Alyssa Panitch - US grants

A state-of-the art (scanning)transmission electron microscope (TEM)will be upgraded to an environmental TEM allowing near-atomic resolution imaging at pressures up to 8 Torr and temperatures up to 900 degree C. These capabilities are vital for proposed nanoscience, biotechnology and environmental science research. Near-atom-scale patterns will be defined by electron-beam decomposition of molecules adsorbed on surfaces. In situ investigation of vapor-liquid-solid grown Si nanopillars will facilitate rapid process optimization allowing growth on technologically relevant Si(100) surfaces. Characterization of artificial bone synthesized using genetically engineered osteoblasts will be facilitated by the capability for imaging hydrated specimens. Imaging at elevated pressure and temperature will be employed to discover novel materials useful for mineral sequestration of greenhouse gases. These advanced characterization capabilities will be fully integrated into the classroom learning experience and will significantly enhance industrial outreach facilitating academic/industrial knowledge transfer.
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A state-of-the art (scanning)transmission electron microscope (TEM)will be upgraded to an environmental TEM allowing near-atomic resolution imaging of diverse samples at pressures of up to 8 Torr and temperatures of up to 900 degree C. These capabilities are vital for cutting edge research proposed in strategic thrust areas at ASU including nanoscience and technology, biotechnology and environmental science. Specifically, electron beam stimulated surface chemistry will be employed for writing near atomic scale patterns, real-time imaging will be used to optimize process conditions for Si nanopillar formation, characterization of tissue engineered artificial bone and in situ investigation of mineral sequestration of greenhouse gases. The advanced characterization capabilities of this instrument will be fully integrated into classroom learning at ASU through its internet connection to the Goldwater Materials Visualization Facility. Further, these capabilities will enhance academic/industrial knowledge transfer facilitated by our highly successful Industrial Associates program.

0238917
Panitch
This work focuses on the synthesis and characterization of biomimetic, self-assembling hydrogels that are useful for delivery of bioactive compounds. These hydrogels will be unique in several respects: they are physical gels with the consistency of ointment that can be polymerized in situ or spread onto an area; drug release from the gels is dependant on the affinity of the drug for the gel; the affinity of the drug for the gel can be tailored; and the dissolution of the gel can be controlled based on the affinity of the constituents for one another. It is hypothesized that physical gels formed by combining peptide-modified poly(ethylene glycol) star polymers (PEG stars) and sulfated polysaccharides can be tailored to control both dissolution of the gel and release of bioactive components. It is further hypothesized that these gels will release bioactive components on a physiologically-relevant time scale. To verify these hypotheses, gels will be made with 4-arm and 8-arm PEG stars and heparin, chondroitin sulfate or dextran sulfate. The gels will be complemented with four distinct polysaccharide-binding peptides, and the release of the peptides will be studied. Finally, the bioactivity and physiological application of the gel will be tested for the case of vasorelaxation.

The overall goal of the project is to develop a new class of hydrogel release systems. These release systems can be polymerized in situ, are soft and pliable and can be used in clinical situations where ointment-like materials with controlled release characteristics are necessary. The first target application is a gel that promotes vasodilation in an in vitro saphenous vein model. The proposed work lends itself to future work in controlled release from both physical gels and covalent gels; biologically- based and synthetic molecules can be tailored to release via similar schemes. In addition, the scaffolds can be used as artificial extracellular matrices, which are capable of sequestering factors, releasing factors and sustaining cell growth and survival.

The educational component consists of curriculum development at ASU as well as outreach to Scottsdale Community College. A survey course of Molecular, Cellular and Tissue Engineering will be developed. This class will serve several purposes: the opportunity for graduate students to become involved in course development and in teaching, the exposure of community college students to bioengineering and the creation of laboratory opportunities for undergraduate students from Scottsdale Community College.

