PROJECT DESCRIPTION A.

STATUS AND OVERVIEW The 2009 NSF EPSCoR Research Infrastructure Improvement (RII) Program presents an exciting opportunity for South Carolina to implement a statewide vision towards building a competitive edge in the emerging field of “organ printing” — operationally defined as computeraided, layer-by-layer deposition of biologically relevant material with the purpose of engineering functional 3D tissues and organs. The long term goals are to build and enhance tissue biofabrication technologies that will: (1) develop into a statewide center of excellence at the interface of engineering, biomathematics and developmental biology; (2) create a transdisciplinary culture of innovation in tissue science and engineering research that links scientific discovery to innovation in advanced bioprinting (tissue biofabrication) technology; (3) produce a diverse group of graduates and trainees who will be creative innovators in an emerging, new biofabrication industry; (4) attract broad interest by faculty and students at colleges and universities across the state; and (5) serve to guide, focus and transform the enhancement of infrastructure into a large scale vision capable of stimulating competitive research proposals and sustainable partnerships among academe and the private sector. This broad-based vision, called “The South Carolina Project,” will be an integrated program to engineer a vascular tree. The Advanced Tissue Biofabrication Center (Figure 1) will be the hub for catalyzing infrastructure enhancements needed to pursue The South Carolina Project.

FIGURE 1. The Advanced Tissue Biofabrication Center (ATBC) will be the RII hub for catalyzing sustainable infrastructure enhancements needed to become a leader in biofabrication.

A1.

Selection of RII Theme In February 2006, the State EPSCoR/IDeA Committee held a strategic planning retreat to consider state and national competitiveness initiatives. In Spring 2006, the national EPSCoR 2020 Workshop identified 8 strategic priorities to guide NSF and EPSCoR in meeting the future research needs of the nation. Based on recommendations from these two forums, SC’s higher education leaders identified strategic focus areas representative of institutional strengths, research infrastructure needs, opportunities for development, and potential for technology commercialization. Each institution drew on external advisors, visiting committees and other consultants to help identify infrastructure improvement activities with high potential for increasing national competitiveness. In October 2006, the State Committee issued a solicitation outlining NSF RII program criteria and the state strategic plan for EPSCoR/IDeA. The call for proposals generated 7 responses that

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were reviewed by a panel of 5 external experts, including 2 National Science Board (NSB) members. They recommended: a) further developing 2 proposals in biofabrication and carbon research; b) maintaining the underlying SC EPSCoR strategy of targeting RII funds to recruit early-career faculty; c) accelerating the SC’s research agenda by recruiting some mid-career “magnet researchers” at associate or full professor levels; and d) formalizing a statewide cyberinfrastructure plan. Final selection of content for the RII proposal took place in July-August 2007. Expanded proposals in biofabrication and carbon sequestration were reviewed by select NSB members and additional experts. Their comments were sent to a panel convened by the State Committee on August 10, 2007, which found that the biofabrication initiative best fit the criteria set forth by SC EPSCoR/IDeA. The State Committee concurred with the panel’s conclusions that: (1) the statewide initiative in tissue biofabrication builds on existing strengths and previous EPSCoR investments in engineering, mathematics and biosciences that will collectively yield substantial added value for building sustainable research capacity and exciting potential for economic development; (2) the RII theme is closely aligned with university, state and national research priorities in advancing tissue science and engineering and addressing research at the interface of the physical and life sciences; and (3) the state should proceed aggressively with its cyberinfrastructure plan. The SC NSF EPSCoR RII proposal, aimed towards building a competitive edge in the field of biofabrication, was submitted in response to NSF 08-500 and reviewed in Feb/Mar 2008. Intellectual and scientific merit were uniformly rated as Excellent, but broader impacts of the proposed plan lacked meaningful involvement of SC’s HBCUs and other predominately undergraduate institutions (PUIs). In May 2008 the SC EPSCoR/IDeA Office sent an invitation to higher administrators at 26 of SC’s PUIs to participate in a workshop offering technical assistance for preparation of pre-proposals aligned with RII priorities and the biofabrication theme. Twenty-two (22) faculty from 13 institutions attended the workshop; pre-proposals were received in mid-June and reviewed by experts. Proposals from Claflin, Furman, SC State University, USC Beaufort, and Voorhees College were selected for further development and inclusion in the present 2009 SC NSF EPSCoR RII proposal. A2.

Current Resource Base in Tissue Biofabrication MUSC’s Department of Cell Biology & Anatomy (CBA) has a reputation of excellence and leadership in developmental biology with emphasis on heart development and vessel assembly. Roger R. Markwald, PhD has served as chair since 1992. The department has 24 full-time, tenured/tenure-track faculty, 11 research faculty and 7 adjunct faculty with grants totaling >$11M/yr from sponsors such as NIH, DoD and NSF. The teaching division has pioneered computer-assisted instruction and distance learning techniques. Several NIH grants and an NSF FIBR (EF-0526854, with U. Missouri and U. Utah) support growing expertise in stem cell biology and organ printing. The department is a leader in building statewide research partnerships. Four Clemson bioengineering faculty members have joint MUSC appointments and full-time space in CBA. A 15-year collaboration with USC’s Department of Cell and Developmental Biology has contributed to shared faculty, resources, and USC’s new Biomedical Engineering Program. Postdoctoral fellows from MUSC and USC regularly guest lecture in bioinformatics and cell biology at Claflin, SC State and Furman. RII investments at Clemson helped assemble a critical mass of faculty in Bioengineering and fostered the joint Clemson/MUSC Bioengineering Program. Launched in September 2003, the joint program lets faculty of both institutions move seamlessly between campuses. Clemson faculty and bioengineering graduate students interact daily with MUSC investigators and trainees. Teleconferencing facilities provide effective, efficient avenues for faculty and graduate students on both campuses to participate in didactic courses, seminars and departmental activities. Clemson is a leader in ink-jet printing approaches using single cell suspensions with a focus on building small tissue fragments that do not require vascularization. MUSC is a leader in developmental biology with approaches based on tissue spheroids leading to tissue self-assembly, fusion and maturation. Clemson engineers and MUSC scientists working together have made pioneering contributions to the field [1,2] with support from NSF and other agencies, including Emerging Frontiers in Research and Innovation (EFRI) and Frontiers in Integrative Biological Research (FIBR) awards.

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SC’s HBCUs and other PUIs offer a substantial research and education base. Claflin University has a new MS program in biotechnology with expanded faculty expertise in protein biochemistry and biostatistics, and an ACS certified chemistry department. South Carolina State University is establishing a specialized computer-aided design and rapid prototyping laboratory to train students in the biomedical applications of layer-by-layer manufacturing technologies. The laboratory will include several high-density 3D printers and imaging software for CT scan conversion. Furman University will soon complete a $62 million expansion and renovation of their science facilities to establish the 210,000 ft2 Charles Townes Center for Science, the largest single academic building project in Furman’s history. USC’s Industrial Mathematics Institute (IMI) was established as part of a highly successful NSF EPSCoR project funded from 1992-95. The goal was to leverage classical mathematical strengths to build new research capacity in numerical analysis, image processing, geophysical modeling and large-scale scientific computing. The 4 targeted hires remain as IMI faculty, each now a full professor with an established research profile and substantial federal and corporate funding. The IMI now has 21 faculty members with grants primarily from NSF, DoD, and corporate sponsors. In Spring 2007, the IMI completed a comprehensive self-study process with a major recommendation to extend collaborations across the state. A3.

