Research Projects

Structural and Mechanical Characterization of Biominerals

In order to understand how biomineralized tissues form, and to elucidate the structure/property relationships within these materials, we need to obtain high resolution images of both the structure and chemistry of these organic-inorganic composites. The Estroff Lab has helped to lead the advancement of state-of-the-art materials characterization techniques for revealing the internal, nanoscale structure of single crystal biominerals. We visualized, for the first time, the presence of organic aggregates within the single crystals that make up mollusk shells, and subsequently imaged the early stages of formation, revealing evidence of a particle-accretion pathway leading to the growth of crystallographically oriented tablets of nacre. To complete the structure-function analysis of these single-crystal composites, we measured a 60% increase in hardness of the calcite in mollusk shells as compared to geologic calcite, and contributed to a larger effort to model the origins of this hardening. More recently, we have interrogated the materials properties of pathological mineral deposits in tissues ranging from human breast tumors, to metastatic tumors in bone, to calcified aortic heart valves. These studies are some of the first to focus on the materials science of pathological mineralization, in contrast the biological approaches more commonly taken. These studies reveal the importance of multimodal imaging, including Raman microscopy, x-ray diffraction techniques, and electron microscopy, in enabling the description of heterogeneity in pathological mineral deposits that could not be seen by histology.

1) Boys, A.J., Kunitake, J.A.M.R., Henak, C., Cohen, I., Estroff, L.A., Bonassar, L.J. "Understanding the Stiff-to-compliant Transition of the Meniscal Attachments by Spatial Registration of Raman Microscopy and Confocal Elastography" ACS Appl. Mater. Interfaces, 2019, 11, 26559-26570. acsami.9b03595

2) Hovden, R.; Wolf, S.E.; Holtz, M.E.; Marin, F.; Muller, D.A.; Estroff, L.A. "Nanoscale Assembly Processes for Nacre Formation in Mollusk Shells (Pinna nobilis): From Disorder to Order." Nature Commun., 2015, 6, 10097

3) He, F., Chiou, A.E., Loh, H.C., Lynch, M., Seo, B.R., Song, Y.H., Lee, M.J., Hoerth, R., Bortel, E.L., Willie, B.M., Duda, G.N., Estroff, L.A., Masic, A., Wagermaier, W., Fratzl, P., Fischbach, C. "Multiscale characterization of the mineral phase at skeletal sites of breast cancer metastasis", PNAS, 2017, 114, 10542-10547, 10.1073/pnas.1708161114

4) Chiou, A.E., Hinckley. J.A., Khaitan, R., Varsano, N., Hernandez, C.J., Estroff, L.A., Weiner, S., Addadi, L., Wiesner, U.B., Fischbach, C., "Fluorescent Silica Nanoparticles to Label Metastatic Tumor Cells in Mineralized Bone Microenvironments", Small, 2020, 2001432, 10.1002/smll.202001432

5) Richards, J.M., Kunitake, J.A.M.R., Hunt, H.B., Wnorowski, A.N., Lin, D.W., Boskey, A.L., Donnelly, E., Estroff, L.A., Butcher, J.T. "Crystallinity of Hydroxyapatite Drives Myofibroblastic Activation and Calcification in Aortic Valves" Acta Biomater., 2018, 71, 24-36

Development of in vitro models of hydroxyapatite-organic matrix-cell interactions in breast cancer

We apply our synthetic expertise to the design of in vitro systems to address questions about cell-mineral interactions, primarily in the context of disease. Our objective is to understand the biological role of the materials properties of mineral deposits in both healthy and diseased tissue. Our work in this area is distinguished by a focus on how the materials science of the system impacts the cellular response to the minerals. We have applied this approach to several different biological systems, specifically microcalcification formation in breast tumors and breast cancer metastasis to bone. For example, we are using a 3D cell culture model, which recapitulates key features of breast tumors, to investigate the biomineralization pathway(s) that lead(s) to the formation of microcalcifications in tumors. In related work, we have developed a suite of synthetic techniques to control the physicochemical properties of apatite crystals, including hydrothermal synthesis of well-defined nanoparticles and a biomimetic method for obtaining mineralized collagen fibrils. We have characterized how these materials interact with biomacromolecules to change their conformation and with cells to change their behavior. This body of work has provided important insight into how the materials properties of bone itself, rather than the cells, can provide microenvironmental cues to drive breast cancer metastasis to bone, and provides new targets for therapeutic strategies.