DESCRIPTION (provided by applicant): While much of the PI's previous research has been peripherally related to biomedicine, it was all done as an engineer's approach to solve biomedical problems. The materials were designed with only a basic understanding of the biological and medical needs. The proposed training opportunity would provide the PI with an in depth knowledge of some aspects of vascular medicine and physiology as well as added knowledge in mathematical modeling and peptide chemistry. The overall goal is to expand the PI's experience and training in biomedicine as well as in peptide chemistry and modeling to position her for a lifetime of research in biomedicine. Cardiovascular disease is the leading cause of death in the United States. The treatment of cardiovascular disease often involves surgically bypassing occluded segments of blood vessels with human saphenous vein grafts. The development of vein graft stenosis within 1 year after implantation occurs in up to 20-40% of grafts and frequently leads to end-organ failure, including myocardial infarction and extremity amputation. Short-term graft failure is due to technical problems and vasospasm during harvest and preparation. Long-term graft failure is due to a hyperplastic wound healing response, intimal hyperplasia. The purpose of this proposal is to develop a protein/peptide based therapeutic agent to enhance graft patency. The hypotheses of this investigation is that synthetic phosphorylated heat shock related protein human (HSP20) analogues (pHSP20) can be optimized and delivered in a controlled manner that will prevent vein graft spasm and intimal hyperplasia. The specific aims are to: 1) Optimize TAT-pHSP20 as a functionally active biomolecule, la) Develop and synthesize a panel of analogues of the TAT-pHSP20 peptides, lb) Determine the bioactivity of the peptides ex vivo using strips of human saphenous vein grafts. 2) Develop and characterize controlled release systems for TAT-pHSP20 to ensure sustained delivery of the biomolecule in an effective therapeutic concentration. 2a) Determine the association and release of TAT from the heparin biogel. 2b) Determine the bioactivity of the biogel ex vivo in a muscle bath using strips of human saphenous vein grafts.

CBET-0754442
Akkus

Collagen plays a central role as a biomaterial and as a scaffold in the regenerative tissue replacement strategies. Surgeries of load bearing tissues such as tendons and ligaments are occurring by hundreds of thousands annually and existing synthetic analogs of collagen have extremely poor biomechanical properties in comparison to the tissues they are targeted to replace. This shortcoming is due, in part, to the lack of orientation in hierarchical orders above the level of fibers.

This project will improve the strength and viscoelasticity of synthetic collagenous constructs to match those of natural counterparts by: a) an unconventional electrochemical process to attain an unprecedented level of molecular alignment and molecular packing density persistent across all levels of structural hierarchies, and, 2) the control of interfibrillar attachment by use of a biomimetic decorin-like linkage molecule. Phase 1 of proposed studies will optimize the mechanical strength and stiffness of the construct by elucidating the mechanisms by which collagen solutions achieve long-range order under the effect of weak currents applied directly to the solutions. The effects of electric current amplitude and collagen concentration on the hierarchical organization of collagen will be investigated to optimize the synthesis process. The strength of resulting oriented collagen gels will be improved by identifying the appropriate type and concentration of crosslinking amongst glutaraldehyde, genipin, nordihydroguaiaretic acid (NDGA) or ribose. Phase 2 will modulate the viscoelastic properties of oriented and crosslinked gels by decorin mimics consisting of dermatan sulfate attached to peptide motifs which selectively bind to type I collagen molecules. Mechanical properties of resulting synthetic constructs will be assessed at the bundle and the fiber levels by macroscale mechanical tests and atomic force microscopy, respectively, and compared to those of rat tendon, a reference natural tissue. The third phase is going to assess the phenotypic and genotypic response of tendon fibroblasts seeded in three-dimensional networks of the oriented collagenous construct in vitro, and, by assessing the non-enzymatic and enzymatic degradation rates of constructs in vitro.

The project will include the outreach component of familiarizing the minority middle-school student population with the emerging field of biomedical engineering. This aim will be attained by a summer activity during which students will conduct hands-on projects in the area of biomedical engineering through coordination with the Minority Engineering Program at Purdue University. Broader impacts will be further strengthened by creation of a laboratory module in an undergraduate biomechanics/biomaterials laboratory by incorporating outcomes of the proposed research and by way of accommodating 9 undergraduates for summer research during the course of the project through Summer Undergraduate Fellowship program (SURF) at Purdue.

In the overall, the proposed study will develop a novel fabrication process towards the design of a new biomaterial which may play a key role in creating strategies towards replacement of tissues such as tendons, ligaments, skin, cornea and vascular walls.