Alignment with University, State and National Research Priorities At the University Level. MUSC and Clemson have a well-established consortium that hosts Clemson bioengineers full-time at MUSC. A new Bioengineering Building planned for Charleston will be the state’s first shared science facility accessible to all higher education institutions in SC. Funding for this building illustrates the commitment that the universities have made to NSF-style transformative and NIH-style translational research. The new building will make it possible to bring engineers, biomathematicians and biologists under one roof to pursue the shared vision of the South Carolina Project and develop a sustainable Advanced Tissue Biofabrication Center. A proposal to support Centers of Economic Excellence (COEE) Chairs in Tissue Biofabrication with an endowment of $10M was approved for funding in June 2008. At the State Level. The SC Dept of Commerce, SCRA and others have identified enhancement of research infrastructure in biotechnology and bioengineering as an essential strategy for attracting bio-technology companies and bio-manufacturing industries. For example, SCRA has created SC Launch!, an incentive program that awards matching grants up to $100,000 to SC-based businesses that obtain SBIR/STTR awards. In addition, 3D Systems Inc., a leader in rapid prototyping and biofabrication, relocated from California to SC to partner with York Technical College in building a unique “3D Systems University” for workforce training in rapid prototyping. The SC General Assembly provides $2-2.5M annually in a line item appropriation to the state's EPSCoR programs. These examples illustrate the alignment of state and private resources with the 2009 RII proposal’s theme of tissue biofabrication, and provide clear indication of a strategic trend in South Carolina toward 21st century high tech manufacturing and knowledge-based industries. At National and International Levels. Two strategic planning documents that identify the technological needs to advance the field of tissue science and engineering have recently appeared [3,4]. The national Multi-Agency Tissue Engineering Science (MATES) group identified 3D biofabrication and “assembling and maintaining complex tissue” as a critical short term strategic priority for federal agencies. An editorial in Tissue Engineering [5] noted that understanding basic biology is a high priority, especially developmental biology. In reporting on an NSF-sponsored USChina workshop on new opportunities in bio-manufacturing, Sun et al. [6] identified advanced organ printing/biofabrication as a top priority. The highly respected “Wohler Report 2006” identified biomedical applications of rapid prototyping as a field with multibillion dollar growth potential. The European Union organized the 1st International Bioprinting Conference in 2006. Leading Asian countries are also developing research centers in biomedical application of rapid prototyping, robotic biofabrication and organ printing. A new international journal Biofabrication (IOP Publishing, UK) will print its first issue in March 2009. Thus, the theme of our NSF RII proposal is timely and well aligned with efforts essential to US technological leadership.

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B.

RESULTS FROM PRIOR NSF SUPPORT South Carolina entered a one-year no-cost extension for the three-year NSF Research Infrastructure Improvement (RII) grant (EPS-0447660), revising the end date to June 30, 2009. The objectives of the 2004 RII proposal were to: (1) advance biomedical engineering at USC; (2) expand biotechnology/genomics at Clemson; (3) develop phenomics capacity at MUSC; (4) enhance research capacity at Claflin and SC State; and (5) implement statewide outreach initiatives. Major activities included recruitment of new, tenure-track faculty, purchase of start-up and shared equipment, and sponsorship of outreach programs. The 2004 RII project goal at the University of South Carolina – to build infrastructure for teaching and research in biomedical engineering – has been achieved. The College of Engineering and Computing (CEC) hired 10 new faculty, 6 with NSF RII support. All are now well-established with >$1.1 million in active grants. A complementary commitment to bioinformatics and computational biology resulted in recruitment of additional faculty with 2 NSF CAREER awards, 2 NIH R01 grants and several other awards. The educational component focused on new BS, MS and PhD programs in biomedical engineering that first admitted students in 2006, and now enrolls >125 undergraduates and >20 graduate (primarily doctoral) students. Clemson University built a strong foundation for biotechnology research with recruitment of 5 new tenure-track junior faculty in bioinformatics and interdisciplinary biomathematics focusing on genetics and biochemistry. Clemson utilized 2004 RII support to expand outreach activities through its DNA Learning Center, providing genetics and biotechnology research experience to more than 780 students and 100 teachers and members of the public in 2007-08. The Medical University of South Carolina used 2004 RII support and institutional investments for imaging instrumentation and faculty recruitment to establish the Phenomics Center. A 7T magnetic resonance imaging (MRI) system has been acquired and installed in space renovated with institutional funds, and 4 new faculty hires have activated laboratory programs and obtained new federal and foundation grants totaling >$1.5 million/year, complementing existing strengths in proteomics, mass spectrometry and traditional microscopy. A parallel effort at South Carolina State University, the state’s largest HBCU, created a new undergraduate minor in neuroscience; hired a neurophysiologist, Lilijana Bozinovska, MD, PhD; equipped neurology/physiology and robotics/biocybernetics laboratories; and developed 4 new courses (Intro to Neurobiology, Brain Science, Biocomputing & Bioinformatics, and Neuroinformatics & Brain-Computer Interface). RII resources were used by Claflin University to recruit 3 new faculty with expertise in biostatistics, protein chemistry, molecular biology and effective pedagogical methods. These hires enabled the creation of an MS program in biotechnology, Claflin’s first graduate program in the sciences, with an enrollment of 17 students in Fall 2007. Outreach programs are multi-faceted and ongoing. The Collaborative Research Program (CRP) provides seed grants to stimulate collaborative research. Nineteen (19) awards were made to teams from 3 PhD granting institutions and 8 undergraduate institutions, including 3 HBCUs. Two CRP awards at Francis Marion University (FMU) provided training for 29 undergraduates and 2 graduate students, and yielded a $250,000 NSF RUI and $60,000 Merck-AAAS award to FMU. The SBIR Phase-0 Program provides seed grants to help SC-based businesses prepare SBIR/STTR Phase-I or Phase-II proposals. Since June 2005, 25 small businesses received Phase-0 support with an average award of $5,910 that led to $2,536,079 in federal SBIR/STTR awards (total return on investment of 10:1). The Postdoctoral Training Program provided postdoctoral trainees teaching experience and brought contemporary research to undergraduate classrooms. Since Fall 2005, 8 postdoctoral scholars taught ~200 students at SC HBCUs. Program data were used to support 2 NIH proposals: an MUSC/Claflin cooperative funded by NIGMS in August 2007, and a submitted USC/Benedict College partnership. Twenty (20) statewide Research Symposia were funded, including the SC Bioengineering Summit and Transforming Undergraduate Education for Future Research Biologists. Seventeen (17) Competitive Centers Development grants with a total investment of $183,819 led to 24 proposal submissions to federal programs (e.g., NSF GOALI, IUCRC, Discovery Research K-12, IGERT and ERC programs) and yielded $1,657,302 in awards.

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C. C1.

RESEARCH PROGRAM Background Bioprinting or “organ printing” can be operationally defined as computer-aided, layer-by-layer deposition of biologically relevant material with the purpose of engineering functional 3D tissues and organs. Organ printing is in essence a biomedical application of rapid prototyping technology or additive layer-by-layer manufacturing. A simple way to describe bioprinting principles is an analogy with traditional printing as invented by Gutenberg. Printing a book requires written text, a printing press, movable type, paper and ink. Similarly, printing or fabricating an organ requires computeraided design (CAD) of the organ (its “blueprint”), a bioprinter or robotic dispenser, a cartridge for dispensing biomaterials, scaffolds or processible biomimetic hydrogels (“biopaper”), and selfassembling cell aggregates or single cells (“bioink”). A more general term, biofabrication, describes an emerging field with keen competition at the national and international level. For example, Sangeeta Bhatia’s group at MIT is working on a combination of dielelectrophoresis with SLA; the Weiss and Campbell groups at U. Pittsburgh are working on ink-jet bioprinting; Shuman Das (Georgia Tech) uses SLS in fabricating solid scaffolds for tissue engineering in orthopedics; Scott Hollister at U. Michigan also uses SLS for orthopedic tissue engineering; Richard Odde, U. Minnesota, is using direct laser writing technology for cell patterning; and Wei Sun at Drexel U. uses robotic dispensing of cells suspended in hydrogel for fabricating avascular 3D tissue constructs and rapid prototyping for fabricating solid scaffolds. International competition includes: Martin Fussengger, ETH Zurich, self-assembling tissue spheroids; Michael Sefton, U. Toronto, endothelialized and encapsulated liver cells for building tissue modules; the Yan group at Tsinghua U., robotic bioprinting of living liver cells suspended in chitosan-collagen hydrogel; the Mulhaupt group at Freiburg, bioplotter technology (with EnvisionTech, Germany) to print living cells in fibrin hydrogel; Prof. Teoh at Natl. U. Singapore and Prof. Hutmacher at Queensland U., FDM technology for creating solid scaffolds; Brian Derby, U. Manchester and Prof. Nakamura in Tokyo, ink-jet printing for cell patterning. This impressive spectrum of innovative approaches adds significantly to the knowledge base for biofabrication. However, nearly all these efforts focus on rapid fabrication of solid scaffolds or on 2D and 3D cell biopatterning. To our knowledge, no one is focusing on bioprinting a 3D branched vascular tree using tissue spheroids as building blocks. South Carolina is a logical home for organ printing. SC inventor Bill Masters obtained one of the first patents for rapid prototyping technology in July 1984. This patent led to one of the first rapid prototyping companies. Ballistic Particle Manufacturing (BPM) was formed in 1989 in Greenville, SC and started selling its first product in 1996. Thomas Boland, PhD, at Clemson, recently received the first patent on ink-jet cell bioprinting. Drs. Boland, Mironov and Markwald have published a series of papers demonstrating the theory and application of computer-based, rapid organ printing [1,2,7-12]. Dr. Mironov established the MUSC Bioprinting Research Center in 2005 with institutional funding. In March 2005, MUSC hosted the 2nd International Workshop on Bioprinting which led to a NSF FIBR grant with U. Missouri and U. Utah. In 2006, the Charleston Bioengineered Kidney Project [10] was launched and the 1st annual Charleston Bioprinting Symposium was organized. Challenges for organ printing technology lie on both the engineering and biological sides [13]. Biology-based questions relate to identifying cell sources, optimizing hydrogels for cell growth and differentiation, and designing “blueprints” for computer-aided printing of functional tissues. Our technology places “bioink” particles (multicellular spheroids) in “bio-paper” (collagen or hydrogel) using a bio-printer (three-dimensional delivery device). The approach mimics early morphogenesis, based on the realization that both genes and physical forces regulate self-assembly and 3dimensional pattern formation, which can be mathematically modeled. A recent study [14] simulated the process of self-assembly by fusion of bioink particles and utilized this novel technology to build contractile cardiac sheets containing vascular structures, starting from embryonic cardiomyocytes and endothelial cells. The post-printing self-assembly of bioink particles resulted in synchronously beating solid tissue blocks containing endothelial cells organized into vessel-like conduits. Major