1) Choi, S., Friedrichs, J., Song, Y.H., Werner, C., Estroff, L.A., Fischbach, C. "Intrafibrillar, bone-mimetic collagen mineralization regulates breast cancer cell adhesion and migration" Biomater., 2019, 198, 95-106. https://doi.org/10.1016/j.biomaterials.2018.05.002

2) Vidavsky, N., Kunitake, JAMR, Chiou, A.E.,Northrup, P.A., Porri, T., Ling, L., Fischbach, C., Estroff, L.A., "Studying biomineralization pathways in a 3D culture model of breast cancer microcalcifications", Biomater. 2018, 179, 71-82. https://doi.org/10.1016/j.biomaterials.2018.06.030

3) Pathi, S.P.; Lin, D.D.W.; Dorvee, J.R.; Estroff, L.A.; Fischbach, C. "Hydroxyapatite Nanoparticle-containing scaffolds for study of breast cancer bone metastasis." Biomaterials, 2011, 32, 5112-5122.

4) He, F.; Springer, N. L.; Whitman, M. A.; Pathi, S. P.; Lee, Y.; Mohanan, S.; Marcott, S.; Chiou, A. E.; Blank, B. S.; Iyengar, N.; Morris, P. G.; Jochelson, M.; Hudis, C. A.; Shah, P.; Kunitake, J. A.M.R.; Estroff, L. A.; Lammerding, J.; Fischbach, C. "Hydroxyapatite Mineral Enhances Malignant Potential in a Tissue -Engineered Model of Ductal Carcinoma in Situ (DCIS)." Biomaterials 2019, 224:119489. doi: 10.1016/j.biomaterials.2019.119489. Epub 2019 Sep 11

5) Vidavsky, N., Kunitake, JAMR, Estroff, L.A. "Multiple Pathways for Pathological Calcification in the Human Body" Adv. Healthcare Mater. 2020, 2001271. https://doi.org/10.1002/adhm.202001271

6) Kunitake JAMR, Choi S, Nguyen KX, Lee MM, He F, Sudilovsky D, Morris PG, Jochelson MS, Hudis CA, Muller DA, Fratzl P, Fischbach C, Masic A, Estroff LA. "Correlative imaging reveals physicochemical heterogeneity of microcalcifications in human breast carcinomas." J. Struct. Biol. 2018, 202, 25-43, https://doi.org/10.1016/j.jsb.2017.12.002

7) Vidavsky, N., Kunitake, JAMR, Diaz-Rubio, M.E., Chiou, A.E., Loh, H.C., Zhang, S., Masic, A., Fischbach, C., Estroff, L.A. "Mapping and profiling lipid distribution in a 3D model of breast cancer progression", ACS Cent. Sci., 2019, 5, 768-780. http://dx.doi.org/10.1021/acscentsci.8b00932

