Kathryn E. Uhrich, PhD - US grants

Aromatic polyahydrides are clinically used as drug delivery systems for treatment of brain cancer. However, the slow degradation rate and the relative insolubility of the degradation products, especially in organic solvents, are major drawbacks for most biomedical applications. To improve the degradability and solubility of the aromatic polyanhydrides, the aromatic rung substitution was altered from para- to ortho- substituted. As expected, the ortho-substituted polymers have excellent solubility properties and appear to undergo surface erosion. Our evaluation of the degradation products obtained from polyanhydrides led to the design of an alternative polymer with potentially significant applications. Replacing the ether bond with an ester bond yields a polymer that degrades into salicylic acid (SA), an anti-inflammatory, antipyretic and analgesic agent. The proposed polymers are biodegradable (bioresorbable) materials that can be used for short-term dental treatments. The polymer's degradation products (SA) can reduce post-operative inflammation and pain following surgery for periodontal diseases. This system is the first example in which the polymer itself is a controlled-release system: the polymer degrades into SA which has anti-inflammatory and analgesic properties. These polymers may find application in decreasing post-operative pain and inflammation, in addition to creating an environment averse to bacterial processes in periodontal disease. Localized release, unlike orally ingested SA, will conceivably reduce the systemic adverse affects of salicylic acid which is generally prescribed after surgery. Periodontal disease comprise a group of related microbial-induced chronic inflammatory disorders that destroy the tissue supporting the teeth. These diseases can result in loss of normal soft and hard tissue of new health periodontal architecture while reducing the post-operative pain after periodontal surgery. Additionally, lowered pH will be unfavorable to some periodontopathic bacteria. The overall objective of this proposal is to investigate the hypothesis that local delivery of salicylic acid via degradable poly(anhydride-esters) (PAE's) membranes will enhance the healing process.

DESCRIPTION (Adapted from the application): This proposal will investigate a new mode for treatment of periodontal diseases. Periodontal diseases comprise a group of related microbial-induced chronic inflammatory disorders that destroy the tissue supporting the teeth. The diseases can result in loss of normal soft and hard tissue architecture at sites adjacent to the affected teeth. The goals of this project are: to accelerate the recovery/restoration of new, healthy periodontal architecture; to reduce post-operative pain after periodontal surgery; and to reduce local pH to create an unfavorable environment for periodontic bacteria. The poly(anhydride-esters)(PAE's) described within are biodegradable (bioresorbable) materials that can be used for short-term dental treatments. The proposal is a demonstrator project for future applications in novel dental biomaterial technology. This system is the first example in which the polymer itself is a controlled-release system; the polymer membrane degrades into salicylic acid (SA), which has analgesic properties. The investigators anticipate that PAE's will simultaneously serve three purposes: accelerating the recovery/restoration of new, healthy periodontal architecture; reducing post-operative pain after periodontal surgery; and reducing local pH to create an unfavorable environment for periodontic bacteria. However, this Proposal focuses on what the investigators consider the most significant aspect of this novel degradable polymer-localized reduction of inflammation and restoration of healthy periodontal architecture. The goals of the proposal are to evaluate the ability of poly(anhydride-esters) to simultaneously reduce inflammation while restoring periodontal tissues. As a function of in vivo polymer degradation, the investigators address the following hypotheses: Does SA reduce the inflammatory response? Is SA observed systemically? Can the release of SA be controlled? Do the polymers restore healthy periodontal architecture? The overall objective of this proposal is to determine if the local delivery of SA via degradable PAE's will simultaneously reduce inflammation and restore healthy periodontal architecture.