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challenges are achieving vascularization and maintaining viability of the printed construct [15]. Without a vascular supply, thickness of tissue constructs is limited to four cell layers or less. Thus, tissues engineered so far are primarily avascular structures like cartilage or cardiac valves. To proceed to true organ level, one must successfully engineer a vascular supply, which requires creating a branching 3D tree-like construct. This challenge is the subject of the South Carolina Project and the research theme of SC’s 2009 NSF EPSCoR RII program (Figure 2).

A. Data Collection and Acquisition

B. Data Analysis and Integration

C. Data Implementation in Bioprinting

FIGURE 2. Biofabrication of a three-dimensional vascular tree is the vision of The South Carolina Project. -6-

C2.

Research Thrust Areas The text below outlines a 5-year research plan to engineer a 3D vascular tree. The overall project is divided into 5 “thrusts”. Thrusts I-III would be performed concurrently in Yrs 1-3 while Thrusts IV and V would be performed over Yrs 3-5, though some tasks necessarily overlap. All five thrusts require enabling research infrastructure improvements in the form of expertise and equipment. Funds to carry out the experimental objectives will come from institutional support and research grants. Each of the five thrusts are led by content experts and include targeted junior faculty and new hires from The SC Project alliance institutions (Claflin, Clemson, Furman, MUSC, SCSU, USC, USC Beaufort, and Voorhees) to fill technological gaps. THRUST I:

Analysis of Structural-Functional Properties of an Authentic (Natural) Branched Vascular Tree Challenges — A vascular tree can be defined as a system of seamlessly connected, dichotomously branched segments. Branching can be symmetric or asymmetric. In real life, branching patterns are organ-specific and usually somewhere between symmetric and asymmetric. Building a vascular tree requires detailed knowledge of anatomical geometry, branching characteristics and real world structure-function properties, including biomechanical properties. Comprehensive integrated datasets are still largely lacking. Analyses of branching geometry are based on 3D images prepared by different methods such as corrosion casting or injection of contrast agents followed by X-ray, MRI or micro-CT imaging, or by computer-aided reconstruction of serial histological sections. We have recently demonstrated that micro-CT provides the most rapid method with sufficient resolution for analysis of any selected organ having a branched vascular tree [16]. We will invest in infrastructure to support the use of CAD technologies to create a blueprint for engineering a seamless branching vascular tree. Data inputs for in silico simulations will be acquired from 3D images of naturally occurring vascular trees (e.g., kidney, lung, heart). Several groups are trying to reconstruct a vascular tree using mathematical approaches based on computer simulations [17-19]. Our approach saves time but requires sophisticated computer science and biomathematics expertise.

Proposed Enabling Infrastructure — 7 New Faculty Hires: 3 Computer Scientists (Voorhees, Yr 1; Furman, Yr 3; USC Beaufort, Yr 2); 3 Biomathematicians (USC, Yrs 1, 2, 3); Mechanical-Chemical Engineer (USC, Yr 1). Tools: Software for 3D reconstruction, finite element analysis, and computational fluid dynamics such as “Fluent”; confocal microscope.

THRUST II:

Directed Differentiation of Adult Stem Cells into Monomer Units of Vascular Cell Types Challenges — The primary challenge focuses on ways to induce adult stem cells isolated from human fat tissue to enter a smooth muscle or endothelial cell lineage. Advantages of focusing on autologous fat tissue derived stem cells are: (a) supply is unlimited and commercially available (from Lonza and Cognate Bioservices); (b) isolation is relatively simple with the Celution system (Cytori Therapeutics); and (c) we have strong preliminary data confirming recent publications [20-22] that indicate the feasibility of directed differentiation of fat tissue derived stem cells into functional smooth muscle cells. As an alternative, we can use adult human bone marrow derived stem cells (from Lonza), or umbilical cord blood derived stem cells (available through Charleston-based CureSource Inc.), though both of these sources provide far less quantities of cells in comparison to fat tissue sources. For Thrust II, infrastructure improvements will support three tasks: 1. Isolate, cultivate and characterize a source of adult human stem cells capable of being induced to differentiate into functional smooth muscle cells. We will apply a cocktail of growth factors used by our consultants and others to induce adult stem cells to differentiate into smooth muscle or endothelial cells. 2. Isolate stem cells in sufficient numbers to create vascular monomeric “units” or segments (equivalent to “twigs” on a mature vascular tree). The fact that human fat tissue derived adult stem cells can be isolated in large numbers in one hour with the Celution system makes them a very attractive cell source to print multicellular vascular units.

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3. Demonstrate that stem cells induced into a muscle phenotype express the appropriate morphological and functional markers. Preliminary experiments by Dr. Rick Visconti at MUSC show that, after incubation with TGF-beta, fat tissue derived adult stem cells start to express both early and late markers of smooth muscle cell differentiation such as smooth muscle actin (α-SMA) and SM22. By combining growth factors and differentiation media, we anticipate being able to generate sufficient numbers of smooth muscle cells to use in bioprinting the vascular units needed in Thrust IV for assembling a vascular tube [23]. To be certain we are dealing with authentic smooth muscle cells, we will do phenotypic characterization with multiple specific markers like α-SMA, SM22, calponin-1, and smooth muscle myosin heavy chain, as well as ultrastructural characterization. To ensure function, we will test for well-known contractility responses to KCl, the L-type channel opener FPL64176, or the SMC agonists 5-HT and ET-1, and the Rho-kinase inhibitor Y-27632. Proposed Enabling Infrastructure — 3 Faculty Hires: Immunologist (Claflin, Yr 1); Molecular/cellular biologist and Stem Cell Biologist (MUSC, Yrs 1, 2). Tools: cell sorter/flow cytometer; “Celution” system.

THRUST III:

Functional Biomechanical Testing of Engineered, Sequential Segments and Comparison to Naturally Occurring (Authentic) Branched Vascular Trees Challenges — Phenotype characterization by morphology alone is insufficient to assess whether stem cells have differentiated into cell lineages equivalent to in vivo cells. For Thrust III, designing special physiological biomonitoring equipment for testing contractile properties of natural and engineered vascular rings will be the major infrastructure challenge. Appropriate datasets for biomechanical properties would enhance in silico modeling of the requirements to engineer the vascular segments. Datasets must include characterizations at multiple levels from nano to cellular to whole tissue. Thrust III’s research cluster will develop or acquire a combination of approaches. At the cell and tissue levels, USC engineers recently performed strain-stress analyses on dissected natural vascular segments using a quantitative computer-aided method of measuring biomechanical properties of vascular wall [24]. In this enabling technology, the displacement of attached fluorescent beads is imaged as a function of applying mechanical forces. Their development of an automated image analysis system and special software will be used to perform precise, effective analysis and mapping of biomechanical properties of natural and engineered vascular segments of increasing diameters. Michael Yost is developing an impedance-based method for non-invasive estimation of biomechanical properties of engineered tissue walls. Atomic force microscopy is a potential approach for functional testing that can provide information on biomechanical properties at all structural levels, including nano. Target faculty and new hires will develop special software to determine if we can use elastic silicon substrates containing gold nanorods to assess contractile forces (technology being developed by Dr. Catherine Murphy at USC). Thrust III aims include (1) comparison of tissue engineered vascular structures with natural ones to prove functionality and maturity of tissue engineered vascular structure; and (2) detailed functional and biomechanical characterization for validation of biofabricated tissue engineered constructs.