DESCRIPTION (provided by applicant): Collagen plays a central role as a biomaterial and as a scaffold in the regenerative tissue replacement strategies. Existing synthetic analogs of collagen have extremely poor biomechanical properties in comparison to the tissues they are targeted to replace due, in part, to the lack of orientation in hierarchical orders above the level of fibers. The overall goal of the proposed study is to demonstrate the feasibility of a novel biomechanically competent collagenous tissue engineering scaffold fabricated by: 1) an unconventional electrochemical process to attain an unprecedented level of molecular alignment and molecular packing density persistent across multiple levels of structural hierarchies, and, 2) the control of interfibrillar attachment by use of a biomimetic decorin-like linkage molecule. Phase 1 of proposed studies will elucidate the mechanisms by which collagen solutions achieve long-range order under the effect of weak currents applied to directly to the solutions. The effects of pH gradient electric current amplitude and collagen concentration on the hierarchical organization of collagen will be investigated to optimize the synthetic process. The strength of resulting oriented collagen gels will be improved by identifying the appropriate type and concentration of crosslinking amongst genipin and glutaraldehyde. {The D-banding pattern and collagen fibril diameter will be improved by modulating the phosphate buffered saline treatment conditions.} The viscoelastic properties of oriented constructs will be modified by decorin mimics consisting of dermatan sulfate attached to peptide motifs which selectively bind to type I collagen molecules. Mechanical properties of resulting synthetic constructs will be assessed by macroscale mechanical tests and compared to those of rat tendon, a reference natural tissue. {Phase 2 is going to assess the differentiation of bone marrow derived mesenchymal stem cell progenitors on this material towards tenocytic lineage and foster this differentiation pathway by the mechanical cue.} Overall, the proposed study will: a) optimize the fabrication process variables of a novel fabrication method to obtain highly oriented tendon-mimicking constructs, and, b) assess the feasibility of the material as a tissue engineering scaffold by investigating phenotypic and genotypic behavior of bone marrow derived stem-cell progenitors seeded within the three-dimensional structures consisting of multiple collagenous bundles. A biomaterial of this nature may play a key role in creating strategies towards replacement of load bearing connective tissues such as tendons, ligaments, bones and vascular walls provided that the current study proves its feasibility. PUBLIC HEALTH RELEVANCE: The overall goal of the proposed study is to demonstrate the feasibility of a novel collagenous tissue engineering scaffold with mechanical properties converging those of tendon or ligaments. The study will assess the promise of this novel material by investigating whether adult stem cells seeded on this material differentiate to act like tendon cells.

The Targeted Math-Science Partnership of Science Learning through Engineering Design (SLED) vision is to increase grade 3-6 student learning of science by developing Indiana's first integrated, engineering design-based approach to elementary/intermediate school science education. The partnership involves Purdue University's colleges of Engineering, Science, Technology, and Education working with four Indiana school districts: Taylor Community School Corporation, Plymouth School Corporation, Lafayette School Corporation, and Tippecanoe School Corporation. The project is devising a design- and standards-based curriculum, inventing design-informed science instructional methods, and implementing on-going assessments to inform the project at the pre- and in-service teacher education levels in central Indiana. The partnership is using summer institutes, linkages with Purdue pre-service teachers, cyber-infrastructure, action research, and graduate coursework to equip teachers with design-based pedagogical skills and science content. An external advisory board consisting of recognized experts in science education, mathematics education, and engineering design meet annually to provide input to the project team.

The project has four interrelated components:

1) collaboration between STEM disciplinary faculty and grades 3-6 teachers to adapt and develop engineering design-based tasks;
2) an in-service teacher professional development program to equip grades 3-6 teachers in partnering schools to use engineering design as a tool for teaching science through authentic, inquiry-based, multi-disciplinary design units;
3) a pre-service teacher education program to prepare future elementary school teachers to teach science using the engineering design process; and
4) research that will investigate how grades 3-6 teachers teach science through the engineering design process and how students learn through design-based activities.