9983272
Uhrich
Micelles are colloids frequently used as drug delivery systems because of several useful properties. First, the hydrophobic microenvironment of micelles can water-solubilize hydrophobic drugs, expanding the pharmaceutical potential of otherwise useful compounds. This function has long been investigated as a means of improving solubility for drug delivery, particularly for parenteral or oral administration, as well as for ophthalmic, topical, rectal and nasal delivery. A second important function of micelles is their small size (less than 100 nm) which allows them to evade the reticuloendothelial system (RES) and behave as passive targeting agents. Third, the interplay between the hydrophobic domains of the polymer carriers and hydrophobic lipids of cell membranes enables micelles to be inserted into or passed through cell membranes. Yet there is no systematic understanding of the factors that govern their ability to interact with cell membranes. Lastly, the major drawback to their extended clinical use is that micelles are thermodynamically unstable; they disorganize upon dilution in the bloodstream, by temperature increases or by interacting with various blood components. The desirable features of micelles as described above can be used to design a polymer system that models micellar systems yet overcomes their major limitation by covalently binding the "unimers" such that dilution is not possible.

Our goal is to develop rationally designed polymeric materials that can be used to understand the interactions and mechanisms of cell-biomaterial interfaces. Our long-term objective is to use these polymeric micelles to probe cell-material interactions then design and develop enhanced drug delivery systems. The foundation of this proposal is our synthesis of hyperbranched polymers that can encapsulate, and subsequently release, hydrophobic molecules as well as to enhance fusion processes in liposomes. These polymeric materials are designed to biodegrade into nontoxic components over defined time period (i.e., months), thus eliminating concerns of long-term effects. With the development of the proposed polymeric systems, we have the capability to systematically study the behavior of micelles - information that was previously unattainable due to the lack of appropriates materials. Completion of this research will impact areas of drug delivery, controlled release, membrane technologies, biomaterials, and biocatalysis.

The continued growth and productivity of our society is dependent upon people with the appropriate technological skills. Minorities and women, while representing a majority in American society, are currently underrepresented in the sciences. It is imperative that we train minorities and women in science and engineering to ensure the health of our economy and provide support such that these students remain in the science pipeline.

Two specific programs are proposed to address these issues. First, to enhance participation of girls in science by reaching elementary school-age girls, an outreach program will be coordinated with Girl Scouts and with women in science at Rutgers University. Second, Rutgers has a strong mentoring program for undergraduate women in science, but there are no formal mentoring programs for graduate women. A program that allies graduate women with faculty mentors will be developed.

This IGERT program at Rutgers University, focused on integratively engineered biointerfaces, will be an intimately collaborative effort of 32 selected faculty from graduate programs in Molecular Biosciences, Physical Sciences (Physics, Chemistry & Chemical Biology), and Engineering (Biomedical Engineering, Ceramics and Materials Engineering, Chemical and Biochemical Engineering, Mechanical and Aerospace Engineering).

Intellectual Merit: The program derives strength from the highly cross-disciplinary nature of over fifteen research project areas identified at the cutting edge of the field of biointerfaces, and programmatic partnerships with five strategic centers of excellence to promote cohesive access for the IGERT community to state-of-the-art research infrastructure. A wide range of thesis project themes is planned for the IGERT trainees, developed around three research and educational thrusts, (1) living cell-based interfaces, (2) microengineered and nanoengineered biointerfaces, (3) biosensing and bioresponsive interfaces. The five major partnering Centers for the IGERT program are: Keck Center for Collaborative Neuroscience, Center for Nanomaterials Research, New Jersey Center for Biomaterials, the Laboratory for Surface Modification, and the Rutgers Center for Computational Design. The educational core of the proposed IGERT program will intimately support the research program, and includes graduate courses in the integrative areas of biointerfacial engineering, as well as course modules on responsible conduct of research, technical communications, entrepreneurship and effective teaching/learning methods.

Broader Impact: The IGERT curriculum is designed to foster a community featuring the next generation of biointerfacial and biomaterials engineers by offering IGERT graduate fellows a range of interactive experiences at multiple levels: multi-disciplinary coursework, lab rotations in two cross-cutting research groups, biannual participation in symposia, and participation in a national/international conference resulting in a white paper. To maximize its impact, the IGERT program will offer varied programmatic pathways to promote diverse modes of professional development of IGERT graduate fellows: (1) Summer research internships at selected international sites for academically inclined students; and (2) Translational research and industrial summer internships for students interested in industrial and entrepreneurial careers. Through a partnership with the Robert Davis Learning Institute of the Rutgers Graduate School of Education Institute, the IGERT program will establish a COLTS (Community of Learners and Thought Shapers) program, inspired by communication-driven cognition models, to encourage IGERT fellows to develop as learners by dynamically communicating their research on integratively engineered biointerfaces.

