Samuel Isaac Stupp - US grants

9977520
Marks

Major Research Instrumentation funds will be used to acquire instrumentation for polymer analysis: a high temperature gel chromatograph (GPC) and a light scattering detector, equipped with an argon ion laser, for additional detection capability. The available GPCs at Northwestern University do not have the high temperature capability or the sensitivity needed for cutting edge research in polymers. This new equipment will be installed in the Analytical Services Laboratory of the Department of Chemistry at Northwestern University. The greatest number of users will come from the Department of Chemistry, but the Department of Chemical Engineering and the Department of Materials Science and Engineering will also have research projects making significant use of this instrumentation. The equipment will address the need of several research groups to characterize polymer samples in terms of their molecular weights, molecular weight distributions, and hydrodynamic volumes in solution. This research covers a broad range of topics including new catalysts for polymerization, self assembly of supramolecular aggregates, thermo-responsive polymers for DNA sequencing, polymer degradation mechanisms, interfacial adhesion of semicrystalline polymers, and polymer processing. In addition to the important research that will benefit from the new instrumentation, there is a strong educational component. The graduate students, postdoctoral fellows, and undergraduate students using the instrument for their research will receive substantial benefit from working with a state-of-the-art instrument. In addition, a further benefit will come from a formal educational component of the instrument being available for laboratory classes. The combination of research and education applications will allow the benefit of this equipment to be felt by an increased number of users.

Major Research Instrumentation program funds will be used to acquire a gel permeation chromatograph for use in polymer analysis. This instrument will be use in a variety of projects of researchers in several departments at Northwestern University. The instrument will have a large impact on the research training of students, postdoctoral to undergraduate, by allowing them hands-on experience on a state-of-the-art instrument.

This is a Focused Research Group(FRG) award co-funded by the Polymers, Ceramics and Metals Programs in the Division of Materials Research. Effective, rapid and permanent skeletal repair is one of the grand challenges of bioengineering and biomaterials research. Load-bearing bone repair is critical in cases of aging-related surgery, accident, disease, and trauma. Current metallic implant technology usually relies on solid implants with a porous coating to enhance cell attachment. Difficulties with stress-shielding and interface failure as well as prolonged recovery times however persist. Here, this Focused Research Group proposes to make a significant contribution in this area by creating a novel biohybrid implant material for bone repair. The biohybrid will consist of a biocompatible titanium foam with pores coated with bioactive organoapatite, in which a biological phase will be grown to provide a biomimetic system with improved strength, stiffness and attachment to the skeleton.
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In the first stage, a fully porous titanium scaffold will be fabricated by a novel process based on the superplastic expansion of argon bubbles in a titanium matrix. In the second step, the inner and outer surfaces of the titanium scaffold will be coated with organoapatite, containing small quantities of organic molecules. Self-assembling molecules and supramolecular clusters will be used to bind the organoapatite to the metal surface. In the third step, bone growth will be induced by rotating the implant in an aqueous solution containing rat calvaria cells. In-vitro testing will assess ability to fully integrate bone into coated Ti foam and the influence of microstructure on mechanical properties and cell ingrowth will carefully studied. Each of the processing steps will be studied in detail, from which models will be developed to predict biologically and mechanically optimal biohybrids. The microstructure of the implant will be studied at each step with particular emphasis on (i) pores in the foamed materials (pore, size, volume fraction, shape and connectivity), (ii) coating morphology and microstructure in the biohybrid, and (iii) cell characteristics in the complete biohybrid. The mechanical properties of the implant will also be studied at each step, with emphasis on both the macroscopic scale (overall strength, stiffness, fatigue resistance) and the microscopic scale (metal/ceramic/bone interfaces). The experimental results will be validated using analytical and numerical mechanics models. The processing, microstructural and mechanical models will be integrate to allow for the design of an optimal biohybrid.