Proposed Enabling Infrastructure — 6 Faculty Hires: Biomedical Engineer with expertise in ECM (USC, Yr 3); Vascular Cell Biologist (USC, Yr 1); 2 Bioinformaticists and Computational Scientist (MUSC, Yr 1; Claflin, Yr 2; USC Beaufort, Yr 3); Vascular Developmental Biologist (MUSC, Yr 3). Tools: Atomic force microscopy.

THRUST IV:

Biofabrication of a Branched Vascular Tree

Challenges — Fabrication of solid tissue spheroids is essential for bioprinting. Our preliminary data demonstrate that human smooth muscle cells will self-assemble into spheroids in hanging drop cultures. By changing the number of cells in the hanging drop, it is possible to control tissue spheroid size. Moreover, two unilumenal vascular tissue spheroids can fuse into one larger diameter. Thus, tissue spheroid size is easy to control. However, scalable technology for mass production of tissue spheroids of standard size is needed. Furthermore, bioprinting a vascular tree requires optimal permissive conditions for vascular tissue spheroid fusion and for precision placement of the tissue spheroids within the scaffold or hydrogel. Thrust IV has the following tasks:

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1. Assemble solid-state monomers of 10,000+ cells into a “polymeric” vascular tree. MUSC investigators and collaborators have shown that biofabrication of solid tissue microspheroids (of 10,000+ cells) can be accomplished due to the viscoelastic properties of stem cells. Within spheroids, different cell types sorted out as predicted by Steinberg’s Differentiation Hypothesis, i.e., endothelial cells formed a lumen in the interior surrounded by smooth muscle cells [25]. We also found that these vascularized microspheroids, when closely positioned by bioprinters, fused with each other to form a linear chain having a continuous lumen lined by endothelial cells. To our knowledge, these are the first data to show the feasibility of producing vascular units that can be potentially mass-produced to form linear branches of a vascular tree. 2. Develop a scalable technology for rapidly dispensing tissue microspheroids. Thrust IV will explore acoustic excitation technology using encapsulation polymers to protect the spheroids during extrusion (printing). Acoustic technology will be tested using a coaxial extruder consisting of two cylinders concentrically placed one into the other. The internal cylinder contains air or fluid; the space between the cylinders is filled with mixture of hydrogel (e.g., fibrinogen/thrombin) [26] and progenitor cells. In a fluidic environment like a hydrogel, two or more closely placed tissue spheroids will fuse. The driving physical forces of this phenomenon are surface tension and the intrinsic tendency of fluidic matter to reduce surface energy, resulting in the dispensing of large numbers of vascularized tissue spheroids of a particular size and shape at high speed. Two libraries of available biomimetic processible hyaluronan-based hydrogels will be used to ascertain the relative contribution of physical forces versus chemical factors in producing a tethering effect. The plan is to find a “smart” hydrogel that has the right levels of differentiation inducible peptides and rigidity to permit optimal formation, differentiation and fusion of the microspheroids. The effect of hydrogel on cell phenotype in the 3D tissue spheroid will be evaluated. Computer modeling will be needed to determine if, after polymerization, fibrin hydrogels undergo gradual remodeling and biodegradation. 3. Create branching points in 3D hollow tubules from printed microspheroids. Precision placement of the vascular microspheroids within the hydrogel will be required. Compounding this challenge is Murray’s Law of Optimal Branching: the diameter of a “maternal” segment must be larger than the diameter of a “daughter” branching segment [27]. Thus, to build in vivo-like “Y” or “T” shaped vascular tubules, our strategy would be to assemble two linear tubes, using tissue spheroids of one size to create the “mother” stem segment and a smaller size to create the “daughter” segments. The two printed vascularized tubes would be allowed to fuse or be precisely positioned to form a T-like structure in which the arms are smaller than the stem. The viscoelastic characteristics of the spheroids permit such fusion phenomena, per Steinberg’s differential adhesion hypothesis. Large scale, rapid, precision placement of vascular units will ultimately require a computeraided robotic bioprinter such as the “Bioassembly Tool” (nScript/Sciperio, Orlando, FL). Such instruments are still prototypal. SC researchers and collaborators are currently exploring 3 potential modes of continuously dispensing and positioning the spheroid building blocks. Bioprinting technology will change rapidly and improve over the course of the RII project. Proposed Enabling Infrastructure — 3 Faculty Hires: Chemical Engineer with hydrogel expertise (USC, Yr 2); Engineer specializing in rapid prototyping (USC, Yr 4); Surface Scientist for hydrogel characterization (Furman, Yr 1). Tools: Acoustic vibration device, extruder and bioassembly tools.

THRUST V:

Accelerated Tissue Maturation of Bioprinted, Branched Vascular Tubes

Challenges — Engineered tubules created by the fusion of vascular microspheroids will take time (possibly weeks) to mature. A major challenge will be to sustain viability of printed constructs during maturation, and even accelerate maturation. How would maturation be measured? One important quantifiable parameter is rigidity, biomechanically measured. Two extracellular structural proteins, collagen and elastin, are responsible for 95% of the biomechanical properties of vascular walls in a natural vascular tree. Collagen and elastin take time to be secreted, assembled into fibrils and crosslinked. Thrust V’s major challenge will be to develop an enabling tool that saves time, e.g., a perfusion bioreactor. Bioreactors not only sustain viability, they can also accelerate differentiation/maturation as seen during embryonic vasculogenesis [28,29]. Additional experts,

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targeted faculty, and academic and industrial consultants will be needed. The expertise of Prof. Vladimir Kasyanov, a member of the Latvian Academy of Sciences at Riga U., will be especially critical. He has worked with USC and MUSC faculty on several iterations of bioreactors [30,31]. Thrust V requires engineering a novel bioreactor to extend bioreactor technology to the next level by having three circulation systems. A goal is to partner this bioreactor with the biomonitoring technology developed in Thrust III. For example, Dr. Yost is developing prototype PWAS biosensors to assess temporal viscoelastic properties in living tissues. Such sensors embedded in the bioreactor framework would establish a novel dynamic system to test “maturogens,” i.e., physical or chemical factors such as fluid flow, sheer stress, growth factors or genetic modifications that can accelerate the maturation of bioprinted vascular branches. Three strategies will be developed and used with the novel bioreactor model to promote maturation of bioprinted vascular constructs: biomechanical conditioning using shear stress, elevated hydrostatic pressure and longitudinal strain; chemical factors such as TGF, PDGF, vitamin C, ribose and lysyl oxidase; and genetic modifications that can affect collagen cross-linking or synthesis (e.g., overexpression of periostin or lysyl oxidase genes) [32]. Outcomes would compare biomechanical data from engineered vascular tubes and authentic blood vessels. Changes in gene expression would be assessed as a test for differentiation with comparison to authentic vascular tissues. Translocation of fluorescent labeled nanorods (Thrust III) will also be explored for estimating or mapping biomechanical properties of living vascular segments at molecular and nano levels. Development of accelerated tissue maturation technology will be considered successful if a maturogen (or treatment) induces stable changes in the biomechanical properties of a vascular segment prior to changes observed in controls of the same diameter. Proposed Enabling Infrastructure — 3 Faculty Hires: Engineer with expertise in mass transfer, (USC, Yr 5); Computational Biologist (MUSC, Yr 4); Chemometrician for analysis of perfused cell culture media (Claflin, Yr 3). Tools: Perfusion bioreactor, impedance measuring system for non-invasively estimating the biomechanical properties of biofabricated vascular walls.

C3.