IGERT is an NSF-wide program intended to meet the challenges of educating U.S. Ph.D. scientists and engineers with the interdisciplinary background, deep knowledge in a chosen discipline, and the technical, professional, and personal skills needed for the career demands of the future. The program is intended to catalyze a cultural change in graduate education by establishing innovative new models for graduate education and training in a fertile environment for collaborative research that transcends traditional disciplinary boundaries. In this sixth year of the program, awards are being made to institutions for programs that collectively span the areas of science and engineering supported by NSF.

[unreadable] DESCRIPTION (provided by applicant): The objective of this symposium is to highlight the latest research results in the emerging topic of the environmental aspects of nanomaterials. The National Nanotechnology Initiative, in its Strategic Plan for 2004, lists the Responsible Development of Nanotechnology as one of its four major goals. Responsible Development includes the study of environment, health, and safety implications, as well as ethical, legal, and societal issues. This forum is intended to bring together materials scientists, chemists, biologists, toxicologists, and ecologists to foster a cross-disciplinary discussion of: 1) the application of nanotechnology to the environment for the purposes of sensing and monitoring, remediation and treatment, and pollution prevention; and 2) the implications of nanotechnology on the environment, including potential health and environmental effects of nanomaterials. The symposium is also intended to encourage industry and research experts to include sustainability and efficiency aspects for materials and energy flow in their development projects. Societal, ethical, regulatory, and policy issues, along with nomenclature and measurement standards, will also be topics of discussion. [unreadable] [unreadable] The symposium is an effort to broadly include an interdisciplinary dialogue on nanotechnology, its applications, and implications. A key goal of this symposium is to bring together researchers to increase the fundamental understanding of nanomaterial interaction at the molecular and cellular level through in vitro and in vivo experiments and models, as well as their fate and transport in the environment throughout their life cycles. We anticipate that this, along with identification and characterization of potential exposure and risk, will contribute to determining human health impact and should be of significant interest to the National Institutes of Health. Technically competent social science research on the interaction between nanotechnology and society will dispel some of the hype and enable constructive public engagement. [unreadable] [unreadable]

This Integrative Graduate Education and Research Traineeship program (IGERT) renewal award establishes a training program focused on the science and engineering of stem cells. New cross-cutting thrusts for Ph.D. research, together with a new multidisciplinary graduate curriculum, will integrate stem cell biology with research in biomaterials, process engineering, and computational modeling. Trainees will participate in an IGERT Research Interchange Forum to develop their abilities to communicate across disparate disciplines. Professional development activities encompassing teaching, mentoring, and outreach will enable IGERT trainees to better realize the impact of their technological know-how. Each IGERT trainee will be guided by an advisory constellation of scholars drawn from over 30 faculty members from Engineering, Molecular Biosciences, Physical Sciences, Business, Public Policy, and Management. The IGERT program will leverage Rutgers' active "diversity infrastructure" to help broaden the participation of underrepresented minority students. In addition to providing research opportunities for visiting underrepresented undergraduates, the IGERT will offer two new initiatives: a teacher-student summer institute at Rutgers, and, a bridge-to-IGERT program. New outreach programs at the intersection of stem cell science and engineering with public policy and business include: (1) an initiative with the School of Management and Labor Relations to "bundle" IGERT research and curriculum into portable modules for scientific workforce training; (2) Rutgers Business School-mediated interactions with pharmaceutical management students and industry; (3) public policy workshops with policy makers, facilitated by the Eagleton Institute of Politics. IGERT trainees will acquire global perspectives through internships and workshops with leading stem cell researchers at over 15 sites in Europe and Asia. IGERT is an NSF-wide program intended to meet the challenges of educating U.S. Ph.D. scientists and engineers with the interdisciplinary background, deep knowledge in a chosen discipline, and the technical, professional, and personal skills needed for the career demands of the future. The program is intended to catalyze a cultural change in graduate education by establishing innovative new models for graduate education and training in a fertile environment for collaborative research that transcends traditional disciplinary boundaries.

