title: Nanoengineered biomimetic hydrogels for guiding human stem cell osteogenesis in three dimensional microenvironments.
abstract: The ability to modulate stem cell differentiation in a three dimensional (3D) microenvironment for bone tissue engineering in absence of exogenous pharmaceutical agents such as bone morphogenic protein (BMP-2) remains a challenge. In this study, we introduce extracellular matrix (ECM)-mimicking nanocomposite hydrogels to induce osteogenic differentiation of human mesenchymal stem cells (hMSCs) for bone regeneration in absence of any osteoinducting factors. In particular, we have reinforced photocrosslinkable collagen-based matrix (gelatin methacryloyl, GelMA) used disk-shaped nanosilicates (nSi), a new class of two-dimensional (2D) nanomaterials. We show that nanoengineered hydrogels supported migration and proliferation of encapsulated hMSCs, with no signs of cell apoptosis or inflammatory cytokine responses. The addition of nSi significantly enhances osteogenic differentiation of encapsulated hMSCs as evident by the increase in alkaline phosphates (ALP) activity and deposition of biomineralized matrix compared to GelMA without nSi. We also show that microfabricated nanoengineered microgels can be used to pattern and control cellular behaviour. Furthermore, we also show that nanoengineered hydrogel have high biocompatibility as determined byin vivoexperiments using immunocompetent rat model. Specifically, the hydrogels showed minimum localized immune responses, indicating it ability for tissue engineering applications. Overall, we showed the ability of nanoengineered hydrogels loaded with 2D nanosilicates for osteogenic differentiation of stem cellsin vitro, in absence of any growth factors such as BMP-2. Ourin vivostudies show high biocompatibility of nanocomposites and show the potential for growth factor free bone regeneration.
authors.affiliation: Biomaterials Innovation Research Center, Division of Biomedical Engineering, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA; Harvard-MIT Division of Health Sciences and Technology, Massachusetts Institute of Technology, Cambridge, MA, USA; Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA, USA; Department of Chemical and Petroleum Engineering, Bioengineering Graduate Program, School of Engineering, University of Kansas, Lawrence, KS, USA.
authors.forename: Arghya
authors.initials: A
authors.lastname: Paul
authors.affiliation: Biomaterials Innovation Research Center, Division of Biomedical Engineering, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA; Harvard-MIT Division of Health Sciences and Technology, Massachusetts Institute of Technology, Cambridge, MA, USA; Department of Chemical and Petroleum Engineering, Bioengineering Graduate Program, School of Engineering, University of Kansas, Lawrence, KS, USA.
authors.forename: Vijayan
authors.initials: V
authors.lastname: Manoharan
authors.affiliation: Biomaterials Innovation Research Center, Division of Biomedical Engineering, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA; Harvard-MIT Division of Health Sciences and Technology, Massachusetts Institute of Technology, Cambridge, MA, USA.
authors.forename: Dorothee
authors.initials: D
authors.lastname: Krafft
authors.affiliation: Biomaterials Innovation Research Center, Division of Biomedical Engineering, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA; Harvard-MIT Division of Health Sciences and Technology, Massachusetts Institute of Technology, Cambridge, MA, USA; Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA, USA; Department of Cardiovascular Surgery, Heinrich Heine University, Medical Faculty, 40225 Duesseldorf, Germany.
authors.forename: Alexander
authors.initials: A
authors.lastname: Assmann
authors.affiliation: Biomaterials Innovation Research Center, Division of Biomedical Engineering, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA; Harvard-MIT Division of Health Sciences and Technology, Massachusetts Institute of Technology, Cambridge, MA, USA; Department of Orthopaedic and Trauma Surgery, Pontificia Universidad Católica del Ecuador, Quito-Ecuador.
authors.forename: Jorge Alfredo
authors.initials: JA
authors.lastname: Uquillas
authors.affiliation: Biomaterials Innovation Research Center, Division of Biomedical Engineering, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA; Harvard-MIT Division of Health Sciences and Technology, Massachusetts Institute of Technology, Cambridge, MA, USA; Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA, USA.
authors.forename: Su Ryon
authors.initials: SR
authors.lastname: Shin
authors.affiliation: Biomaterials Innovation Research Center, Division of Biomedical Engineering, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA; Harvard-MIT Division of Health Sciences and Technology, Massachusetts Institute of Technology, Cambridge, MA, USA; Department of Mechanical and Industrial Engineering, College of Engineering, Qatar University, Doha, Qatar.
authors.forename: Anwarul
authors.initials: A
authors.lastname: Hasan
authors.affiliation: Department of Electrical and Computer Engineering, King Abdulaziz University, Jeddah 21589, Saudi Arabia.
authors.forename: Mohammad Asif
authors.initials: MA
authors.lastname: Hussain
authors.affiliation: Center of Nanotechnology, King Abdulaziz University, Jeddah 21589, Saudi Arabia.
authors.forename: Adnan
authors.initials: A
authors.lastname: Memic
authors.affiliation: Department of Biomedical Engineering and Department of Materials Science and Engineering, Texas A&M University, 5024 Emerging Technology Building, College Station, TX 77843.
authors.forename: Akhilesh K
authors.initials: AK
authors.lastname: Gaharwar
authors.affiliation: Biomaterials Innovation Research Center, Division of Biomedical Engineering, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA; Harvard-MIT Division of Health Sciences and Technology, Massachusetts Institute of Technology, Cambridge, MA, USA; Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA, USA; Department of Bioindustrial Technologies, College of Animal Bioscience and Technology, Konkuk University, Hwayang-dong, Gwangjin-gu, Seoul 143-701, Republic of Korea; Department of Physics, King Abdulaziz University, Jeddah 21569, Saudi Arabia; WPI-Advanced Institute for Materials Research, Tohoku University, Sendai, Japan.
authors.forename: Ali
authors.initials: A
authors.lastname: Khademhosseini
keywords: bone regeneration; hydrogels; nanomaterials; nanosilicates; tissue engineering