Research Infrastructure Improvement (RII) Strategies Based on the strengths and strategic priorities of SC’s institutions of higher education, we propose to expand infrastructure for tissue-based bioengineering and conduct the South Carolina Project to focus and align research strengths, increase competitiveness for research funding, and build research capacity in an area unique to the state. The research infrastructure enhancements described below are essential components for engineering branched, lumenized tubules that can be scaled up (industrialized) for future assembly of a functional, branched vascular tree, addressing perhaps the greatest obstacle to engineering successful tissue and organ replacements. C3a. Establish a Statewide Resource Center for Advanced Tissue Biofabrication. The Advanced Tissue Biofabrication Center will be the repository for new biofabrication-related equipment and will serve as the catalyst for motivating the research task forces (thrusts) and educational activities of the South Carolina Project. Vladimir Mironov, MD, PhD will direct this resource center. He currently directs the MUSC Bioprinting Center, which will expand from 600 to 2400 sq. ft., including remodeled tissue culture rooms and space for bioinformatics and computer sciences. Equipping the center will be addressed through recruitment packages and institutional support as well as RII funds budgeted for instrumentation. C3b. Hire Twenty-Two (22) New Faculty with Expertise in Biofabrication. Biofabrication requires a multidisciplinary approach. Progress in this field depends on skillful integration of expertise from different disciplines. Identifying, recruiting and retaining faculty with advanced expertise requires a coordinated team approach. To the extent possible and desirable, we propose “parallel cluster hiring” – a strategy successfully deployed in the 2004 NSF EPSCoR RII – to achieve the proposed hires described in Table 1 and ensure that they are seamlessly integrated into the statewide biofabrication effort. Promising candidates will be invited for coordinated interview visits and to deliver widely-publicized seminars. Successful candidates will have their “tenure home” in designated departments with dual appointments at corresponding colleges or institutions. Each

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participating institution has also invited the RII Scientific Director (Roger Markwald) or his designee to serve as an ex-officio member of the faculty selection committees in each department, with the understanding that the respective departments retain primary influence and decision-making capacity in determining the best candidate who meets the overall goals of their current departmental needs while providing appropriate support to the NSF RII program. To facilitate access and sharing of applicants’ files, the SC EPSCoR/IDeA Office has pilot tested a secure website for sharing faculty applications among institutional/departmental leaders; legal and confidentiality issues have been addressed. Every effort will be made to recruit a diverse cadre of candidates, including underrepresented minorities, women and/or individuals with disabilities. The Scientific Advocate Network program described in Section D is a key component for identifying minority candidates. TABLE 1 Hire #1 Senior Applied Mathematician USC / Mathematics An applied mathematician expert in mathematical analysis of time-dependent conservation principles and nonlinear dynamics of model equations specific to the structure and function of manufactured biological tissues. The individual should have sufficient background in numerical methods and simulation to direct and interact effectively with numerical analysts and computational scientists toward in silico fabrication of viable branched vascular trees. Hire #2 Mechanical-Chemical Engineer/Molecular Biomechanics USC / Engineering & Computing A biomechanics specialist with combined expertise in material properties of soft and solid tissue and biological aspects of mechanotransduction. This specialist must be able to identify molecular and cellular mechanisms of mechanosensing and mechanotransduction as well as force transduction in extracellular matrices. The role of extracellular matrix rigidity, quantitatively determined by rheometer and other methods, in cell lineage differentiation and specification will be one of several important topics of research. Hire #3 Biomedical Engineer/Extracellular Matrices (ECM) USC / Dev. Biology & Anatomy Biomedical or chemical engineer with strong molecular biology expertise in design and synthesis of extracellular matrices using synthetic and overexpressed peptides and self-assembly cross-linking synthetic technology. Development of nanostructured vascular extracellular matrix using self-assembly is essential for biofabrication of the vascular tree. Specialists with broad expertise in structural and synthetic chemistry of extracellular molecules (e.g., collagen and elastin) and strong expertise in the molecular biology of extracellular proteins can effectively design and synthesize nanostructualized vascular extracellular matrix. Hire #4 Mathematical Modeler USC / Mathematics Mathematician with expertise in geometrical and physical modeling of multiscale biomaterials, with application to bioassembly. Design, modeling and computer simulation of cell self-assembly and patterning processes is essential for rational design of branched vascular trees. Strong background in analytical and computational mathematics with skills to collaborate seamlessly with the Senior Applied Mathematician and other project members is essential. Hire #5 Chemical Engineer/Hydrogels USC / Engineering & Computing Biomedical or chemical engineer with expertise in designing and synthesizing biomimetic, stimuli-sensitive, processible nanopatterned hydrogels and synthetic extracellular matrices. Candidates will have expertise in creating a library of tailored hydrogels with specified measurable physico-chemical properties and biological activities. Understanding cell-hydrogel interactions and biomimetic hydrogel factors or signals that determine cell activities such as proliferation, migration, adhesion and extracellular matrix production will require chemical and biological expertise. Hire #6 Numerical Analysis/Simulation Scientist USC / Mathematics Mathematician with expertise in numerical analysis and stochastic computational analysis emphasizing computational fluid dynamics and biomaterials, including soft living tissues. These areas will be critical for in silico vascular tissue maturation using iterative modeling processes controlled from biophysical and biomechanical principles in the presence of uncertainty. The research program must complement other hires in Mathematics. Hire #7 Vascular Cell Biologist USC / Dev. Biology & Anatomy A vascular biologist with strong expertise in cell biology, genomics, proteomics and interactomics for detailed structural-functional characterization of authenticity of biofabricated segments of vascular tree. Expertise in high throughput in vitro assay systems to assess changes in cell adhesion, shape or proliferation after treatment with differentiation or maturation factors is essential. Capacity to develop molecular tools for systematic identification of gene changes in differentiation or adhesion following treatment with maturogens (e.g., periostin) or biomechanical conditioning (e.g., flow dynamics) is highly desirable. Expertise in atomic force microscopy is also desirable. Hire #8 Engineer/Robotic Biofabrication USC / Engineering & Computing Computer engineer with expertise in CAD. Robotic biofabrication requires expertise in design and fabricating prototype bioprinter, automated robotic dispenser, and rapid fabrication systems (e.g., coaxial extruder, acoustic actuator) as well as computer-aided design of future tissue and organ constructs. Strong expertise in computer-aided rapid prototyping is essential for designing optimal conditions for rapid biofabrication and extrusion processes. Experience with rapid prototyping (e.g., SLA, SLS or 3DP) is highly desirable. This expert must be able to design a whole biofabrication process in silico and implement it as a prototype for robotic biofabrication tools.

