Giving Cells What They Want: Biomaterials as ECM Analogues for Skeletal Tissue Engineering
Lawrence Bonassar, Ph.D.
Department of Biomedical Engineering and the Sibley School of Mechanical and Aerospace Engineering
The extracellular matrix (ECM) of skeletal tissues plays a variety of roles necessary for proper cellular function. In both bone and cartilage, the ECM gives both mechanical support and transmits mechanical signals to cells embedded within, while also enabling soluble and insoluble signaling pathways through integrins and growth factor receptors. The use of biomaterials to regulate mechanical, soluble, and insoluble signals will be presented in the context of applications for regeneration of bone, articular cartilage, intervertebral disc, and meniscus. Generation of implants with controlled physical and chemical environments has required the development of new processing schemes for cells and materials, including tissue injection molding, 3D tissue printing, and living lithography. These techniques will be discussed with particular focus on developing design paradigms for tissue regeneration for orthopaedic applications.
Bonassar, Ph.D. is currently Associate Professor in the Department of Biomedical Engineering and the Sibley School of Mechanical and Aerospace Engineering at Cornell University.
Since 2005 he has served as the Associate Chair of Biomedical Engineering with responsibility for coordinating educational activities between the Ithaca and New York City campuses. He joined Cornell University in 2003 after five years on the faculty of the University of Massachusetts Medical School in the Center for Tissue Engineering. He completed postdoctoral fellowships in the Orthopaedic Research Laboratory at the Massachusetts General Hospital and in the Center for Biomedical Engineering at the Massachusetts Institute of Technology after completing his PhD at MIT in 1995. Dr. Bonassar’s research focuses on tissue engineering strategies for skeletal tissue regeneration, including modification and processing of biomaterials and mechanical stimulation of cell-seeded biomaterials. He is an active member of the Orthopaedic Research Society and the Tissue Engineering Society International, and currently serves on the editorial board of the journal Tissue Engineering.
218 Upson Hall
Ithaca, NY 14853
Biomimetic composites for Bone Tissue Engineering
Jie Song, Ph.D., Departments of Orthopedics/Cell Biology
University of Massachusetts Medical School
Despite exciting recent advances in the design of bone-like materials, orthopedic implants that mimic both the structure and mechanical properties of bone are still lacking. We are interested in developing biomimetic composite implants with improved mechanical properties, better structural integration of the organic and inorganic components, and more bio-responsive interface with the cellular and tissue environment.
The controlled integration of organic and inorganic components confers natural bone with superior mechanical properties. Bone biogenesis is thought to occur by templated mineralization of hard apatite crystals (e.g. hydroxyapatite, HA) on an elastic protein scaffold, a process we sought to emulate with synthetic hydrogel polymers. Crosslinked polymethacrylamide and polymethacrylate hydrogels functionalized with mineral-binding ligands were used to template the growth of preferentially aligned HA nanocrystals using a urea-mediated mineralization process. The morphology, crystallinity as well as the interfacial adhesion strength of the templated mineral growth was shown to be dependent on both the type and the density of mineral-binding ligands presented on the hydrogel scaffold.
In parallel, bulk hydrogel-HA composites with mineral content approximating that of human bone were developed via a fast and convenient procedure suitable for clinical use. Termed “FlexBone”, these composites exhibit unusually high resilience to compression and fracture under physiological loadings despite their high mineral contents. We demonstrate that tailored microstructural and mechanical properties of the composites can be achieved by the selective use of HA powder of varied sizes and aggregation.
Finally, progress towards the molecular level understanding of mineral-ligand interactions as well as the evaluation of cell-ligand interactions will be discussed.
Jie Song, Ph.D. received her Ph.D. in organic chemistry with Prof. Rawle Hollingsworth from Michigan State University in 1999.
After completing her postdoctoral training at UC Berkeley and the Lawrence Berkeley National Laboratory (LBNL) with Prof. Carolyn Bertozzi, she joined the Materials Sciences Division at LBNL as a staff scientist in 2002. For the past two years, she has also been a lead scientist in the Biological Nanostructures Division of the Molecular Foundry, a DOE-funded nanoscience center at Berkeley. Jie Song recently joined the faculty in Orthopedics and Cell Biology at UMass Medical School. Her primary research interest is the design of functional polymers and organic-inorganic composites for tissue engineering, sensing and biomedical imaging applications.
