventing cardiac dysfunction. We concluded that this engineered nanocarrier system can serve as a delivery platform for treating heart injuries through sustained bioavailability of cardioprotective therapeutics.
View details for DOI 10.1016/j.biomaterials.2014.08.045
View details for Web of Science ID 000346541100028
Personalized disease-specific protein corona influences the therapeutic impact of graphene oxide
2015; 7 (19): 8978-8994
The hard corona, the protein shell that is strongly attached to the surface of nano-objects in biological fluids, is recognized as the first layer that interacts with biological objects (e.g., cells and tissues). The decoration of the hard corona (i.e., the type, amount, and conformation of the attached proteins) can define the biological fate of the nanomaterial. Recent developments have revealed that corona decoration strongly depends on the type of disease in human patients from which the plasma is obtained as a protein source for corona formation (referred to as the 'personalized protein corona'). In this study, we demonstrate that graphene oxide (GO) sheets can trigger different biological responses in the presence of coronas obtained from various types of diseases. GO sheets were incubated with plasma from human subjects with different diseases/conditions, including hypofibrinogenemia, blood cancer, thalassemia major, thalassemia minor, rheumatism, fauvism, hypercholesterolemia, diabetes, and pregnancy. Identical sheets coated with varying protein corona decorations exhibited significantly different cellular toxicity, apoptosis, and uptake, reactive oxygen species production, lipid peroxidation and nitrogen oxide levels. The results of this report will help researchers design efficient and safe, patient-specific nano biomaterials in a disease type-specific manner for clinical and biological applications.
View details for DOI 10.1039/c5nr00520e
View details for Web of Science ID 000354204400038
Patching up broken hearts: cardiac cell therapy gets a bioengineered boost.
Cell stem cell
2014; 15 (6): 671-673
Preclinical and clinical studies for cardiac cell therapy have only seen moderate success due to poor engraftment and survival of transplanted cells. In this issue of Cell Stem Cell, Ye et al. (2014) employ a growth-factor-loaded fibrin patch and show improved cardiovascular cell survival after cell transplantation into a porcine model of ischemia reperfusion.
View details for DOI 10.1016/j.stem.2014.11.008
View details for PubMedID 25479741
Protein corona change the drug release profile of nanocarriers: The "overlooked" factor at the nanobio interface
COLLOIDS AND SURFACES B-BIOINTERFACES
2014; 123: 143-149
The emergence of nanocarrier systems in drug delivery applications has ushered in rapid development of new classes of therapeutic agents which can provide an essential breakthrough in the fight against refractory diseases. However, successful clinical application of nano-drug delivery devices has been limited mainly due to the lack of control on sustained release of therapeutics from the carriers. A wide range of sophisticated approaches employs the formation of crosslinkable, non-crosslinkable, stimuli-responsive polymer nanocarriers in order to enhance their delivery efficiency. Despite the extensive research conducted on the development of various nanocarriers, the effect of the biological milieu on the drug release profile of these constructs is not yet fully investigated. In particular, the formation of a protein corona on the surface of nanocarriers, when they interact with living organisms in vivo is largely decisive for their biological function. Using a number of synthetized (i.e., superparamagnetic iron oxide nanoparticles and polymeric nanocapsules) and commercialized nanocarriers (i.e., Abraxane®, albumin-bound paclitaxel drug), this study demonstrates that the protein corona can shield the nanocarriers and, consequently, alters the release profile of the drugs from the nanocarriers. More specifically, the protein corona could significantly reduce the burst effect of either protein conjugated nanocarriers or carriers with surface loaded drug (i.e., SPIONs). However, the corona shell only slightly changed the release profile of polymeric nanocapsules. Therefore, the intermediary, buffer effect of the protein shells on the surface of nanoscale carriers plays a crucial role in their successful high-yield applications in vivo.
View details for DOI 10.1016/j.colsurfb.2014.09.009
View details for Web of Science ID 000347580500020
View details for PubMedID 25262409
Use of bio-mimetic 3D technology in therapeutics for heart disease
View details for DOI 10.4161/bioe.27751
Ultra-rapid Manufacturing of Engineered Epicardial Substitute to Regenerate Cardiac Tissue Following Acute Ischemic Injury.
Methods in molecular biology (Clifton, N.J.)