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Hire #9 Engineer/Mass Transfer Specialist USC / Engineering & Computing Chemical or biomedical engineer with expertise in fluid mechanics, mass transfer and computer modeling. Survival of bioprinted tissue and organ constructs is dependent on effective mass transfer. Design and fabrication of a pressure-controlled, temporal removable irrigation-based bioreactor is a long term goal that requires mass transfer expertise in convection and diffusion of both oxygen and nutrients. Hire #10 Molecular Cell Biologist MUSC / Cell Biology & Anatomy Primary responsibility will be to provide the tools and technology for collecting, harvesting, sorting, storing and culturing adult stem cells. This individual will implement and direct a new cell sorting/flow cytometry facility in the ATB Center. Ability to train and collaborate is essential. A critical responsibility will be to provide morphological and molecular characterization of cell phenotypes resulting from treatments with tissue determinants or maturogens. Hire #11 Bioinformaticist MUSC / Bioinformatics Computational biologist with experience in fundamental developmental cell biology. Primary responsibility will be data mining related to DNA microarray or proteomic assays with a goal of verifying tissue differentiation and authenticity of engineered constructs. A major requirement will be to catalog and annotate data resulting from microarrays and create datasets (e.g., matrix “interactome”) that can be shared with the biofabrication e-community. Hire #12 Stem Cell Biologist MUSC / Cell Biology & Anatomy Cell biologist with expertise in stem cell technology and biochemistry to play critical role in Thrusts I and II. Individual will lead collaborations in normal embryonic and postnatal regulatory studies of vascular tissue formation to obtain reference points and control parameters needed to verify authenticity of tissue engineered constructs. Expertise to lead analyses of ECM formation and organization after treatment with maturogens is highly desirable. Hire #13 Vascular Developmental Biologist MUSC / Cell Biology & Anatomy Developmental biologist with expertise in designing gene constructs and molecular tools to study differentiation of stem cells into vascular cell types. Individual will incorporate gene discoveries from microarray or genetic studies into assays to test for differentiation into vascular smooth muscle or endothelium, and create in vitro assays to test spatial temporal gene expression in living tissues assembled from vascular microspheroids. Individual will work closely with Senior Stem Cell Biologist; this position could be included in recruitment package for the senior hire. Hire #14 Computational Biologist MUSC / Bioinformatics Computational biologist or specialist in mathematical modeling and computer simulation of biological structure and process. Individual must understand biological processes and have extensive knowledge of mathematical modeling with skill to visualize models. This expert will analyze images of natural and engineered vascular trees acquired by MRI or microCT, and use CAD software and mathematical modeling to transform these images into “blueprints”. Post-printing processes will also require mathematical modeling and predictive computer simulations to optimize physico-chemical properties of hydrogel and cell aggregates. Hire #15 Immunologist Claflin / Biology Immunologist knowledge and expertise in the area of vasculogenesis using umbilical cord blood stem cells. Several thousand specimens of umbilical cord blood have been donated to the SC Center for Biotechnology at Claflin. An individual with interest in developing human leukocyte antigen (HLA) knock-out blood vessels, using RNAi methodology, for human vascular grafting without fear of immune rejection by the host or graft-versus host reaction is needed. Cord blood provides a reliable source of human endothelial cells essential for building a vascular tree. Hire #16 Bioinformaticist Claflin / Math & Computer Sci A bioinformaticist is needed to build additional capacity in the Claflin’s Biotechnology and Bioinformatics Program initiated in 2002. This position be a joint appointment between the departments of Biology and Mathematics/Computer Sciences. This person will work with biofabrication researchers in analyzing expression and characterization of cells using microarrays and other –omics technologies. Hire #17 Chemometrician Claflin / Chemistry Chemometrics represents a key technology for the analysis of complex multi–parametric data describing biological systems and also provides a means of collecting relevant information through statistical experimental design. Chemometrics adds an important dimension to the SC Project, e.g., for systematic analysis of perfused cell culture media of biofabricated tissue engineered constructs in search of potential reliable biomarkers of tissue maturation. This hire will be a joint appointment between the departments of Chemistry and Biology. Hire #18 Surface Scientist Furman / Chemistry Preferred candidates will have research interests in surface characterization/catalysis using FT-IR and polarization modulation techniques that may synergize with existing Furman research on liposomes dispersed into alginate fibers. Hire #19 Computer Scientist Furman / Computer Science Recruiting for this position will focus on candidates with established research interests in the areas of computer-aided design (CAD), computer modeling, and/or image processing with interdisciplinary focus on imaging including CT, MRI/MRA, confocal microscopy, and microCT.

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Hires #20,21 Computational Scientists USC Beaufort / Science & Math Two new tenure track faculty members in the area of computational science, at least one of whom will be an expert in computational biology, will be hired to support the new Computational Science degree program. Preferred candidates will have a PhD in computer science, math or a related field with advanced training in machine learning, data mining, bioinformatics, biologically inspired computing, or other areas at the interface of computer science and biology. Data mining and dataset development are critical to the five research thrust areas of The SC Project. Hire #22 Computer Scientist Voorhees / Computer Science Voorhees College is seeking to fill a position in the Computer Science Department and serve as Department Chair. Applicants must have a PhD in Computer Science with potential to conduct research in a liberal arts setting. The selected candidate is expected to demonstrate ability in the continued development of the department to include interdisciplinary collaborations, particularly biology and mathematics, and development of a bioinformatics course. Preference will be given to candidates with interests in bioinformatics, computational biology, and data mining.

C3c. Identify, Enlist and Mentor Target Faculty. South Carolina’s 2004 NSF EPSCoR RII grant resulted in hiring of 5 new faculty at Clemson in bioengineering, computer sciences, and computational biology; 4 new faculty at USC to in tissue-based biomedical engineering, including nanotechnology and protein delivery vehicles; and 3 new faculty at Claflin in biostatistics, protein chemistry, and molecular biology. To increase research capacity in tissue biofabrication, we will enlist the expertise of existing junior faculty. Clemson and MUSC have budgeted NSF and institutional funds specifically for junior faculty development. Additional funds administered through the SC EPSCoR/IDeA Office (GEAR Program) are also available. Target faculty will be competitively selected based on relevance to the South Carolina Project and ability to contribute to specific technical challenges. The incentive will be “supplemental start-up" funds, access to equipment, student stipends students, and/or summer salary. However, the real benefit will be integration into a large, statewide program that can enhance their competitiveness for federal and non-federal research grants. C3d. Establish Data Management, Bioinformatics and Global E-Community (Network). Databases will be developed that will progressively integrate cell and developmental biology, computational biology, anatomical and histological images, morphometrics, biomechanical data, genomics and proteomics on each branch or sequential segment of natural or bioprinted vascular tissues. To our knowledge, there are no specific databases on a vascular tree (except anatomical). Local and global collaborations will be essential to integrate databases and implement this complex cross-disciplinary engineering project. A major step is to establish an e-community with current partners and potential new national and international contributors, including the following: New Zealand. Prof. Peter Hunter, U. Auckland, with Nicolas Smith developed a detailed, anatomically correct computational model of a coronary vascular tree as part of the international Physiome Project. Singapore. Prof. Ian Gibson, Natl. U. Singapore, created a virtual community of world leaders in rapid prototyping (RP). Prof. Chua Chee Kai, Nanyang Tech U., created a library of scaffold designs for RP. China. Prof. Yan and Dr. Feng Lin, Tsinghua U., Beijing, developed a CAD design (“blueprint”) of an ideal vascular tree and are designing a biofabrication device. United Kingdom. Profs. Denis Noble and Peter Kohl, Oxford U., are developing a computational functional model of the human heart based on detailed knowledge of anatomy and histology. Romania. Dr. Adrian Neagu, U. Timisoara, and Prof. Gabor Forgacs, U. Missouri, have a unique collection of Monte-Carlo simulations and animations of vascular tube bioassembly from tissue spheroids [33,34]. USA. Prof. Ghassan Kassab, Indiana U. (IUPUI), is collecting data on biomechanical properties of the branches of an in vivo human coronary vascular tree.

C3e. Stimulate Academic-Industrial Collaborations. Technology transfer and academic– industrial collaboration are essential for commercialization of biofabrication technology and development of an advanced biomanufacturing industry in South Carolina. Rapid prototyping is now a $100 billion/yr industry and rapidly growing. The market leader, 3D Systems, Inc. relocated from

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Valencia, CA to Rock Hill, SC in 2006, offering new opportunities for academic-industrial collaboration in biomedical applications of rapid prototyping technology. Organovo is currently licensing technology patented by MUSC’s Bioprinting Center, and will continue as industrial partner to commercialize technology developed in The South Carolina Project. Another is nScript/Sciperio (Orlando, FL), a leading developer of commercial bioprinters; SC investigators have been asked to test prototypes of their 2nd generation “Bioassembly Tool.” The project team will also seek collaborations with two leading companies in fat tissue derived stem cell technologies: Cognate BioServices (Baltimore, MD) and Cytori Therapeutics (San Diego, CA). Cytori recently developed a new device, “Celution,” for rapid isolation of large numbers of adult stem cells from fat tissue obtained by liposuction [35]. A SC biotech company, Cell and Tissue Systems (Charleston, SC), has an interest in the development of perfusion media for perfusion bioreactors. Important future targets to enhance and sustain infrastructure include developing academic-industrial consortia and SBIR/STTR grants between the ATBC and companies like 3D Systems, Organogenesis (Canton, MA), FirstString (Charleston, SC), and Organovo (New York). D.