Bio-Inspired Crystal Growth of Complex Crystals

The Estroff Lab has advanced the field of bio-inspired crystal growth in which we learn new "tricks" from biology and apply them to synthetic systems. We have significantly contributed to the field's understanding of the mechanisms by which biological and synthetic crystals occlude additives ranging from small molecules to gel fibers to nanoparticles, and the effect of these additives on the materials properties of the resulting complex crystalline structures. We have developed multiple bio-informed synthetic strategies to grow complex crystals with a variety of inclusions and properties. We have focused on crystal growth in hydrogels as an approach for preparing gel/single-crystal composites. Importantly, we demonstrated that gel-grown crystals can incorporate the gel matrix to form crystalline materials reminiscent of biogenic single-crystal composites. More recently, we have expanded our tool-box to include crystal growth in confinement as a means to promote inclusion of second-phase particles, e.g., incorporation of plasmonic nanoparticles within semiconductor rods. Very recently, we have introduced a nanostructured block-copolymer based template (iSTAMP) to direct the crystallization of materials. We can change, in a controlled fashion, the nanoscale geometry, topology and surface chemistry of this template, thus enabling us to explore the connection between chemical functionality and topology in directing nucleation and growth. This powerful new platform can interrogate information transfer between the organic and inorganic components during the early stages of crystallization.

1) Palin, D., Style, R.W., Zlopasa, J., Petrozzini, J.J., Pfeifer, M.A., Jonkers, H.M., Dufresne, E.R., Estroff, L.A. "Forming Anisotropic Crystal Composites: Assessing the Mechanical Translation of Gel Network Anisotropy to Calcite Crystal Form", J. Am. Chem. Soc., 2021, 143, 3439-3447. https://doi.org/10.1021/jacs.0c12326

2) Asenath-Smith, E.; Li, H.Y.; Keene, E.C.; Seh, Z.W.; and Estroff, L.A. "Crystal Growth of Calcium Carbonate in Hydrogels as a Model of Biomineralization." Adv. Funct. Mater., 2012, 22, 2891-2914

3) Li, H.Y.; Xin, H.L.; Muller, D.A.; Estroff, L.A. "Visualizing the 3D internal structure of calcite single crystals grown in agarose hydrogels." Science 2009, 326, 1244-1247

4) Oleske, K.W., Barteau, K.P., Beaucage, P.A., Asenath-Smith, E., Wiesner, U., Estroff, L.A. "Nanopatterning of Crystalline Transition Metal Oxides by Surface Templated Nucleation on Block-Copolymer Mesostructures" Cryst. Grow. Des., 2017, 17, 5775-5782. 10.1021/acs.cgd.7b00767

Tissue Engineering of Interfacial Tissue Structures

We apply our understanding of biomineralization to designing tissue engineering strategies for gradient tissues such as the bone-cartilage and bone-meniscus interface. We have performed correlative chemical, structural, and mechanical analysis of the stiff-to-compliant gradient in the meniscus-to-bone enthesis. The results of this study in turn inform the design of tissue engineered constructs of similar mechanically robust interfaces. Ultimately, these efforts can lead to implantable materials for the repair of damaged interfacial tissues in the body.

1) Boys, A.J., Zhou, H., Harrod, J.B., McCorry, M.C., Estroff, L.A., Bonassar, L.J. "Top-down Fabrication of Spatially Controlled Mineral Gradient Scaffolds for Interfacial Tissue Engineering.", ACS Biomater. Sci. Eng., 2019, 5, 2988-2997 10.1021/acsbiomaterials.9b00176

2) Zhou, H., Boys, A.J., Harrod, J.B., Bonassar, L.J., Estroff, L.A. "Mineral Distribution Spatially Patterns Bone Marrow Stromal Cell Behavior on Monolithic Bone Scaffolds." Acta. Biomater. 2020, 112, 274-285. 10.1016/j.actbio.2020.05.032

3) Iannucci, L.E., Boys, A.J., McCorry, M.C., Estroff, L.A., Bonassar, L.J. "Cellular and Chemical Gradients to Engineer the Meniscus-to-Bone Insertion" Adv. Healthcare Mater. 2019, 1800806, 10.1002/adhm.201800806

4) Boys, A, McCorry, M.C., Rodeo, S., Bonassar, L., Estroff, L.A., "Next Generation Tissue Engineering of Orthopedic Soft Tissue-to-Bone Interfaces" MRS Commun., 2017, 7, 289-308

Last Revised: 2022/03/09

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