The cytoskeleton is instrumental in most aspects of cell function, which if controlled and modified, could enable early detection and viable treatment for cancer, Alzheimer's, muscular dystrophy, viral infections, and other devastating conditions. Nanoscale structure is key to the function of the cytoskeleton, which is composed of a set of one-dimensional objects with diameters on the order of 10 nm, including actin, intermediate filaments and microtubules. Functions such as cell division, cell motility, membrane trafficking, intracellular transport of cargo, cell-cell interactions, signal transduction and the establishment and maintenance of cell form are all associated with cytoskeletal processes. Understanding the cellular nanomachinery involved in organizing and moving cytoplasm could offer fundamental insights into cell proliferation, morphogenesis, tissue organization, wound healing, the immune response, stem cell differentiation, development and plasticity of the nervous system and the response of an organism to infectious microbes. Engineering principles and the characteristics of these natural 'devices' will drive the development of new nanoscale tools for cytoskeletal biology. Similarly, elucidating nanoscale aspects of biological phenomena will generate fresh strategies to cure or prevent disease. These strategies will likely rely on either nanotechnology tools or synthetic, biocompatible nanostructures rather than the small molecule drugs and proteins currently in use. We propose to establish a Nanomedicine Development Center to 1. study the assembly and dynamics of cytoskeletal structures, 2. unravel function and regulation of these structures in intracellular traffic, cell division and cell motility, 3. develop and implement nanoscale strategies and tools to overcome the challenges of cytoskeletal research, and 4. build prototype devices and nanomaterials to implementing these new insights for diagnostic and therapeutic purposes. The new Center will be housed at Northwestern's interdisciplinary Institute for Bioengineering and Nanoscience in Advanced Medicine. (IBNAM)

DESCRIPTION (provided by applicant): Regenerative medicine is one of the great biomedical challenges of this century, seeking to regenerate parts of the human body throughout life lost to trauma, disease, or genetic factors. Real progress will hinge on our ability to combine effectively the frontiers of technology, biology, and clinical medicine to develop regenerative strategies. This Bioengineering Research Partnership (BRP), proposed by a team of seven investigators in the fields of neurology, surgery, endocrinology, materials science, chemistry, biomedical engineering, and chemical engineering, focuses on two specific challenges of great clinical importance, regeneration of the central nervous system (CNS) and cell replacement therapies for diabetic patients. In this application the target of the team is to develop multiple scaffold technologies and use CNS regeneration and pancreatic tissue replacement as their testing ground. The CNS targets include injection of self-assembling molecules and genetically engineered stem cells into the injured spinal cord or brain following stroke, and the diabetes targets include the development of a subcutaneous islet transplant. The four basic technologies are self-assembling nanofibers customizable to bear multiple tissue specific biological epitopes or have programmable delivery of growth factors; microporous biodegradable scaffolds that deliver genes or growth factors and guide cell migration; post-translationally modified recombinant polypeptides with customizable architecture and bioactivity; and enzyme-driven liquid-to-solid transitions of soluble bioactive peptides. The integrated scaffold technologies proposed include, the use of self-assembling nanofiber technology to modify microporous materials and create micro-nano hierarchical scaffolds, the adaptation of recombinant polypeptides for in situ enzyme driven solidification, and the development of bioactive two-phase molecular composite scaffolds containing linear polypeptides and peptide nanostructures.

