1. Solid-state chemistry can have significant impact on health and medicine, areas of high visibility and societal impact Metals, metal alloys, ceramics, non-absorbable polymers: the "stuff" of devices & implants Solid-state chemistry has an important role in tissue engineering and certain disease pathways: crystallization, solid-state reactivity, surface modification and reactivity, aggregation Complex interactions with proteins and cells need to be defined at a fundamental level The effects of nanosized features on these interactions and the ability of biology to “sense” different crystal structures (e.g. atomic spacing, surface structure and composition) need to be unraveled Need improved understanding of crystallization in biological systems Scientists, engineers, and clinicians must bridge a “culture” gap for interdisciplinary interactions Need improved understanding of crystallization processes in the organic solid state, including control of solid state structure (polymorphism) Requires support of far-reaching cross-disciplinary interactions May require joint funding initiatives among different agencies Solid-state chemistry, biology, biomaterials, and health

2. Solid-state chemistry and biology Bioactive glasses: SiO 2 –CaO–P 2 O 5 –MO (M= Na, Mg, etc.) Bone-forming activity associated with: - composition - porosity - specific surface area - crystallinity - particle size Slow induction period for crystalline apatite formation Lack of plasticity limits practical applications Requirements for bioactive glass: - can be injected and molded into irregularly shaped defects in bones and teeth - hardens rapidly - promotes rapid formation of biocompatible HA layers that promote cellular processes

3. Solid-state chemistry: new biocompatible cements Plastic but rapid setting cement from mesoporous bioactive glass in ammonium phosphate solution Fully set cement retains geometrical shape and mechanical strength Induces accelerated in vitro calcium-deficient hydroxyapatite nanocrystals (Ca 10 (PO 4 ) 6 (OH) 2 ) during setting (30 minutes) Mesoporosity + surface composition + regulation of Ca 2+ = superior in vivo bone-forming? extruded, 10 min. molded, 10 min. Stucky, et al., Adv. Mater. 2006, 18, 1038

4. Solid-state chemistry and bioactive surfaces Human osteoblast cells on Si-3 after 1.5 hours: actin filaments (red); focal adhesions (green) Solid monolayer films with reactive tails AFM: 1.8 nm thick, roughness = 0.4 nm Adhesion of osteoblasts, fibroblasts, tumor cell lines. Also two different Chinese hamster ovary (CHO) cell lines with RGD-binding  5  1 and  v  3 integrins Generic surfaces with hydrolytic stability and physiologic activity CHO  4 adhered specifically to an anti-  4-integrin antibody CHO  5 cells adhered specifically to an anti-  5- integrin antibody Generic IgG antibody surfaces with immobilized monoclonal antibodies bind specific cell lines Schwartz, et al., Langmuir, 2004, 20, 5501

5. Solid-state chemistry and disease: kidney stones Kidney stones afflict > 10% of the U.S. population Stones are aggregates of crystalline biominerals that form in vivo Stones contain small amounts of protein that serve as “glue” Four critical steps: (1) nucleation, (2) crystal growth, (3) aggregation, (4) attachment Calcium oxalate monohydrate (COM) aggregates and adheres to epithelial cells => disease Calcium oxalate dihydrate (COD) “protective” => symptomatic Adhesion force measurements (with AFM) reveal the source of the pathological differences between COM and COD COM surfaces more adhesive than COD => associated with structure and composition of crystal faces A surprising link between solid-state chemistry, crystal structure, surface chemistry, and disease Therapies designed to shrink most adhesive faces of COM or suppress COM formation may prevent stone disease Processes relevant to other calcification processes as well as other crystallization-based diseases (gallstones, gout)

6. Solid-state chemistry and disease: kidney stones largest COM face in vivo, most adhesive by AFM largest COD face in vivo, least adhesive by AFM www.herringlab.com COM (100) stacks in a stone Ward, et al., J. Am. Chem. Soc., 2003, 125, 2854 Ward, et al., Proc. Nat. Acad. Sci. 2005, 102, 267 Ward, et al., J. Amer. Soc. Nephrol. 2005, 16, 1904

7. Pharmaceutical (organic) solid state chemistry: an “anti-nugget” Chemburkar, et al., Org Proc. Res. Dev. 2000, 4, 413. Bauer, et al., Pharm. Res. 2001, 18, 859. Law, et al., J. Pharm. Sci. 2001, 90, 1015. Morrisette, et al., PNAS 2003, 100, 2180. Ritonavir (Norvir, Abbot Labs) 1996: introduced as protease inhibitor Not bioavailable as solid form Oral liquid or semi-solid capsules Second, less soluble conformational polymorph formed upon standing Different bioavailability profile, needed to be reformulated, as Form II ($$$) Now 5 polymorphs total Regulating crystallization outcomes imperative! Need methods for reliable computational strategies for crystal structure prediction and efficient methods for discovery of polymorphs Need universal models for crystallization of complex molecules