Specific outcomes that the partnership is working to produce include:

1) In-service professional development for 200 elementary/intermediate school teachers and preparation of 100 pre-service teachers in the use of engineering design to teach science through authentic, inquiry-based, multi-disciplinary design projects.
2) Improved science achievement of 5,000 students in grades 3-6 in the partner schools through exposure to engineering design-based curriculum and activities implemented by teachers.
3) A library of tested, design-based curricular materials to support teaching science in grades 3-6.
4) Creation of a cyber-infrastructure-enabled community of practice related to science education through engineering design that can disseminate grades 3-6 engineering design-based curriculum materials.
5) Research on the understanding of how teachers teach science through the engineering design process and how young students learn science through design-based activities.
6) Institutionalization of engineering design-based innovation through the development of an undergraduate engineering design-focused science methods course, a graduate course for in-service teachers and STEM graduate students, and the integration of engineering design-based curriculum in grades 3-6 of partner schools.

DESCRIPTION (provided by applicant): The objective of this proposal is to develop and implement an educational experience that trains undergraduates to work on multidisciplinary teams to design solutions that address challenging, real-world biomedical problems at the interface of engineering and living systems. The proposed training employs pedagogical elements of modeling, scaffolding, coaching and fading to teach design principles. Active learning studio style courses that address responsible conduct in research are coupled with inquiry-based and design laboratories that are supported by faculty and clinical mentors within multidisciplinary and multicultural environments to transform the undergraduate students to practicing engineers well equipped with theoretical knowledge, creativity, ethical behavior, and strong problem solving skills. Within the proposed curriculum, the students fully experience the design process from need identification and idea generation through the iterative process to ultimately resolve the problem. Exposure to principles and successful examples of technology transfer, intellectual property, and commercialization prepare the students to take their design from the classroom to the clinical market. Recruitment activities will specifically target increasing the numbers of students from underrepresented racial, ethnic, and female groups as well as individuals with disabilities and those from disadvantaged backgrounds. Dissemination of findings and best practices will be through conference presentations, journal articles, and the internet. PUBLIC HEALTH RELEVANCE: Our proposed design training will prepare our undergraduate biomedical engineers to work on multidisciplinary teams and effectively generate and contribute to the solution of challenging, complex, real-world clinical and healthcare problems. These students will understand the product cycle, be able to recognize the potential for a new discovery or technology to address a current need, be creative and design solutions to clinical problems, and be prepared to translate their innovations into clinical solutions.

DESCRIPTION (provided by applicant): The number of percutaneous coronary intervention (PCI) procedures, commonly known as balloon angioplasty, has increased by 30% over the past 10 years totaling more than 1.3 million patients in the U.S. annually at a cost of more than $60 billion [1]. However, PCI procedures are not without post-procedure complications including thrombosis and restenosis [2]. PCI procedures result in injury of the vessel wall, which in turn initiates inflammation and coagulation through platelet activation. Attenuating the inflammatory and coagulation responses can mitigate the negative impact of the injury [3-5]. Drug-eluting stents (DESs) have been used widely due to their ability to prevent restenosis. However, a complication of DESs is development of late in-stent thrombosis at the same rate as the bare metal stents (BMSs). The DESs used in clinical application deliver an anti-proliferative agent, such as sirolimus or paclitaxel (PTX), which inhibits not only smooth muscle cells (SMCs) proliferation, but also prevents proliferation of endothelial cells (ECs). Controlling the late thrombosis, which occurs between 1 month and 1 year after stenting, requires solving fundamental problems related to the lack of EC growth in the stented area, while maintaining the inhibition of intimal hyperplasia offered by the antiproliferative drug. The main objective of this project is to further develop our in vitro model of both normal and hyperplasic vessels [6], in order to test novel therapies that, in conjunction with stents, will control thrombosis and inflammation, and therefore, intimal hyperplasia, thus improving the outcomes for DESs. The hypothesis of this proposal is that the late in-stent thrombosis is largely due to the lack of growth of ECs over the stented area, and further, that both SMC proliferation and lack of EC growth can be controlled through early steps of preventing initial platelet binding, attenuating inflammation and limiting the SMC mitogenic response. To address this hypothesis we have developed four specific aims in which we will investigate the delivery of a peptide drug that has been designed to inhibit inflammation and restenosis without affecting EC migration and proliferation, and shown in vivo to inhibit intimal hyperplasia. We will couple release of this drug from a DES with a temporary monolayer coating of blood vessel with peptidoglycan (dermatan sulfate (DS)) conjugated with collagen-binding eicosapeptide, RRANAALKAGELYKSILYGC (abbreviated SILY)) that prevents platelet adhesion and activation in order to limit platelet activation and SMC proliferation leading to intimal hyperplasia and late-term thrombosis. Finally, we will deliver probucol to promote EC growth over the stented area. At the end of the proposed studies we will have a simple vessel coating approach and a DES targeted to inhibit SMC proliferation and promote reendothelialization that will have been evaluated for in vivo proof-of- concept and will be ready for extensive in vivo evaluation for improving the outcomes of PCI procedures. !