Regenerative medicine is one of the great biomedical challenges of this century, requiring research at the interface of the physical and life sciences as well as engineering. Cell-based therapies for tissue and organ regeneration will involve not only stem cell biology but also the crafting of bioactive matrices to support tissue growth. This will require cutting-edge supramolecular chemistry, nanotechnology, and microscale process engineering. Thus a central component of the proposed Center of Excellence in Translational Human Stem Cell Research at Northwestern University will be a Matrix Synthesis and Biomaterials Core. This core will develop novel synthetic scaffold materials for use in preclinical studies with human stem cells. These synthetic biomaterials will be made available to other investigators in the proposal, facilitating collaborative development of molecularly designed scaffolds for in vitro culture of human stem cells, as well as viable stem cell delivery strategies for cell-based therapeutics. Our technological hypothesis is that optimal regeneration of human tissues from stem cells will ultimately require molecular, nanoscale and microscale design of scaffold materials, which will have broad applicability to the treatment of a wide range of human diseases. Because less invasive delivery of scaffolds is desirable for clinical use, in situ self-assembly could be an important element of scaffold technologies. Thus scaffolds that can assemble themselves from simple liquid injections are desirable. Furthermore, artificial scaffolds for culturing human stem cells could eliminate the need to culture these cells on fetal animal cell layers, reducing the consequent barriers to human transplantation for cell-based therapeutics. By promoting differentiation into desired lineages, these scaffolds could also reduce the economic cost of such therapies, reducing the need for separation and purification of biological factors during expansion of progenitor cells. An iterative, discovery-driven process will be used to identify and then optimize scaffold materials to achieve the goals of this proposal, including the regeneration of central nervous system tissues and pancreatic islets.

Intellectual Merit
The United States and Japan have recognized Nanoscience and Nanotechnology as frontier areas
of research with potentially widespread societal impact, promising to transform health,
electronics, transportation, the environment, and national security. In both countries, significant
investments in these areas have been made and their rapid growth is expected to continue in the
future.
To be successful, research and training efforts in this emerging arena have to be highly
interdisciplinary and interactions will have to span not only across fields and professional hubs,
but also across international boundaries, so that the strengths and resources available in each
country can also benefit other countries. With this in mind, the Japanese Ministry of Education,
Science, Culture, Sports, Science and Technology (MEXT) and the United States National
Science Foundation (NSF) initiated the support of scientific exchange visits between the two
countries. We propose to organize the next exchange visit to several Japanese universities for
twelve US scientists early in their academic careers, with research interests broadly defined as
Nanoscience and Bionanotechnology. The Japanese government will sponsor a similar trip of
twelve young scientists from Japan to several US universities as the counterpart component in
this exchange program. The focus on young scientists is driven by the premise that the
possibilities for building long-term and meaningful partnerships are far higher if contacts are
made early in one's career.

Impact of Proposed Research
Links established between scientists in the US and Japan at the very early stages of their
academic careers will lay the foundation for a long-term fruitful collaboration over an extended
period, maximizing the likelihood for a successful global interdisciplinary effort and productive
relationship between these two and other countries.

One of the great challenges in bioengineering is the effective repair of the human skeletal system. At the same time, bone is a very rich substrate to learn about structure-property relations in materials. Despite decades of research and the importance for human health and quality of life, ideal systems for skeletal repair have not yet been achieved. The ability to synthesize novel biomimetic micro- and nanostructured materials will enable the development of materials designed to trigger bone repair and perhaps to achieve the remarkable properties of bone in artificial systems. Porous metal coatings that allow bone ingrowth for device fixation have been developed, however success is limited by debonding of the coatings, as well as by the biological unpredictability of bone growth. This project explores the alternative approach of using fully porous metallic foam for the implant device, which both provides a porous structure ideal for bony ingrowth and lowers implant stiffness, thereby reducing stress-shielding problems seen with solid metallic implants. This approach combines with the modification of internal surfaces in titanium or titanium alloy foams with self-assembling polymers designed to be bioactive and this way recruit the appropriate cells to grow bone within the pore volume. The supramolecular polymers are also used in this project to encapsulate bone cells during their self-assembly in the interior of metallic foams. Analytical modeling of the porous Ti is used in the project to provide good estimates of the elastic moduli, and using finite element analyses stresses are predicted as bone fills the pores.

