Senior Member of the Staff
Head, Department of Biomineralization
Associate Professor, Department of Developmental Biology,
Harvard School of Dental Medicine
email:
Worcester Polytechnic Institute, B.S., 1972, Chemistry
University of Vermont, Ph.D., 1976, Chemistry
The substances that make up hard biological structures, from bones to seashells, are formed through a process called biomineralization. The Margolis laboratory is finding out how one essential mineralized tissue, dental enamel, acquires its distinctive properties. Each tooth must have precisely the right composition, structure, hardness, and durability to function effectively without significant breakdown. By studying enamel formation and the factors that affect its stability, we hope to learn more about how to preserve and/or restore teeth for a lifetime of use.
Each of the mineralized tissues of the human body derives its functional capabilities from its unique structure and composition. As a result of differences in mineral and matrix protein content, crystal sizes, and crystal organization, mineralized tissues vary significantly with respect to physical properties. Research in our laboratory is currently focused on elucidating mechanisms involved in the formation (amelogenesis), preservation and repair (regeneration) of dental enamel. Much of this work is built upon a fundamental understanding of the kinetic and thermodynamic factors that control crystal growth and dissolution of enamel mineral and prototype mineral phases (e.g., hydroxyapatite) that are associated with the hard tissues of the human body.
Currently, we are using in vitro approaches to elucidate the structure and mechanism of formation of higher-order assemblies of enamel matrix proteins and their influence on mineralization and crystal organization. We propose that organized mineral structures are generated within organized super-assemblies of matrix proteins in cooperation with other macromolecules that help guide crystal growth and shape. Our working hypothesis is that higher order assemblies of full-length amelogenin, in association with soluble acidic proteins (e.g., enamelin and ameloblastin), regulate the nucleation, growth, shape, and arrangement of initial enamel mineral crystals. Under appropriate mineralizing conditions, such assemblies support the formation of parallel arrays of very thin ribbons of enamel mineral. The growth of these enamel ribbons in thickness and width is inhibited by soluble hydrophobic enamel proteins (e.g., soluble amelogenins) that adsorb onto specific faces of the growing crystals. To improve our understanding of how matrix proteins regulate mineralization in tissues like enamel, we are conducting studies to characterize specific enamel matrix components with respect to their ability to form higher-order assemblies that ultimately regulate organized mineralization. In addition, we are testing the ability of key enamel matrix proteins to bind to mineral surfaces and regulate crystal shape and kinetics of crystal growth. Importantly, these findings are being integrated with those obtained using other biophysical approaches (in collaboration with investigators from the Max Planck Institute) designed to determine the structure and mechanism of formation of proposed higher-order assemblies of the full-length amelogenin and the mechanism by which such assemblies regulate the formation of organized mineral structures. Long-term, such information should provide new insights for the development of bio-inspired materials and novel approaches for mineralized tissue repair and regeneration.
Building on our knowledge of calcium phosphate chemistry and our current understanding of how mineral deposition and organization are regulated in developing mineralized tissues, we are currently carrying out research to investigate novel approaches to the repair (remineralization) of diseased or damaged dental tissues. These studies are designed to improve our understanding of how biomimetic approaches can be used to remineralize carious enamel and properly restore normal tooth enamel structure and properties. Our overall working hypothesis is that the restoration or regeneration of proper tooth structure and function can be achieved through the regulation of mineral ion diffusion, crystal growth kinetics and crystal orientation. Presently, we are exploring the use and effectiveness of novel acidic remineralizing solutions in vitro and the use of novel supersaturated calcium phosphate solutions that are stabilized by pyrophosphate, where remineralization is regulated by added phosphatases. Similar studies are planned using supersaturated solutions that are stabilized by salivary proteins. We propose to extend these studies to include the use of other biologically relevant molecules to regulate the rate, crystal shape, and orientation of growing enamel crystals in the repair of damaged dental enamel. These later studies will be carried out in collaboration with Dr. Elia Beniash and other members of the Department of Biomineralization.
Our research is designed to find out how nature produces a highly functional mineralized tissue (i.e., dental enamel) and to use this insight to develop new approaches for the repair and/or regeneration of damaged or diseased mineralized tissue.
Baldassarri M, Margolis HC, Beniash E. 2008. Compositional determinants of mechanical properties of enamel. J. Dent. Res. 9(2):44-5.
Margolis HC, Beniash E, Fowler CE. 2006. Role of macromolecular assembly of enamel matrix proteins in enamel formation. J. Dent. Res. 85(9):775–793.
Fowler CE, Beniash E, Yamakoshi Y, Simmer JP, Margolis HC. 2006. Cooperative mineralization and protein self-assembly in amelogenesis—silica mineralization and assembly of recombinant amelogenins in vitro. Eur. J. Oral Sci. 114(Suppl. 1):297–303.
Yin A, Margolis HC, Yao Y, Grogan J, Oppenheim FG. 2006. Multi-component adsorption model for pellicle formation: The influence of salivary proteins and non-salivary phosphoproteins on the binding of histatin 5 onto hydroxyapatite. Arch. Oral Biol. 51(2):102–110.
Beniash E, Simmer JP, Margolis HC. 2005. Effects of recombinant mouse amelogenins on the formation and prganization of hydroxyapatite crystals in vitro. J. Struct. Biol. 149(2):182–190.
Aichmayer B, Margolis HC, Sigel R, Yamakoshi Y, Simmer JP, Fratzl P. 2005. The onset of amelogenin nanosphere aggregation studied by small-angle x-ray scattering and dynamic light scattering. J. Struct. Biol. 151 (3):239–249.
Smith CE, Chong DL, Bartlett JD, Margolis HC. 2005. Mineral acquisition rates in developing enamel on maxillary and mandibular incisors of rats and mice: Implications to extracellular acid loading as apatite crystals mature. J. Bone Miner. Res. 20(2) :240–249.
Yin A, Margolis HC, Grogan J, Yao Y, Troxler RF, Oppenheim FG. 2003. Physical parameters of hydroxyapatite adsorption and effect on candidacidal activity of histatins. Arch. Oral Biol. 48(5):361–368.
Zhang YP, Kent RL Jr, Margolis HC. 2000. Enamel demineralization under driving forces found in dental plaque fluid. Eur. J. Oral Sci. 108 (3):207–213.
Margolis HC, Zhang YP, Lee CY, Kent RL Jr, Moreno EC. 1999. Kinetics of enamel demineralization in vitro. J. Dent. Res. 78 (7) :1326–1 335.
Felicitas Bidlack, Ph.D.
Seo-Young Kwak, Ph.D.
Amy E. Litman, M.S.
Hajime Ymazaki, M.S.