2014; 1210: 239-248
Considering the impaired regenerative capacity of adult mammalian heart tissue, cardiovascular tissue engineering aims to create functional substitutes that can restore the structure and function of the damaged cardiac tissue. The success of cardiac regenerative therapies has been limited mainly due to poor control on the structure and properties of the tissue substitute, lack of vascularization, and immunogenicity. In this study we introduce a new approach to rapidly engineer dense biomimetic scaffolds consisting of type I collagen, to protect the heart against severe ischemic injury. Scaffold biomechanical properties are adjusted to mimic embryonic epicardium which is shown to be optimal to support cardiomyocyte contractile work. Moreover, the designed patch can serve as a delivery device for targeted, controlled release of cells or therapeutic macromolecules into the lesion area.
View details for DOI 10.1007/978-1-4939-1435-7_18
View details for PubMedID 25173173
Nanoparticles-induced inflammatory cytokines in human plasma concentration manner: An ignored factor at the nanobio-interface
Journal of the Iranian Chemical Society
View details for DOI 10.1007/s13738-014-0486-7
The effect of bioengineered acellular collagen patch on cardiac remodeling and ventricular function post myocardial infarction
2013; 34 (36): 9048-9055
Regeneration of the damaged myocardium is one of the most challenging fronts in the field of tissue engineering due to the limited capacity of adult heart tissue to heal and to the mechanical and structural constraints of the cardiac tissue. In this study we demonstrate that an engineered acellular scaffold comprising type I collagen, endowed with specific physiomechanical properties, improves cardiac function when used as a cardiac patch following myocardial infarction. Patches were grafted onto the infarcted myocardium in adult murine hearts immediately after ligation of left anterior descending artery and the physiological outcomes were monitored by echocardiography, and by hemodynamic and histological analyses four weeks post infarction. In comparison to infarcted hearts with no treatment, hearts bearing patches preserved contractility and significantly protected the cardiac tissue from injury at the anatomical and functional levels. This improvement was accompanied by attenuated left ventricular remodeling, diminished fibrosis, and formation of a network of interconnected blood vessels within the infarct. Histological and immunostaining confirmed integration of the patch with native cardiac cells including fibroblasts, smooth muscle cells, epicardial cells, and immature cardiomyocytes. In summary, an acellular biomaterial with specific biomechanical properties promotes the endogenous capacity of the infarcted myocardium to attenuate remodeling and improve heart function following myocardial infarction.
View details for DOI 10.1016/j.biomaterials.2013.08.017
View details for Web of Science ID 000326426500006
View details for PubMedID 23992980
- Exocytosis of nanoparticles from cells: Role in cellular retention and toxicity ADVANCES IN COLLOID AND INTERFACE SCIENCE 2013; 201: 18-29
EPICARDIUM-DRIVEN DIFFERENTIATION OF HUMAN EMBRYONIC STEM CELL DERIVED CARDIAC PROGENITORS SEEDED IN A 3D COLLAGEN PATCH
WOUND REPAIR AND REGENERATION
2013; 21 (6): A79-A79
View details for Web of Science ID 000326327100106
Temperature: The "Ignored" Factor at the NanoBio Interface
2013; 7 (8): 6555-6562
Upon incorporation of nanoparticles (NPs) into the body, they are exposed to biological fluids, and their interaction with the dissolved biomolecules leads to the formation of the so-called protein corona on the surface of the NPs. The composition of the corona plays a crucial role in the biological fate of the NPs. While the effects of various physico-chemical parameters on the composition of the corona have been explored in depth, the role of temperature upon its formation has received much less attention. In this work, we have probed the effect of temperature on the protein composition on the surface of a set of NPs with various surface chemistries and electric charges. Our results indicate that the degree of protein coverage and the composition of the adsorbed proteins on the NPs surface depend on the temperature at which the protein corona is formed. Also, the uptake of NPs is affected by the temperature. Temperature is, thus, an important parameter that needs to be carefully controlled in quantitative studies of bio-nano interactions.
View details for DOI 10.1021/nn305337c
View details for Web of Science ID 000323810600013
Hydraulic permeability of multilayered collagen gel scaffolds under plastic compression-induced unidirectional fluid flow
2013; 9 (1): 4673-4680
Under conditions of free fluid flow, highly hydrated fibrillar collagen gels expel fluid and undergo gravity driven consolidation (self-compression; SC). This process can be accelerated by the application of a compressive stress (plastic compression; PC) in order to generate dense collagen scaffolds for tissue engineering. To define the microstructural evolution of collagen gels under PC, this study applied a two-layer micromechanical model that was previously developed to measure hydraulic permeability (k) under SC. Radially confined PC resulted in unidirectional fluid flow through the gel and the formation of a dense lamella at the fluid expulsion boundary which was confirmed by confocal microscopy of collagen immunoreactivity. Gel mass loss due to PC and subsequent SC were measured and applied to Darcy's law to calculate the thickness of the lamella and hydrated layer, as well as their relative permeabilities. Increasing PC level resulted in a significant increase in mass loss fraction and lamellar thickness, while the thickness of the hydrated layer dramatically decreased. Permeability of lamella also decreased from 1.8×10(-15) to 1.0×10(-15) m(2) in response to an increase in PC level. Ongoing SC, following PC, resulted in a uniform decrease in mass loss and k with increasing PC level and as a function SC time. Experimental k data were in close agreement with those estimated by the Happel model. Calculation of average k values for various two-layer microstructures indicated that they each approached 10(-15)-10(-14) m(2) at equilibrium. In summary, the two-layer micromechanical model can be used to define the microstructure and permeability of multi-layered biomimetic scaffolds generated by PC.