55 Lake Avenue North
Worcester, MA 01655
Characterizing Cellular Responses to Bioactive Collagen Threads: Applications for Orthopedic Tissue Regeneration
George Pins, Ph.D., Department of Biomedical Engineering,
Worcester Polytechnic Institute
Designing biomaterials scaffolds that promote tendon and ligament regeneration requires creating tissue constructs that replicate the mechanical properties of the native tissue, promote cell infiltration and biodegrade at a rate that matches the rate of new tissue formation. Towards this goal, a variety of synthetic and biologically-derived fibrous materials have been studied as scaffolds to promote the repair and regeneration of torn tendons and ligaments. A recent study described a method for self-assembling solutions of collagen molecules into fibers or threads that exhibit mechanical properties and aligned fibrillar substructure comparable to native tendon structures. To assess the capacity of these collagen threads to facilitate new tissue deposition, we developed an in vitro model system to characterize cell attachment, proliferation and migration on the surfaces of these scaffolds. The utility of this model system will be discussed with an emphasis on its value as a tool for identifying design parameters that will enhance the rate of tissue ingrowth on the surfaces of collagen threads.
George Pins, Ph.D. is currently Assistant Professor in the Department of Biomedical Engineering at Worcester Polytechnic Institute.
Prior to joining WPI, Dr. Pins was a research scientist at Tensegra, Inc., in Norwood, MA. At Tensegra, he used novel manufacturing techniques to develop several medical devices including hydrocephalus shunt filters and artificial disk replacements. He completed his post-doctoral training in tissue engineering in the Center for Engineering and Medicine at Massachusetts General Hospital and the Shriners Hospital for Children after completing his PhD at Rutgers University. Dr. Pins’ research focuses on the design of biomimetic tissue scaffolds and the characterization of cellular responses to precisely tailored cues on the surfaces of biomaterials. This work aims to provide a greater understanding of cell-matrix interactions that regulate wound healing, ultimately leading to improved three-dimensional scaffolds designed to enhance the regeneration of soft tissues such as tendons, ligaments and skin. He is an active member of the Biomedical Engineering Society and the Tissue Engineering Society International.
Department of Biomedical Engineering
100 Institute Road
Worcester, MA 01609
Mechanotransduction Studies in Articular Cartilage Explants: What we’ve Learned and Potential Applications to Tissue Engineering Research
Paul Fanning, Ph.D., Departments of Orthopedics/Cell Biology
University of Massachusetts Medical School
The proper functioning of articular cartilage is based in large part upon its mechanical properties which is supported by a highly mechanoreceptive tissue architecture. The role and the precise mechanisms of how chondrocytes receive and process information concerning their mechanical microenvironment is currently in its initial stages of research in orthopædics. The use of cell signaling research tools and mechanobiological methodologies used to elucidate the nature of the biochemical details involved in receiving and turning mechanical cues into biochemical signals will be discussed. Attention will be drawn to manipulating existing ex vivo mechanobiological compression systems to more accurately reflect the in vivo situation in both normal and osteoarthritic cartilage microenvironments. Such systems could be useful in the testing and characterization of various scaffolds for cartilage tissue engineering.
Paul Fanning, Ph.D. is currently Assistant Professor in the Department of Orthopedics and Physical Rehabilitation at the University of Massachusetts Medical
School. Other academic appointments include the Departments of Cell
Biology, General Surgery, and the Graduate School of Biomedical Sciences. He joined the research faculty of the UMass Department of Orthopedics in 2005. Prior to joining Orthopedics, he conducted mechanobiological research in the area of urology in the Dept. of Surgery at UMass (2002-2005). He completed postdoctoral research fellowship training (2001) in the Orthopædic Research Laboratory at Massachusetts General Hospital in close collaborations with the Center for Biomedical Engineering at the Massachusetts Institute of Technology and the Metabolism Section of the Joslin Diabetes Center. He completed his Ph.D. from the Harvard Graduate School of Arts and Sciences, Division of Medical Sciences in 1999. Dr. Fanning’s research focuses on the cellular signal transduction mechanisms regulated by mechanical loading in cartilage health and disease, especially as they relate to osteoarthritis.
55 Lake Avenue North
Worcester, MA 01655
Interface Tissue Engineering: the Bridge to Functional Tissue Systems
Helen H. Lu, Ph.D.