This Focused Research Group project is being co-funded by the Polymers and Metals Programs in the Division of Materials Research and the Mechanics and Structures of Materials Program in the Division of Civil and Mechanical Systems. This interdisciplinary project aims to develop superelastic nickel-titanium metallic foams with moduli comparable to bone, which contain bioactive materials on their internal surfaces that invite rapid bone growth. These superelastic alloys may be useful for stimulating bone cells mechanically given their extensive recoverable deformation and will enable a novel insertion technique. The proposed work integrates the capabilities of three groups in metallurgical synthesis (Dunand), self-assembly (Stupp), and biomechanics (Brinson) to develop a mechanically- and biologically-active osteomimetic material with novel functions for optimized skeletal repair. Overlapping research and collaborative interactions will be pursued using the successful framework that was developed in a previous program on Ti foams. Porous NiTi samples created in the Dunand laboratory will be transformed into bioactive materials by self-assembly of supramolecular polymer coatings from the Stupp laboratory. These bioactive materials will be investigated for biological activity via bone ingrowth studies (Stupp) and linked to mechanical properties via cyclic in situ loading (Brinson). Feedback on the bioactivity (Stupp) as a function of loading, pore morphology and local properties from modeling (Brinson) will in turn suggest improvements in foam processing (Dunand).

As a research area, skeletal repair has broad impact because it is not only critically important to human health, human productivity, and quality of life, but it is at the same time highly interdisciplinary, and can therefore have great impact on graduate and undergraduate education. The approach to the subject in this proposed program offers a great opportunity for interdisciplinary training of students, integrating advanced metallurgy, organic chemistry, cell biology and mechanics to investigate a complex problem. The project's interdisciplinary nature is also a good platform to generate new ideas on biomimetic design of microstructure and nanostructure in materials using a mechanically adaptable, self-healing material as the model.

DESCRIPTION (provided by applicant): Hard tissues in the human body, such as bone and tooth enamel, are architecturally highly complex tissues with superior strength modulus and rigidity compared to other tissues. Their formation involves specific and tightly regulated molecular events between cells and their surrounding extracellular environments. Following injury or disease, the adult human body cannot initiate molecular mechanisms for repair similar to those that occur during initial hard tissue development. The emerging field of regenerative medicine aims at the successful structural and functional replacement of tissues lost to trauma or disease. With life expectancy increasing worldwide, age related tissue degradation, injury, or disease of skeletal and dental tissues pose a significant expense to healthcare, individual productivity, and the maintenance of an active lifestyle. In response to this pressing need, breakthroughs are needed to transform the strategies used for hard tissue regeneration. Our collaborative team seeks to uncover principles governing this regenerative response in hard tissue using three-dimensional self-assembling bioactive scaffolds as a model therapeutic material. Using a multidisciplinary approach spanning the fields of nanoscience, synthetic chemistry, genetics, and developmental biology, we propose the development of highly bioactive materials containing bottom up designed nanostructures with potential to effectively regenerate bone and tooth enamel. Our team aims to accomplish three main goals: 1) use rational molecular design to optimize new materials that can trigger the regeneration of bone and enamel, including the development of artificial substitutes that emulate the architecture of hard tissue matrices; 2) improve our understanding of the cellular and molecular mechanisms operating during hard tissue development and regeneration in order to optimize clinical regenerative strategies; and 3) assess the scalability of our technology toward future clinical trials.