DESCRIPTION (provided by applicant): The incidence of type 2 diabetes mellitus is on the rise to the extent that diabetes rapid and widespread nature has been referred to as pandemic in the United States; type 1 diabetes is also increasing at an unexpected rate. As such, there is an urgent need for innovative therapeutics and technologies to deal with this situation, and hence a need to train a cadre of future scientists who can engineer devices and therapeutics with in-depth knowledge and training to link their research to clinical care to address the prevention and treatment of diabetes. The Indiana Bioengineering Interdisciplinary Training for Diabetes Research program was conceived to meet this need. A novel and notable aspect of our program is the interaction and integration of premier faculty of the Weldon School of Biomedical Engineering at Purdue University with the exceptional diabetes research faculty of the Indiana University School of Medicine, providing and elite training experience for future bioengineer-diabetologists. This educational model has already proven feasibility, by virtue of the successes of our Indiana MSTP T32 and our Indiana CTSI training programs. The aim of the Indiana Bioengineering Interdisciplinary Training for Diabetes Research program is to provide interdisciplinary, integrated research training to develop predoctoral students into bioengineers capable of leading integrative and team-based approaches to solve issues relevant to the understanding, prevention and treatment of diabetes and diabetic complications. This unique and integrated format benefits from co-directorship by each institutional program using the multi-PI mechanism, with Dr. A. Panitch (Biomedical engineering PI, Purdue University) and Dr. D. Thurmond (Diabetes research PI, Indiana University School of Medicine) coordinating a select group of exemplary bioengineering and diabetes-based research faculties to co-mentor our students, in combination with a carefully designed flexible curriculum that provides in-depth training for students in engineering relevant to diabetes. Our program emphasizes coursework that broadens research training at the bench with quantitative skills, provides opportunities for public speaking, provides a range of enriching extracurricular opportunities, and allows for integration of medicine and science/engineering throughout all years of training. Defined oversight mechanisms are in place to track the progress of trainees throughout the program. By training in an environment and culture that gives strong interdisciplinary support for bioengineering and diabetes research, there is a significant probability that the bioengineering trainees will sustain an interest in diabetes, even as their specific research interests evolve over their careers.

DESCRIPTION: Osteoarthritis (OA) is a debilitating disease that, according to the Arthritis Foundation, affects over 27 million Americans. The disease is characterized by a breakdown of articular cartilage extracellular matrix (ECM) molecules, including collagen type II, aggrecan, and hyaluronic acid (HA). As the ECM degrades, symptoms appear including pain and increasing joint stiffness. Once loss of collagen occurs, it is believed that the opportunity for unaided cartilage regeneration is lost. With this in mind, we previously described synergistic effects of combining a functional mimic of aggrecan with aligned cartilage to prevent matrix degradation and promote cartilage ECM synthesis by primary bovine chondrocytes. However, in humans, we are limited in our supply of chondrocytes, and harvest of primary articular chondrocytes can lead to donor site morbidity. Adult mesenchymal stem cells (MSCs) are a promising cell source because they can be harvested without injury, have a high proliferation capacity, and can differentiate into chondrocytes under appropriate environmental conditions. One major challenge of utilizing MSCs, however, is that grafts seeded with MSCs do not produce as much matrix as grafts seeded with differentiated chondrocytes. Thus, it is vital to establish conditions for effective differentiation and subsequent matrix production. Our long-term goal is to use MSCs in tissue-engineered cartilage to replace cartilage damaged by osteoarthritis. To achieve this goal, our objective is to create an environment that resists the destructive cycle of cartilage degradation from OA, mimics the native cartilage structure, and promotes chondrogenic differentiation of MSCs. To address these issues, we have developed the following specific aims. Aim 1: Evaluate the effects of alignment, aggrecan mimic concentration, and BMP peptide concentration on stem cell differentiation. Aim 2: Investigate the effect of synergistic interactions on cartilage differentiation. The results from this applicaton will elucidate properties of the local microenvironment that affect stem cell differentiation, resulting in enhanced matrix production and mechanical properties. These studies will thus serve as preliminary data for a future NIH R01 application that will evaluate these constructs in an in vivo defect model. Identification of material-based cues that result in improved cartilage grafts is essential in the development of safe and effective clinical therapies involving adult ste cells.