DESCRIPTION (provided by applicant): Bone defects cause functional deficits as well as disfigurement that can severely harm the patients'physical and psychological health. Unlike bone fractures that are usually treated immediately after injury, most cranial-facial bone defects are treated after the initial pathological condition or traumatic injury has been resolved. Thus, methods to heal these defects must promote bone formation at a quiescent site while prohibiting growth of soft tissues into the defect site that stop bone formation. One difficult aspect of bone tissue engineering in the craniofacial and dental areas is complications from soft tissue ingrowth into the active site of new bone formation. Soft tissue ingrowth into a device essentially halts further bone formation. This host response creates a challenge for tissue engineering in that any solution must limit soft tissue interference without impairing bone formation or inducing so much new bone formation that the desired functional or aesthetic morphology of the new bone is not achieved. Our goal is to engineer a device that balances rapid bone formation with limited soft tissue interference that can augment or heal cranial-facial bone defects. Having shown that arachidonic acid metabolism can modulate inflammation related to bone formation, we propose to develop a device that separates cyclooxygenase inhibition (limits soft tissue growth) from 5-lipoxygenase inhibition (promotes osteoblast activity and bone formation). We will use a poly (anhydride-ester) of salicylic acid (PolyAspirin) to inhibit cyclooxygenase and a 5-lipoxygenase inhibitor within a calcium sulfate carrier and calcium phosphate scaffold to promote osteogenesis. The use of small molecule inhibitors as the active ingredients of this device will allow production of low-cost, long shelf-life devices for treating cranial-facial bone defects. PUBLIC HEALTH RELEVANCE: Bony defects of the skull and other cranial-facial bones are common traumatic and pathological injuries. Current methods to treat cranial-facial bone defects are associated with second-site morbidity from autograft harvest, use of potentially infectious allograft bone, poor long-term efficacy, technically challenging procedures, and high costs. Our goal is to develop a low-cost, easy to use and store, tissue engineering device to treat cranial-facial bone defects that accelerates healing by modulating the host inflammatory response.

0923246
Bartynski
Rutgers U. New Brunswick

Technical Summary: X-ray photoelectron spectroscopy (XPS) is widely used as an analytical technique to determine the nature of the near-surface region of a material. Shifts in the core level binding energies of atoms at or near the surface of a material can reveal changes in oxidation state, surface potential or band bending, chemical or physical inhomogeneity, or dynamic response (i.e., screening) that are distinct from those of the bulk of the material. However, a growing number of modern applications employ materials in complicated structures that are laterally inhomogeneous and thus it is critical to perform XPS in a spatially resolved manner, along with high photon flux, and high energy resolution. Examples, that are currently active research areas at Rutgers include the study of: (i) transition metal ions and their diffusion in ZnO for room temperature spintronics, (ii) surface modification of organic single crystal surfaces, (iii) surface functionalization and characterization of novel nanocrystals used to enhance biomolecule imaging, (iv) surface characterization of plasma-treated and chemically-modified polymer films for cellular and related bioactivity studies, and (v) interface properties of nanoscale self-assembled solid state systems. The Rutgers Laboratory for Surface Modification (LSM) is a multidisciplinary research center that hosts a comprehensive set of facilities used to examine surfaces, interfaces, thin films, and nanoscale materials, and has strong collaborations with state-of-the-art research and development laboratories around the world. A gap in our suite of tools is lack of a modern high resolution XPS system that can adequately address the key issues in the study of modern materials systems. The state-of-the-art instrumentation requested in this proposal would replace a 20-year-old machine and will significantly strengthen our capabilities by enabling high energy resolution studies, in parallel with high resolution lateral imaging and depth profiling. These features are central to the diverse research and education activities both within Rutgers as well as the regional community.