TECHNICAL SUMMARY: Precise dimension and shape control remains a great challenge in the design of nanoscale organic structures. This program studies two different strategies toward precise control over size and shape in supramolecular assemblies. One approach involves the use of molecular templates to truncate one-dimensional self-assembled structures, and a second one explores the use of mechanical forces to spontaneously terminate the growth of assemblies or determine their precise shape and size. In the first approach synthetic dumbbell-shaped molecules with a rigid and hydrophobic linear core are proposed as templates to dictate the length of assemblies formed by peptide amphiphiles. The hydrophobic segments of these molecules should be attracted to the template core and growth of the assembly limited by the hydrophilic termini of the template. In terms of function, it is also of interest to investigate the electronic properties of these assemblies, as well as their ability to encapsulate active molecules with reproducible stoichiometry. The second approach examines two problems, the use of supramolecular strain mechanics to define helical shape in one-dimensional nanostructures and also to define the shape of nanostructures shaped as platonic solids. The first problem utilizes charged peptide lipid molecules in which bulky groups strain the b-sheets formed when self-assembly occurs in organic solvents. Preliminary studies have shown that bulky endgroups attached to the periphery of b-sheets cause nanofibers to relax into helical nanostructures with pitch determined by sterics. The research will validate this model and also study the use of templates to obtain precise assemblies. In the second problem, the challenge is to achieve precise definition of three-dimensional structures. The goal in the program is to construct structures with non-spherical geometries similar to natural virus capsids. Mixtures of oppositely charged amphiphilic molecules containing various types of rigid and hydrophobic segments are proposed as a strategy to assemble nanoscale platonic solids such as icosahedral objects. In these objects supramolecular strains associated with curvature could lead to packing with planar facets.


NON-TECHNICAL SUMMARY: Learning from the complex structure formations seen in nature has been one of the major goals of synthetic chemistry. Ultimately, this would not only allow us to design materials more effective in "human repair", but it would also enable us to construct artificial molecular machinery to carry out processes important for modern technology, for example in electronic and sensing devices. This is a subject requiring interdisciplinary research and links to other scientists around the world. The work cuts across physical sciences, life sciences, and engineering disciplines, and it is therefore an excellent platform for education of future scientists and for international collaborations. As a step toward this goal, the research proposed herein involves accurately controlling the shape and size of several self-assembling polymers previously discovered in this laboratory. This program explores two approaches toward this goal. One involves the use of molecules as external templates to dictate the dimension of the assemblies. The other approach programs assemblies through the molecular structure of building blocks to form nanostructures with non-spherical shapes similar to those acquired by viruses.

[unreadable] DESCRIPTION (provided by applicant): [unreadable] Northwestern University's Bioengineering Research Partnership (BRP) is comprised of investigators in the fields of neurology, surgery, endocrinology, materials science, chemistry, and biomedical and chemical engineering and is focused on central nervous system regeneration (CNS) and cell replacement therapy for diabetes. The BRP's general aims are to: (i) develop fundamental technologies to more sophisticated levels in an environment where feedback is provided by clinical investigators; (ii) cross breed and integrate four basic technologies to generate hybrid ones that can be clinically translated; (iii) make the technologies available for in vitro and in vivo testing in models of CNS regeneration and diabetes; and (iv) facilitate the mechanisms for iterative modification of the technologies in a team environment based on biological results and clinical insight. Dr. Galina Smushkin, a medical resident, plans to pursue a career in endocrinology research. The proposed project will integrate her into the BRP team, allowing her to gain valuable research training and experience and to perform novel research at the interface of material science, diabetes, and stem cell biology. The proposed hypothesis is that self-assembling nanofibrils can be used to deliver bioactive molecules to help direct differentiation of embryonic stem (ES) cells into insulin-secreting cells. This hypothesis will be tackled in the following specific aims: (1) developing a novel means to deliver either growth factors or DNA encoding a transcription factor using self-assembling nanofibrils; and (2) enhancing the differentiation of murine ES cells into insulin-secreting using these self-assembling nanofibrils. Dr. Smushkin will be co-mentored by the BRP PI, Sam Stupp, Ph.D., a materials scientist who leads the BRP interdisciplinary research team, and by a BRP Co-l, William Lowe., M.D., an endocrinologist studying cell replacement therapy for diabetes. Dr. Stupp will train the applicant in all experimental details related to the use of synthetic nanostructures, and Dr. Lowe will guide her in the areas of diabetes and stem cell biology. Dr. Smushkin's work will benefit from close interactions with the entire BRP team of investigators and their cross-discipline expertise. She will not only acquire new research training, skills and insights, but she will also be exposed to cutting edge, collaborative, and multidisciplinary environments and practices driving and shaping the scientists of tomorrow. [unreadable] [unreadable] [unreadable]