DESCRIPTION (provided by applicant): While anti-inflammatory agents and hyaluronic acid-base viscous replacements have been developed to treat people with osteoarthritis, there has been little impact on the progression and treatment of the disease. What is more, there are few therapeutic strategies that aim to interact with the existing extracellular matrix (ECM) to stem disease progression and potentially provide an environment conducive to autologous repair. Osteoarthritis is a debilitating disease that, according to the Arthritis Foundation, affects over 7 million Americans. The disease is characterized by a breakdown of articular cartilage; including ECM molecules type II collagen, aggrecan, and hyaluronic acid (HA). Osteoarthritis is often triggered by injury, resulting in release of catabolic cytokines (e.g. IL-1ß) and enzymatic (e.g. aggrecanase, hyaluronidase, and matrix metalloproteinase (MMP)) expression by chondrocytes. Aggrecanases initially degrade the aggrecan core protein. Once aggrecan is degraded, both HA and type II collagen are exposed and become susceptible to hyaluronidases and MMPs, respectively. Hyaluronidase cleaves HA, producing HA oligosaccharides that trigger additional MMP synthesis [1]. The MMPs, specifically MMP3 and MMP13, degrade type II collagen. Like HA oligosaccharides, type II collagen fragments further stimulate cartilage catabolism through induction of cytokines and MMPs [2]. Importantly, therapies that protect the ECM from degradation may halt this viscous cycle that perpetuates cartilage breakdown. Recently, we reported on a new class of biosynthetic molecules, coined peptidoglycans that mimic many of the functions of proteoglycans [3-5]. The peptidoglycans can be designed to limit hyaluronidase degradation of HA and MMP degradation of collagen. Unlike the native proteoglycans, peptidoglycans are not susceptible to proteases because peptidoglycans do not contain the proteoglycan core protein. The peptidoglycans instead contain small peptides that simulate the desired core protein activity. Given the need to prevent ECM degradation to limit OA progression coupled with the preliminary evidence of the abilities of peptiodglycans, we hypothesize that proteoglycan mimics can protect HA and type II collagen in articular cartilage from cytokine-induced enzymatic degradation, thus suppressing cartilage erosion associated with OA. We further hypothesize, that lubricin mimics that interact with both HA and type II collagen can be used to restore the low friction properties of articular cartilage, thus protect th surface from mechanical wear. Our immediate goals are to optimize the peptidoglycans ex vivo, improve our mechanistic understanding of their function, and assess in vivo efficacy of the compounds. Our long term goals include formulating the peptidoglycans for delivery to injured joints to alleviate OA symptoms and protect against further ECM degradation.

Non-technical Abstract:

Intracellular bacterial infections are caused by bacteria that reside in host cells such as macrophages and multiply, avoiding detection and destruction by the host immune system. These infections are currently managed by oral or injectable antibiotics, which reach the infected cells only after spreading in the entire body. The therapeutic outcomes of traditional antibiotics treatment have not been satisfactory, because many antibiotics do not enter mammalian cells and access the intracellular pathogens. Moreover, the pathogens tend to develop resistance to the antibiotic treatment as a consequence of persistent suboptimal delivery of antibiotics. For the effective management of intracellular bacterial infections, there is a critical unmet need for new types of antimicrobials, which will effectively eradicate intracellular bacteria without inducing resistance, and an appropriate carrier system that will deliver the new agents specifically to the infected macrophages and the pathogens resident in the cells. In this research the PIs propose to develop new materials that may be of potential use in addressing intracellular bacterial infections. Specifically, the PIs will use positively charged peptides with potent antimicrobial activity to replace traditional antibiotics. The PIs will administer these peptides using pH-sensitive polysaccharides, which will take the peptides to the infected cells and help unpack them where the peptides are most needed. This project has the potential to bring about novel materials that may be of use relative to intractable intracellular infections. In addition, it will create a sustainable research platform for interdisciplinary collaborations and contribute to the next generation science education through active participation in institutional outreach service and joint summer research fellowship programs.