View details for DOI 10.1016/j.actbio.2012.08.031
View details for Web of Science ID 000313376900022
View details for PubMedID 22947324
- Effect of chitosan incorporation on the consolidation process of highly-hydrated collagen hydrogel scaffolds Soft Matter 2013
- Plasma concentration gradient influences the protein corona decoration on nanoparticles RSC ADVANCES 2013; 3 (4): 1119-1126
Antibacterial properties of nanoparticles.
Trends in biotechnology
2012; 30 (10): 499-511
Antibacterial agents are very important in the textile industry, water disinfection, medicine, and food packaging. Organic compounds used for disinfection have some disadvantages, including toxicity to the human body, therefore, the interest in inorganic disinfectants such as metal oxide nanoparticles (NPs) is increasing. This review focuses on the properties and applications of inorganic nanostructured materials and their surface modifications, with good antimicrobial activity. Such improved antibacterial agents locally destroy bacteria, without being toxic to the surrounding tissue. We also provide an overview of opportunities and risks of using NPs as antibacterial agents. In particular, we discuss the role of different NP materials.
View details for DOI 10.1016/j.tibtech.2012.06.004
View details for PubMedID 22884769
Silver-Coated Engineered Magnetic Nanoparticles Are Promising for the Success in the Fight against Antibacterial Resistance Threat
2012; 6 (3): 2656-2664
The combination of patients with poor immune system, prolonged exposure to anti-infective drugs, and cross-infection has given rise to nosocomial infections with highly resistant pathogens, which is going to be a growing threat so termed "antibiotic resistance". Due to their significant antimicrobial activity, silver nanoparticles are recognized as a promising candidate to fight against resistant pathogens; however, there are two major shortcomings with these nanoparticles. First, the silver nanoparticles are highly toxic to the healthy cells; second, due to the protection offered by the biofilm mode of growth, the silver nanoparticles cannot eradicate bacterial biofilms. In order to overcome these limitations, this study introduces a new class of engineered multimodal nanoparticles comprising a magnetic core and a silver ring with a ligand gap. The results indicated promising capability of the designed multimodal nanoparticles for high-yield antibacterial effects and eradication of bacterial biofilms, while the particles were completely compatible with the cells. Utilizing a gold ring as an intermediate coating on the produced nanoparticles may exploit new opportunities for theranosis applications. This will require special consideration in future works.
View details for DOI 10.1021/nn300042m
View details for Web of Science ID 000301945900083
View details for PubMedID 22397679
- Large Protein Absorptions from Small Changes on the Surface of Nanoparticles JOURNAL OF PHYSICAL CHEMISTRY C 2011; 115 (37): 18275-18283
Fibroblast contractility and growth in plastic compressed collagen gel scaffolds with microstructures correlated with hydraulic permeability.
Journal of biomedical materials research. Part A
2011; 96 (4): 609-620
Scaffold microstructure is hypothesized to influence physical and mechanical properties of collagen gels, as well as cell function within the matrix. Plastic compression under increasing load was conducted to produce scaffolds with increasing collagen fibrillar densities ranging from 0.3 to above 4.1 wt % with corresponding hydraulic permeability (k) values that ranged from 1.05 to 0.03 ?m², as determined using the Happel model. Scanning electron microscopy revealed that increasing the level of collagen gel compression yielded a concomitant reduction in pore size distribution and a slight increase in average fibril bundle diameter. Decreasing k delayed the onset of contraction and significantly reduced both the total extent and the maximum rate of contraction induced by NIH3T3 fibroblasts seeded at a density of either 6.0 x 10? or 1.5 x 10? cells mL?¹. At the higher cell density, however, the effect of k reduction on collagen gel contraction was overcome by an accelerated onset of contraction which led to an increase in both the total extent and the maximum rate of contraction. AlamarBlue™ measurements indicated that the metabolic activity of fibroblasts within collagen gels increased as k decreased. Moreover, increasing seeded cell density from 2.0 x 10? to 1.5 x 10? cells mL?¹ significantly increased NIH3T3 proliferation. In conclusion, fibroblast-matrix interactions can be optimized by defining the microstructural properties of collagen scaffolds through k adjustment which in turn, is dependent on the cell seeding density.