Non-Technical Summary: Materials interact with their surroundings through their surfaces. Very often, the chemical or physical environment of surface atoms is significantly different from those of the bulk A powerful way to probe surface properties is to expose a material to X-rays of a specific wavelength and study the electrons that are emitted from surface. As only electrons that originate from the first one or two nanometers of the surface are able to escape the material, this technique is very surface sensitive. Moreover, these electrons escape with well-defined energies that not only depend upon the atomic species, but also exhibit small variations depending on the environment of the atom. The study of these electrons, known as X-ray photoelectron spectroscopy (XPS), enables one to determine the chemical and physical state of these near-surface atoms. In modern materials systems, such as nanoscale crystals used to enhance imaging of biological systems, or potentially revolutionary semiconductors made entirely of organic molecules, the atomic environment in one region of the surface can differ from that of another region. Therefore, it is critical to perform XPS studies in a spatially resolved manner. The Rutgers Laboratory for Surface Modification (LSM) is a multidisciplinary research center that hosts a comprehensive set of facilities used to examine surfaces, interfaces, thin films, and nanoscale materials, and has strong collaborations with state-of-the-art research and development laboratories around the world. A gap in our suite of tools is lack of a modern high resolution XPS system that can adequately address the key issues in the study of modern materials systems. The state-of-the-art instrumentation requested in this proposal would replace a 20-year-old machine and will significantly strengthen our capabilities by enabling high energy resolution studies, in parallel with high resolution lateral imaging and depth profiling. These features are central to the diverse research and education activities both within Rutgers as well as the regional community.

DESCRIPTION (provided by applicant): This study targets atherosclerosis, a chronic inflammatory disorder of the blood vessel wall, which underlies nearly 50% of all deaths in westernized countries and is the primary cause of mortality in patients with diabetes. This proposal utilizes rational molecular design approaches to a novel class of therapeutics - amphiphilic polymers that serve as athero-protective and anti-inflammatory therapeutics. The most innovative component is that molecularly designed polymers may have the potential to inhibit atherosclerosis by multiple scavenger receptor targeting and blockage during the early stages of atherogenesis. This binding behavior could be critical to blocking oxidized LDL uptake and more effectively abrogate the athero-inflammatory cascade, and retard the progression of atherosclerosis. The central hypothesis regarding the enhanced polymer structures is that combinations of strengthened hydrophobic features in conjunction with anionic charge and hydrophilic tails will yield polymers with optimal targeting to multiple scavenger receptors on both macrophages and endothelial cells, specifically SR-A, CD36 and LOX-1. To test this hypothesis, three specific aims are proposed. Aim 1 is focused on the molecular modeling (docking and scoring) and design of novel polymer classes for enhanced binding to multiple scavenger receptors. This effort will yield new polymer structures with a more rigid and space-filling backbone that, in conjunction with charge and hydrophilicity, enhance binding affinities to scavenger receptors - particularly under physiologic conditions. Aim 2 is focused on investigating the molecular mechanisms and polymer interactions with cultured macrophages and endothelial cells for inhibition of athero-inflammation in vitro. Aim 3 is focused on the evaluation of in vivo polymer efficacy in terms of binding to atherosclerotic lesions and degree of regression of athero-inflammatory markers using an animal model of accelerated atherosclerosis. At minimum, new insights will be obtained regarding multiple scavenger receptor blocking as a strategy to counteract the progression of atherosclerosis. The potential impact of this research proposal is high; the overall outcome may be a new approach to treating coronary artery disease - using enhanced polymers as multifunctional inhibitors. PUBLIC HEALTH RELEVANCE: This project is concerned with the design of polymeric biomaterials with biological activity and efficacy against atherosclerosis, the progressive blockage of lipid (fat) filled blood vessels leading to heart attacks and strokes, a leading cause of adult mortality in the U.S. Outcomes will be insights into the structure-function relations between polymers and their blockage of cholesterol uptake; effects on inhibition of inflammation; and the identification of improved biodegradable polymeric materials as therapeutics for treatment of vascular and inflammatory diseases.