DESCRIPTION (provided by applicant): The central nervous system (CNS) is a highly complex collection of specialized cells whose successful function relies on effective cellular communication to transport signal information across all the body's tissues and systems. Injury to these cells, whether through toxic molecules or processes, mechanical stresses, or age-related/genetic illnesses, leads to the breakdown of this communication and subsequent cell death. Regenerative medicine procedures to regain the functionality of the CNS after these insults is therefore of critical importance in the medical community. However, the fully developed CNS in the adult human body has limited capacity to regenerate tissues and to form these essential new cellular connections when lost. Among the great needs in this field are therapies to treat spinal cord injury (SCI) in order to prevent or reverse paralysis, novel treatments for stroke and neurodegenerative diseases, as well as strategies to recover the function of optic and auditory nerves. New therapies could profoundly enhance quality of life for individuals facing these problems and significantly reduce health care costs as well. For example, in the United States alone, SCI affects 12,000 individuals every year, and approximately 259,000 Americans currently live with the devastating effects of SCI. Novel therapeutic approaches to CNS regeneration will have significant impact on health care and patient well-being. In this renewal application three investigators, from the medical, chemical, and materials sciences, propose research to develop therapies for that could be used to prevent paralysis after spinal cord injury and also a different therapy that could be surgically implanted to reverse paralysis. The approach involves the use of especially designed molecules known as peptide amphiphiles that self-assemble in the spinal cord into nanofibers. These nanofibers carry biological signals that promote regeneration in the traumatized tissue, and biodegrade within weeks into harmless nutrients. The specific strategy involves the use of several peptide-based signals that emulate the effect of natural proteins, and also the delivery of genes that will lead to the production in the cord of regenerative growth factors. For acute injury the therapy takes the form of an injectable liquid, and for the chronic injury it consists of a pre-fabricated gel implant to be placed after removal of the glial scar in paralyzed patients. Both therapies will be tested in well established mouse models for spinal cord injury.

DESCRIPTION (provided by applicant): Atherosclerosis remains the leading cause of death and disability in the United States. Current therapeutic modalities for the treatment of severe coronary and peripheral artery disease include balloon angioplasty and stenting, endarterectomy, or bypass grafting. Unfortunately, a large number of these procedures fail due to the development of arterial restenosis secondary to neointimal hyperplasia. The overall goal of this Bioengineering Research Partnership (BRP) is to develop highly innovative targeted therapeutics delivered by bio-inspired tailorable constructs to prevent restenosis following vascular interventions. We expect to develop biocompatible nano- and microscale therapies that will be delivered systemically at the time of arterial intervention, target the manipulated arteria segment, and deliver molecular therapies and drugs to that site to inhibit restenosis. Each of the three platforms proposed are bio-inspired and share common physicochemical properties such that unique aspects of each one may be leveraged by the others to achieve maximal therapeutic efficacy. Preliminary data demonstrate the successful synthesis and in vivo targeting of a novel injectable peptide amphiphile (PA) to the site of vascular injury following intra-arterial injectio. We have also designed a biomimetic high density lipoprotein (HDL) using a gold nanoparticle (AuNP) as a template to control the size, shape, and surface chemical properties of the formed HDL AuNPs. Lastly, micron scale cell- like structures has been synthesized to mimic elements in the blood stream. Overall, we hypothesize that novel; targeted bioengineered therapeutic agents will prevent the development of restenosis following arterial interventions. To investigate this hypothesis, the specific aims are as follows: 1) synthesize and characterize novel bio-inspired delivery vehicles that are targeted to the site of vascular injury and deliver effective therapeutic agents; 2) evaluate the effect of the targeted engineered therapeutic delivery vehicles on cells from the vascular wall in vitro; 3) determine the specificity, safety, biocompatibility, and efficacy of the targeted engineered therapeutic delivery vehicles at inhibiting neointimal hyperplasia in vivo. Through our multidisciplinary team of investigators, we have already accrued preliminary data that supports the feasibility of our approach. With the support of this BRP, we will provide targeted therapies to prevent restenosis for patients undergoing any vascular intervention. These therapies could revolutionize how atherosclerotic arteries are treated and thus represent a paradigm-shifting technology. Finally, the bioengineered therapies developed in this proposal will be targeted to multiple cell types. Thus, project success will profoundly impact the fields of interventional cardiology, interventional radiology, cardiothoracic surgery, and vascular surgery, but will have more broad ranging impact in the fields of preventive cardiology, cancer, inflammation, and rheumatology.