View details for DOI 10.1002/jbm.a.33008
View details for PubMedID 21268235
Engineered nanoparticles for biomolecular imaging
2011; 3 (8): 3007-3026
In recent years, the production of nanoparticles (NPs) and exploration of their unusual properties have attracted the attention of physicists, chemists, biologists and engineers. Interest in NPs arises from the fact that the mechanical, chemical, electrical, optical, magnetic, electro-optical and magneto-optical properties of these particles are different from their bulk properties and depend on the particle size. There are numerous areas where nanoparticulate systems are of scientific and technological interest, particularly in biomedicine where the emergence of NPs with specific properties (e.g. magnetic and fluorescence) for contrast agents can lead to advancing the understanding of biological processes at the biomolecular level. This review will cover a full description of the physics of various imaging methods, including MRI, optical techniques, X-rays and CT. In addition, the effect of NPs on the improvement of the mentioned non-invasive imaging methods will be discussed together with their advantages and disadvantages. A detailed discussion will also be provided on the recent advances in imaging agents, such as fluorescent dye-doped silica NPs, quantum dots, gold- and engineered polymeric-NPs, superparamagnetic iron oxide NPs (SPIONs), and multimodal NPs (i.e. nanomaterials that are active in both MRI and optical methods), which are employed to overcome many of the limitations of conventional contrast agents (e.g. gadolinium).
View details for DOI 10.1039/c1nr10326a
View details for Web of Science ID 000293521700001
View details for PubMedID 21717012
- Rodent model for adult stem cell transplantation for bone repair Journal of Bone and Joint Surgery 2011; 93: 553
- Large Protein Absorptions from Small Changes on the Surface of Nanoparticles Journal of Physical Chemistry 2011
- Characterization and modelling of a dense lamella formed during self-compression of fibrillar collagen gels: implications for biomimetic scaffolds Soft Matter 2011; 7: 2918
Reduced hydraulic permeability of three-dimensional collagen scaffolds attenuates gel contraction and promotes the growth and differentiation of mesenchymal stem cells
2010; 6 (10): 3978-3987
Optimal scaffold characteristics are essential for the therapeutic application of engineered tissues. Hydraulic permeability (k) affects many properties of collagen gels, such as mechanical properties, cell-scaffold interactions within three dimensions (3D), oxygen flow and nutrient diffusion. However, the cellular response to 3D gel scaffolds of defined k values has not been investigated. In this study, unconfined plastic compression under increasing load was used to produce collagen gels with increasing solid volume fractions. The Happel model was used to calculate the resulting permeability values in order to study the interaction of k with gel mechanical properties and mesenchymal stem cell (MSC)-induced gel contraction, metabolism and differentiation in both non-osteogenic (basal medium) and osteogenic medium for up to 3 weeks. Collagen gels of fibrillar densities ranging from 0.3 to >4.1 wt.% gave corresponding k values that ranged from 1.00 to 0.03 microm(2). Mechanical testing under compression showed that the collagen scaffold modulus increased with collagen fibrillar density and a decrease in k value. MSC-induced gel contraction decreased as a direct function of decreasing k value. Relative to osteogenic conditions, non-osteogenic MSC cultures exhibited a more than 2-fold increase in gel contraction. MSC metabolic activity increased similarly under both osteogenic and non-osteogenic culture conditions for all levels of plastic compression. Under osteogenic conditions MSC differentiation and mineralization, as indicated by alkaline phosphatase activity and von Kossa staining, respectively, increased in response to an elevation in collagen fibrillar density and decreased gel permeability. In this study, gel scaffolds with higher collagen fibrillar densities and corresponding lower k values provided a greater potential for MSC differentiation and appear most promising for bone grafting purposes. Thus, cell-scaffold interactions can be optimized by defining the 3D properties of collagen scaffolds through k adjustment.
View details for DOI 10.1016/j.actbio.2010.04.028
View details for Web of Science ID 000282207100017
View details for PubMedID 20451675
- Effect of rubber particle cavitation on the mechanical properties and deformation behavior of high-impact polystyrene Journal of Applied Polymer Science 2007; 104 (2): 1110