Technical Abstract:

Intracellular bacterial infections are currently managed by systemic administration of antibiotics. However, their therapeutic outcomes have not been satisfactory, because of the inefficient intracellular delivery of antibiotics and frequent emergence of bacterial resistance to the treatment. For the effective management of intracellular bacterial infections, there is a critical unmet need for new types of antimicrobials, which will treat persistent and multi-drug resistant intracellular bacterial infections, and an appropriate carrier system that will deliver the new agents specifically to the infected macrophages and the pathogens resident in the cells. Ideal treatment of intracellular pathogens should have low potential to induce bacterial resistance and be able to travel across the eukaryotic cell membrane and access pathogens residing inside the cells. To satisfy these requirements, the PIs will develop antimicrobial semi-nanoparticles (SNPs), consisting of (i) cationic antimicrobial peptides (CAMPs), a new class of antibacterial agents, and (ii) pH-sensitive polysaccharides, a carrier of CAMPs. The underlying hypothesis of this approach is that CAMPs will overcome the prevalent bacterial resistance through distinct mechanisms of action, and a pH-sensitive SNP system will offer a means to target the organs harboring infected cells (liver and spleen) and traffic CAMPs within the cells to access the intracellular pathogens. This research will bring about three outcomes with broad impact: medical benefits to patients with intractable intracellular infections; sustainable research platform for interdisciplinary collaborations; and outreach activities for advanced science education, including leadership in institutional service programs and implementation of joint summer research fellowships.

Intellectual Merit:
This project creates an I-Corps Site at Purdue University.

NSF Innovation Corps (I-Corps) Sites are NSF-funded entities established at universities whose purpose is to nurture and support multiple, local teams to transition their technology concepts into the marketplace. Sites provide infrastructure, advice, resources, networking opportunities, training and modest funding to enable groups to transition their work into the marketplace or into becoming I-Corps Team applicants. I-Corps Sites also strengthen innovation locally and regionally and contribute to the National Innovation Network of mentors, researchers, entrepreneurs and investors.

The overall goal of this project is to expand Purdue's innovation ecosystem. This Site increases the number of successful commercialization projects by developing the commercialization and entrepreneurial skills of faculty, postdocs, and graduate students through the resources and infrastructure provided by Purdue's Burton D. Morgan Center for Entrepreneurship (BDMCE) and their Foundry program. These activities are supported through the involvement of key researchers and mentors who help create and support I-Corps teams in the areas of biomedical technology and engineering technologies. The objectives of Purdue?s Sites include: 1) Increase the level of customer development activity by I-Corps Site teams by providing support through the BDMCE's Foundry; 2) Develop the commercialization and entrepreneurial skills of graduate students in life sciences/health care, engineering technologies and management through the support of I-Corps Site teams in several domain-specific Lean LaunchPad courses; and 3) Build a better understanding of the characteristics, motivations, and needs of university-supported commercialization teams through assessment and evaluation

Broader Impacts:
By enabling over thirty teams a year to actively move through the Foundry's processes, the outcomes of this project will include the increase in both activity and knowledge that will mpact the innovation ecosystem at Purdue. In addition, this can lead to the rise in the quality and quantity of end products supported by the BDMCE. Faculty involved in the project will also increase their experience as mentors, researchers and innovators through their sustained involvement in this I-Corps project.

By supporting entrepreneurial teams in several technology/market domains, Purdue may further their understanding and codification of the processes and activities that are appropriate to commercialize each technology -- and those that are not -- and contribute to the global body of knowledge about entrepreneurship. The project's assessment outputs, and the academic articles that they will enable, will help both Purdue and other universities better understand best practices for the support of student-led teams. Also, in line with their overall goal, the Purdue I-Corps Site will help ensure that more research benefits society.