DIVERSITY PLAN South Carolina has a diverse higher education system with 17 public colleges and universities (including 4 two-year regional campuses of the University of South Carolina), and 21 private colleges and universities, including 2 two-year institutions. The state’s 8 Historically Black Colleges and Universities (HBCUs) include 1 public, 5 private, 1 two-year community, and 1 technical college. The SC Technical College System is comprised of 16 campuses with average minority enrollment of >36%; all are regionally accredited by SACS to award two-year associate degrees. The SC EPSCoR/IDeA program will implement three strategies to increase diversity as an integral part of the state’s research infrastructure improvement plan. D1. Support new education programs aligned with the statewide biofabrication theme that increase diversity across institutions, disciplines, and individuals. The adoption of a unified statewide theme in biofabrication for the 2009 RII presents an exciting opportunity for South Carolina to diversify the network of participating institutions and stimulate new education programs that infuse greater diversity into the state’s workforce. These new programs include: Program Type 2+2 2+2 Baccalaureate degree Masters degree

Institution(s) Claflin University / Greenville Tech Voorhees College / Denmark Tech USC Beaufort SC State University

Discipline Biotechnology Biotechnology/Molecular Biology Computational Sciences Biorobotics/Biofabrication

Additional opportunities to increase diversity across institutions are available through other federally-funded programs. For example, Furman University has developed significant experience and positive rapport with SC’s HBCUs through complementary research programs funded by NSF REU programs in chemistry and the NIH-funded INBRE program. Three faculty and their research students from Claflin have spent at least one full summer engaged in collaborative research on the Furman campus within the last few years, and 12 minority students from SCSU, Allen University, Voorhees College and Claflin have participated in summer research experiences with Furman INBRE target faculty in chemistry, biology and psychology over the last four summers. As ties to SC’s HBCUs are further strengthened through the NSF RII program, faculty and students will seek to develop research collaborations wherever possible with faculty on HBCU campuses. Collaborative projects that engage HBCU faculty and students will be a priority of the proposed Grants for Exploratory Research (GEAR) program offered by the SC EPSCoR/IDeA State Office. D2. Facilitate coordination of federally-funded statewide diversity programs. South Carolina is home to 8 HBCUs, 7 of which currently administer NSF-funded HBCU-UP programs. An Alliance for Minority Participation (AMP) program, led by SCSU, is also actively engaging several SC institutions. NSF-funded Advanced Technological Education (ATE) grants are active at 5 of SC’s technical colleges, 4 of which focus on engineering technologies. Coordination and communication among these groups could lead to heretofore unexplored synergies and transformative approaches

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to address STEM needs, long-term goals, and mission. The Innovative Integration Board (IIB), modeled after the NSF I3 program, will actively promote and coordinate the creative integration of the RII with NSF-funded and institutionally-driven diversity programs at SC’s HBCUs. Mr. LaMont Toliver, Director of the Meyerhoff Program at U. Maryland-Baltimore County, will serve as Chair. Proposed members hold faculty and leadership appointments in SC’s 4 largest HBCUs, and/or are Managing Directors for NSF/LS-AMP, NSF/HBCU-UP and NSF/ATE programs. The SC EPSCoR/IDeA Office will coordinate 2 Board meetings per year, rotating sites among the participating institutions. The IIB will identify and pursue ways and means to leverage resources that bridge SC’s minority serving programs with the RII. The Board will increase communication among the programs’ leadership thereby creating new multidisciplinary opportunities for a diverse group of future scientists. D3. Implement statewide programs to promote diversity in academe. The SC EPSCoR/IDeA Office will develop a Scientific Advocate Network (akin to a resource library) of minority graduate students, postdoctoral fellows, faculty or STEM professional educators to present seminars in disciplines relevant to The South Carolina Project and other areas of S&T excellence. Invited speakers will be exposed to STEM career opportunities in South Carolina, thereby expanding candidate pools for future faculty and research staff positions. Speakers will serve as advocates for the state’s S&T research enterprise by encouraging minorities to consider SC as a career destination. Speakers experienced in recruitment, mentoring and retention of historically underserved or underprivileged populations will share effective strategies to diversify the professoriate and STEM workforce. SC institutions may submit applications to the SC EPSCoR/IDeA Office for up to $3,000 in funding from the SAN program to support seminar-related expenses. EPSCoR/IDeA staff will assist departmental seminar programs at host institutions in publicizing invited speakers, and scheduling activities during their visit, e.g. tour of campus and research facilities, meetings with department/division chairs/deans, consultation with faculty involved in related research areas, etc. Other outcomes would include a sustained relationship with the SAN member as a potential new scientific collaborator or valued consultant. The SC EPSCoR/IDeA Office will continue to support the statewide Annual Ernest E. Just Symposium hosted by MUSC during African-American History Month (February). The symposium celebrates the career and scientific achievements of an internationally recognized African-American developmental biologist born in Charleston in 1883. It is an outstanding forum to encourage minority students to pursue scientific research careers through discussions of Just’s career and presentations by leading scientists and educators. It attracts accomplished African-American and other diverse scientists who serve as role models, speakers and future collaborators. Feedback from past symposia indicates that undergraduate participants highly value sessions with admissions personnel who offer specific advice on preparing for and applying to graduate programs in STEM fields. RII resources will support attendance by STEM students and faculty advisors from HBCUs across the Southeast. Students will have the opportunity to meet with admissions coordinators from SC colleges and universities with STEM graduate programs, including MUSC, USC, Clemson, Claflin, Furman and Winthrop University. Student progress to graduate school and research careers will be tracked as a primary outcome of the symposium. E.

WORKFORCE DEVELOPMENT PLAN The core philosophy guiding our Workforce Development Plan is the engagement of a diverse group of institutions that bring complementary approaches to the research, education, training and production of SC’s future STEM workforce. This diverse group – comprising 3 research intensive institutions, 3 HBCUs (1 public and 2 private), and 2 other PUIs (1 private and 1 public), with outreach to 2 technical colleges and the K-12 community – form an alliance of institutions in support of The SC Project. Our overarching strategies include the following. E1. Build research and education capacity in the RII alliance institutions, aligned with their mission and needs. A primary strategy of the SC EPSCoR/IDeA Program has been to develop intellectual resources by providing support for early career faculty who bring access to

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critical technologies not yet represented in the state’s targeted areas of S&T development. As described in Section C, twenty-two (22) new faculty will be hired into 6 institutions: Claflin (3); Furman (2); MUSC (5); USC Beaufort (2); USC Columbia (9); and Voorhees College (1). These faculty in turn can attract promising students to the emerging field of biofabrication through didactic training and research experiences. Efforts directed towards strengthening STEM research and education in SC’s undergraduate institutions and technical colleges, and interfacing with K-12/pre-college level programs, are critical for building SC’s workforce and economy. Students trained in STEM areas can enhance the quality of the workforce, which in turn can attract biotechnology industries and enhance SC’s economy. More students may choose to stay in SC given better employment opportunities. This logic defines the proposed RII activities of the HBCUs and other predominately undergraduate institutions. Claflin University is an independent, predominately undergraduate HBCU located in Orangeburg, SC, consistently rated in the top tier of undergraduate institutions. Claflin proposes to use new RII funds to (1) recruit and mentor 3 new faculty with expertise in immunology, bioinformatics, and chemometrics as described in Table 1; (2) partner with Greenville Technical College to build the dual-degree, 2+2 program in biotechnology that was approved by the SC Commission on Higher Education in 2007; and (3) train Masters level and undergraduate students, and provide outreach to middle and high school teachers, guidance counselors and students for workforce building in bioscience research. The proposed RII activities will add 3 additional faculty who will comprise a 5-member research core contributing to the scientific needs of the SC Project. Other workforce outcomes will include research training in biotechnology-related methods for 40 high school science teachers, 20 high school students, 48 undergraduate students, and 8 master’s level students and the increased awareness of 50 high school guidance counselors in the state with regard to career choices in the bioscience fields. It is anticipated that 90 percent of those trained will be from underrepresented populations or minority serving institutions and schools. Furman University is a nationally recognized leader in undergraduate research. Their proposed NSF RII activities encompass a five-component plan: (1) development of a Biomaterials research initiative aimed at growing Furman’s current faculty research capabilities, productivity and funding success through competitive summer research support; (2) addition of considerable new expertise in biomaterials research and biofabrication through three new faculty hires, two supported by NSF RII funding (in Surface Chemistry and Computer Science, see Table 1); (3) establishment of a faculty development program to be conducted in collaboration with SC’s Comprehensive Research Universities (CRUs) that will provide mentoring and teaching experiences for SC postdoctoral fellows, while providing sabbatical opportunities for Furman faculty to engage in tissue biofabrication collaborations with CRU faculty; (4) development of a summer undergraduate research program designed to provide significant research opportunities on the Furman campus for minority students from Claflin University and other SC HBCUs; and (5) expansion of a K-12 (6th-12th grades) STEM outreach program within the Greenville County School District designed to provide academic assistance and peer mentoring, while stimulating science/math engagement for African-American and other minority students in the local community. South Carolina State University is the state’s largest and public HBCU. Their proposed objective in the 2009 SC RII is to establish a masters degree program in Biorobotics and Biofabrication. The masters program is planned to contain a core curriculum and two distinct but complementary biotechnology “arms” in Biorobotics and Biofabrication. The total of 36 credits is distributed with 18 credits for core courses, 9 for electives, 3 for research seminar, and 6 for the masters thesis. To broaden the teaching portfolio at SCSU, faculty from MUSC, USC, Clemson, and York Technical College/3D Systems University, which currently offers courses in 3D printing, rapid prototyping and rapid manufacturing of non-human structures, will be appointed as adjunct SCSU faculty and be engaged in collaborative research and course teaching throughout the project. Competencies would instill ability to process morphological datasets of radiologic images from point of origin into devices that allow 3D printing, rapid prototyping or rapid manufacturing to create