Department of Biomedical Engineering
Tissue engineering is a promising approach in regenerative medicine and our research centers on the formation of functional tissue systems. This functionality is achieved by bridging different types of tissue through regeneration of the native tissue-tissue interface. This is particularly important for the musculoskeletal system, where overall joint motion depends largely on the synchronized interactions and functional integration between bone and soft tissues such as ligament, tendon or cartilage. Functional orthopedic tissue engineering thereby requires the consideration of more than one type of tissue and interface regeneration. Biological fixation of soft tissue grafts to bone remains a significant clinical challenge in the treatment of osteoarthritis and sports-related injuries. To address this challenge, we have focused our efforts on elucidating the structure-function relationship at the soft tissue-to-bone interface, which have yielded physiologically relevant design parameters for interface tissue engineering. We have also fabricated biomimetic, multi-phased scaffolds and explored the effects of cell-cell interactions in facilitating the simultaneous regeneration of more than one type of tissue. This lecture will discuss the design and testing of these biomimetic scaffolds in vitro and in vivo, as well as the application of innovative co-culture models to evaluate cell-cell interactions on these scaffolds. Example scaffolds systems based on biodegradable polymers and calcium phosphate composites for tendon- or cartilage-to-bone integration will be presented, along with a discussion of the potential mechanism regulating the formation and maintenance of tissue-tissue interfaces.
Helen Lu, Ph.D. received her B.S.E. and Ph.D. in Bioengineering from the University of Pennsylvania. After post-doctoral training in Orthopedic Tissue Engineering at Drexel University and later at Tufts University,
she joined the faculty at Columbia University in 2001. Dr. Lu is currently an Assistant Professor of Biomedical Engineering and the Director of the Biomaterials and Interface Tissue Engineering Laboratory at Columbia. She also holds a joint appointment as an Assistant Professor of Dental and Craniofacial Bioengineering at the College of Dental Medicine. Dr. Lu’s research focuses on Interface Tissue Engineering and the elucidation of structure-function relationships existing at soft tissue-to-bone interfaces. Her group is also interested in co-culture model design and composite biomaterials for utilization in orthopedic and dental medicine. Dr. Lu’s past honors include a NIH National Research Service Award, Early Faculty Career Award in Translational Research from the Wallace H. Coulter Foundation, and she is the inaugural recipient of the international Y’ROBOTS award for Young Researchers in Orthopedic Biomechanics and Sports Medicine in 2005. Dr. Lu’s research program is supported by the Whitaker Foundation, the Wallace H. Coulter Foundation, and the National Institutes of Health.
351 Engineering Terrrace
1210 Amsterdam Avenue
New York, NY 10027
Directing Stem Cells Toward Functional Tissue Outcomes
David L. Kaplan, Ph.D., Department of Biomedical Engineering,
In the context of biomaterials and tissue engineering, matrices or scaffolding plays a central role for successful formation of functional tissues in vitro for integration in vivo. Stem cells require appropriate signaling, transmitted via these material matrices, to direct their functional outcomes in tissue systems. This signaling may include chemical, morphological, structural and mechanical cues, and these features are imparted at the stage of matrix design and at different material length scales. Importantly, the rate and extent of matrix remodeling also needs to match the desired tissue regeneration goals for integration in vivo, to avoid interfering with normal repair mechanisms while maintaining sufficient structural and mechanical function until integration is achieved. Therefore, we are particularly interested in understanding fundamental and practical relationships between biomaterial matrix features, stem cells and functional tissue outcomes. We focus on fibrous protein matrices, including those formed from collagens and silks, to provide important degradable protein polymeric models to study these complex interrelationships. For example, collagen assembly directly impacts mechanical and biological functions in vivo, and mimicking this in vitro affords new insight into cell and tissue outcomes. Silks formed by insects and spiders provide fertile ground for fundamental and applied inquiry due to the novel structures and properties of the materials formed by spinning in Nature. The utility of these proteins for the formation of new biomaterials, along with their utility towards functional tissue engineering applications will be highlighted with particular emphasis on relationships of fibrous protein structure, morphology and chemistry to cell and tissue responses for skeletal tissue repair.
David Kaplan, Ph.D. is Professor & Chair of the Department of Biomedical Engineering, Professor in the Department of Chemical & Biological Engineering, and holds secondary appointments in the Department of Biology and the Tufts University School of Dental Medicine at Tufts University.
His research focus is on biopolymer engineering related to the study of structure-function relationships, with emphasis on studies related to biomaterials and tissue engineering. His research is currently supported by the NIH, NSF, NASA, DoD, USDA and others. He directs the NIH P41 Tissue Engineering Resource Center at Tufts University, MIT and Columbia University. He has published over 350 peer reviewed papers, serves on the editorial boards of four journals, and is Associate Editor for Biomacromolecules.
Department of Biomedical Engineering
Medford, Massachusetts 02155 USA