With this award from the Major Research Instrumentation program (MRI), the Chemistry Research Instrumentation and Facilities program (CRIF), The Divsion of Material Research (DMR) and the MPS Office of Multidisciplinary Activities (OMA), Rutgers University-New Brunswick will develop a scanning probe microscope (SPM) with an electrochemical station and optical microscope capable of doing dip-pen nanolithography (DPN). Scanning probe microscopy methods are among the most powerful and versatile classes of microscopic tools available. They can be used for simple topographic imaging, more sophisticated chemical, physical, biological and mechanical characterization, and for nanolithography and nanomanipulation. There is a growing need for new multifunctional SPMs that can benefit multiple fields. To this end, the development proposed will involve the design, acquisition, and integration of various components to make a multifunctional SPM instrument. The plan is to develop a new type of SPM instrument equipped with a dip-pen nanolithography module, an optical microscope, an external electrical/electrochemical instrument and a temperature/gas/liquid controller to allow the analysis of various bio/nano materials. The newly-developed multifunctional SPM will also be used for demonstrations in laboratory classes and for K-12 laboratory experiences hosted at Rutgers. Access to the SPM will be made available to faculty and students at the numerous colleges in the neighboring area.

The proposal is aimed at enhancing research and education at all levels, especially in areas such as studies of inorganic-organic hybrid materials, multi-functional materials, and nanomaterials for organic sodium ion batteries. The system will be used to investigate optical antennae, semiconductor ferroelectronics and graphene film production. It will also be used in bio-nano research including cell-cell and cell-substrate interactions, cell migrations, stem cell differentiations, protein misfolding, enzyme characterization/optimization, and biopolymer fabrication while maintaining an in vivo-like environment. By using the SPM tip as an electrode and combining it with an electrode holder and probe station, the electrical properties of target materials (e.g., conductance, resistance, capacitance, defects) can be analyzed precisely. The proposed system will also be available for analyzing the electrochemical characteristics of samples such as the corrosion, redox phenomenon, and deposition using different electrochemical techniques.

PROJECT SUMMARY Recently, we created a series of unique, sugar-based cationic amphiphiles that are effective against bacteria, and more importantly, differ in their bactericidal mechanism. Specifically, amphiphiles with different relative charge location targeted different types of bacteria. While the overall charge and hydrophobicity were maintained, the relative charge location significantly influenced their mechanism-of action: amphiphiles with two charged head groups (bola-like) separated by a long hydrophobic spacer were more effective against Gram-positive bacteria, whereas the amphiphiles with two charged heads in close proximity (gemini-like) were more effective against Gram-negative. This discovery ? that minor changes to similar sugar backbones yielded selectively targeting antimicrobials - is the basis of this R21 proposal In preliminary studies for this R21 proposal, we investigated the activity of these cationic amphiphiles against one of the major contributors to bacterial vaginosis (BV) against a Gram-variable pathogen, Gardnerella vaginalis (G. vaginalis). As G. vaginalis is a ?Gram-variable? microorganism, exhibiting features resulting in different Gram-staining at various stages of its life, it is critical to elucidate key structure features to elicit bioactivity of cationic amphiphiles against ?strictly? Gram-positive and Gram-negative bacteria strains separately, and then translate our findings into a rational design of cationic amphiphiles for Gram-variable microorganism. Thus, the overall goal of this proposal is to investigate how specific structure features of these cationic amphiphiles influence antibacterial activities against Gram-variable microorganisms. This project combines multi-investigator expertise in synthetic chemistry and biomaterials design (Uhrich lab), and microbiology (Chikindas lab) to rethink bacterial vaginosis (BV) treatment and rationally design new selectively targeted antimicrobials capable of controlling this multi-microbial infection. Antimicrobials targeting Gram- variable bacteria will be designed based on the key structural features of cationic amphiphilic antimicrobials that make them active against Gram-positive and Gram-positive bacteria. This goal will be addressed through the following Specific Aims: Specific Aim 1 ? Molecular Design: To design non-cytotoxic cationic amphiphilic antimicrobials that selectively target Gram-variable bacteria. Specific Aim 2 ? Biofilm Efficacy: To investigate efficacy of cationic amphiphilic antimicrobials for Gram-variable G. vaginalis biofilm prevention and eradication. The insights from the study can also guide the design of antimicrobials which can be widely applicable for other antimicrobial peptides (AMP) mimicking systems, as well as prudent development of therapeutics designed to target different bacteria types and/or membrane structures.