The Soft and Hybrid Nanotechnology Experimental (SHyNE) Resource NNCI site is a collaborative venture between Northwestern University (NU) and the University of Chicago (UC), building upon each institution's long history of transforming the frontiers of science and engineering. Soft nanostructures are typically polymeric, biological and fluidic in nature while hybrid represents systems comprising soft-hard interfaces. SHyNE facilities enable broad access to an extensive fabrication, characterization and computational infrastructure with a multi-faceted and interdisciplinary approach for transformative science and enabling technologies. In addition to traditional micro/nanofabrication tools, SHyNE provides specialized capabilities for soft materials and soft-hard hybrid nano-systems. SHyNE enhances regional capabilities by providing users with on-site and remote open-access to state-of-the-art laboratories and world-class technical expertise to help solve the challenging problems in nanotechnology research and development for non-traditional areas such as the agricultural, biomedical, chemical, food, geological and environmental, among other industries. A critical component of the SHyNE mission is scholarly outreach through secondary and post-secondary research experience and integration with curricula at both universities, as well as, societal outreach through a novel nano-journalism project in collaboration with the Medill School of Journalism. SHyNE promotes active participation of underrepresented groups, including women and minorities, in sciences and utilizes Chicago's public museums for broader outreach. SHyNE leverages an exceptional depth of intellectual, academic and facilities resources to provide critical infrastructure in support of research, application development and problem-solving in nanoscience and nanotechnology and integrates this transformative approach into the societal fabric of Chicago and the greater Midwest.

SHyNE is a solution-focused, open-access collaborative initiative operating under the umbrella of NU's International Institute for Nanotechnology (IIN), in partnership with UC's Institute for Molecular Engineering (IME). SHyNE open-access user facilities bring together broad experience and capabilities in traditional soft nanomaterials such as biological, polymeric or fluidic systems and hybrid systems combining soft/hard materials and interfaces. Collectively, soft and hybrid nanostructures represent remarkable scientific and technological opportunities. However, given the sub-100nm length-scale and related complexities, advanced facilities are needed to harness their full potential. Such facilities require capabilities to pattern soft/hybrid nanostructures across large areas and tools/techniques to characterize them in their pristine states. These divergent yet integrated needs are met by SHyNE, as it coordinates NU's extensive cryo-bio, characterization and soft-nanopatterning capabilities with the state-of-the-art cleanroom fabrication and expertise at UC's Pritzker Nanofabrication Facility (PNF). SHyNE addresses emerging needs in synthesis/assembly of soft/biological structures and integration of classical clean-room capabilities with soft-biological structures, providing expertise and instrumentation related to the synthesis, purification, and characterization of peptides and peptide-based materials. SHyNE coordinates with Argonne National Lab facilities and leverages existing super-computing and engineering expertise under Center for Hierarchical Materials Design (CHiMaD) and Digital Manufacturing and Design Innovation Institute (DMDII), respectively. An extensive array of innovative educational, industry and societal outreach, such as nano-journalism, industry-focused workshop/symposia and collaborations with Chicago area museums, provide for an integrated and comprehensive coverage of modern infrastructure for soft/hybrid systems for the next generation researchers and the broader society.

Project Summary After blood, bone is the most frequently transplanted tissue, with 1.6 to 2 million transplants performed in the US alone each year. Spine fusions are among the most common orthopaedic procedures requiring bone healing, with over 500,000 performed annually. Although transplantation of the patient's own bone is considered the gold standard for spine fusion, its use is challenged by donor site morbidity and inadequate availability of donor bone. Recombinant bone morphogenetic protein-2 (rhBMP-2) is a growth factor that is FDA-approved as a bone graft substitute, but serious adverse effects associated with its use have caused significant concerns by patients, physicians, and hospitals. Universally safe and effective bone graft substitutes for spine fusion do not currently exist for these procedures. Our long-term goal is to develop a highly effective strategy to regenerate bone using recombinant growth factor-free bioactive nanoscale materials, suitable to spine fusion and other orthopaedic applications. We will achieve this goal by implementing a multiaxial strategy to improve cell signaling for osteogenesis at the bone defect site, using two complimentary approaches: 1) application of our discovery that glycosylation of peptide amphiphile nanofibers achieves biomimetic presentation and enhanced signaling of host-derived growth factors involved in bone regeneration; 2) application of a second discovery that certain peptide nanofiber designs can invade cell membranes to enhance osteogenic signaling. The nanofiber scaffold developed in this work will be used either on its own or in combination with bone marrow stromal cells (BMSC) rather than with recombinant growth factor. Our studies will facilitate the repair and regeneration of bone by enhancing the bone-forming capacity of a patient's own native growth factors. Such an approach could obviate the need for recombinant factors, thereby providing a safer and more effective therapeutic strategy for bone regeneration in spinal fusion and other orthopaedic applications.

With the support of the Macromolecular, Supramolecular and Nanochemistry Program in the Division of Chemistry, Professor Samuel Stupp and Professor Monica Olvera de la Cruz of Northwestern University will explore nano-sized structures formed by the assembly of molecules (named amphiphiles) containing two distinct segments: one that has affinity for water and one that does not mix well with water. Specifically, the investigators will study how the arrangement of various species that bear one or more charged species (ions or electrolytes) can be used to change the structure and function of the nano-sized structures. The building blocks will be based on peptides, and therefore the findings can illuminate several biologically important processes. This work is inspired by the natural functions of cells, including signaling, movement, and ultimately survival, all of which depend on the tight regulation of ions inside and outside the cell membrane. The researchers will use a simultaneous experimental and computational approach to understand how added electrolytes interact with nanomaterials and how they impact critical cellular functions such as catalysis, energy storage, and bioactivity. This work is expected to have a broad impact on education as it is a risky approach that attempts to innovate beyond traditional scientific inquiries and therefore has a great deal of potential for unexpected discoveries, a good motivator for early career scientists.

The planned research under this study is to investigate how the presence of ions affects the shape and dimensions of supramolecular nanostructures based on self-assembling peptide amphiphile molecules. The work will also probe how the spatial positioning of these ions within nanostructures and in their immediate environment affects their mobility. The study is motivated by a recent discovery in the Stupp laboratory, which surprisingly showed that ion clouds can be engineered around supramolecular nanostructures and controlled by internal interactions between ionic liquids and the self-assembling PA molecules. The hypothesis is that large organic ions can act as dopants that produce denser clouds as electrolyte reservoirs that will impact in turn on properties such as bioactivity and external control of charge transport. By varying ionic strength of solutions and ion type, it is expected that hydration of the supramolecular structures will change as well as polarize associated water molecules and, in this way, provide for an opportunity to possibly tune ionic mobility. This work could lead to novel materials and also have great impact on our understanding of the role of environmental ions in biological systems.

This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.