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needed tissues. Courses will include tools and techniques, a human gross anatomy course specifically designed to teach the anatomy needed to create specific tissues, and mentored handson training in prototyping laboratories. A long term goal will be to offer this MS degree to students at distant locations who could take coursework through live 2-way audio-videos, asynchronous webcasts and online modules. This approach would allow statewide access to training, provide a unique resource for industrial recruitment and economic development, and generate new jobs for South Carolinians in a high tech, high growth field. Furthermore, this new workforce would be relatively difficult to outsource overseas due to FDA regulations. The University of South Carolina Beaufort (USCB) is SC’s newest four-year university located in the Lowcountry area of the state. Although this area is well known for the wealthy residents of Hilton Head Island, this wealth has not made its way into the surrounding areas. The current economy of this Lowcountry region is based predominately on agriculture and the hospitality/tourism industry, both of which rely heavily on low paying jobs. An Economic Diversification Plan for the region identified the need for employees skilled in the use of computers and computational technology for security and logistical analyses for the planned expansion of the Port of Savannah into neighboring Jasper County; for CAD design processes used in architecture and manufacturing; and for medical database mining and analyses. USCB’s proposed objectives for the 2009 SC RII are to (1) hire two new tenure track faculty in the area of computational science (see Table 1), at least one of whom will be an expert in computational biology; (2) enhance the research equipment infrastructure of USCB by establishing a Computational Core Facility containing workstations, storage server, desktop and laptop computers, along with ancillary small equipment, software and licenses; (3) implement a degree program in computational science that will have at least 48 students enrolled by 2013; and (4) provide research experience for undergraduate students to learn techniques in computing as well as basic methods of research design. Voorhees College is a non-research intensive, private, rural HBCU located in Denmark, SC. The College’s STEM departments seek more interdisciplinary collaborations among Biology, Computer Science, and Mathematics. The processing of biologically-derived information broadens career options for graduates in STEM disciplines. Voorhees College proposes three RII activities: (1) hire a tenure-track faculty member to chair the Computer Science Department (see Table 1) and develop a Computer Science curriculum that integrates computer science with applied mathematics and biology; (2) leverage SC AMP, NSF RII and institutional funds to “shore up” the College’s educational capacity in molecular biology/biotechnology; and (3) use NSF RII funds to support a Bridge Program to target the needs of students transferring from Denmark Technical College, one of SC’s eight HBCUs located adjacent to the Voorhees campus. This six-week residential bridge program will provide academic enrichment and undergraduate research experience in Computer Science, Mathematics, and Biology. Voorhees College’s long term goal is to offer a BS degree via a 2+2 program with Denmark Tech, which has an enrollment of 1,408 students with 93% African American representation. E2. Implement innovative and transformative approaches for a new workforce in biofabrication. Much effort has been devoted to prioritizing the technological needs to advance the field of tissue science and engineering. Given sufficient resources, in the foreseeable future we will be able to manufacture human tissues in a bio-laboratory environment. Interestingly, there is currently no known educational program to train the individuals who will work in this emerging field. The proposed RII initiative to build a Masters degree program in Biorobotics and Biofabrication — led by South Carolina State University in conjunction with MUSC, USC, and Clemson — is a step in this direction. Existing faculty within the participating institutions, in addition to the 22 new hires (see Table 1), provide a substantial base of expertise to build towards an innovative, competitive workforce to address the educational and technological needs of a new 21st century biofabrication industry. Additional short term activities include the following: E-Textbooks. Electronic textbooks on Biomedical Applications of Rapid Prototyping and Introduction to Organ Printing will be developed and evaluated for age-appropriate audiences. The

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pedagogical rationale and advantages of e-textbooks are obvious. They serve as an open access teaching resource facilitating broad knowledge dissemination, that can incorporate animation and movies, cross-linking and cross-reference to a glossary and important hyperlinks, with timely updating. E-textbooks are interactive, allowing students to ask questions and obtain self-evaluation of knowledge mastery. E-textbooks are a critically important, integral element for effective training of a highly skilled workforce for a new industry, and an essential teaching resource for new degree programs as they emerge. Certified Training Course. Rapid prototyping is already a billion dollar industry. Training the next generation of specialists in rapid prototyping and promoting awareness about potential biomedical applications are essential for further growth. A 3-day training course in Biofabrication: Biomedical Applications of Rapid Prototyping will be developed, including lectures by academic and industrial experts. Demonstrations of rapid prototyping equipment and software will be offered through the CAD/RP Laboratory at SCSU in conjunction with York Technical College/3D Systems University. Course enrollment will be limited to ~24. Registration fees will cover major costs. Experts in the field as well as educational methodologies will be used to evaluate and certify the course. Biomathematics Curriculum Development. The USC Industrial Mathematics Institute recently completed a comprehensive self-study and external review with recommendations to integrate IMI research activities into the department’s education and degree programs, and extend collaborations to engineering and science programs in SC. The IMI Director will assist a curriculum committee in the revision of core courses in computational and applied mathematics to include modern topics related to computational nanoscience and biomathematics. In addition to revising courses in Mathematical Modeling, Numerical Analysis, Numerical Optimization, and Numerical Partial Differential Equations, the committee will develop a year-long introductory sequence to formulate, analyze and approximate the multiscale models necessary for effective simulation of computational tissue engineering. More advanced courses, designed by the new biomathematics faculty hired with RII support, would be offered as experimental and special topics courses. F.

CYBERINFRASTRUCTURE PLAN Cyberinfrastructure is a statewide priority with funding from the SC General Assembly. Health Sciences South Carolina (HSSC) was established as the focal point for developing statewide cyberinfrastructure resources. The HSSC collaborative includes the state’s research universities and largest healthcare systems. Supported by a $21 million grant from The Duke Endowment and private sector contributions, HSSC has a unique governance structure that supports research and education across the state with numerous Centers of Economic Excellence and enterprise-wide communications and IT resources. These resources include a collaborative Federated ID system and a database of researchers across the state for identifying research interests and collaborators. HSSC works closely with the South Carolina Light Rail (SCLR), a dark fiber broadband network that ultimately will include 40 channels of 10 Gigabytes each and optical switch linkages. The emergence of broad support for SCLR is among the most important milestones in South Carolina’s cyberinfrastructure development process. The SC General Assembly provided $4.5 million to implement the network backbone and strengthen connections to national networks and computing grids (Figure 3). Phase I of SCLR, activated in August 2007, linked Clemson University to the Southern Light Rail (SLR) at Georgia Tech and thence to the National Lambda Rail (NLR). Through NLR and Internet2, South Carolina’s researchers will access major computing facilities such as the National Tera Grid, Oak Ridge National Laboratory, Lawrence Livermore National Laboratory, Savannah River National Laboratory, and international sites. Phase II, to be completed this year, establishes high speed connectivity along the I-26 corridor, linking the Upstate to the Midlands (Columbia and Orangeburg) and Lowcountry (Charleston) and encompassing the state’s other two research universities and majority of our HBCUs and 4-year colleges. A recent $7.95 million award from the FCC’s Rural Health Care Pilot Program supports implementation of a wireless broadband network for the state’s rural counties, connecting 4 large underserved regions to a fiber optic network and Internet 2. The contract to build the network was awarded in September 2008.

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FIGURE 3. Map of the South Carolina Light Rail (SCLR), showing Phases I and II with linkage to rural areas and undergraduate colleges and universities. SCLR currently connects to the Southern Light Rail and National Lambda Rail through linkage to Georgia.

SCLR is conceived as a high-speed, high-capacity optical network to support scientific and clinical research, instruction, improved health care, and economic development. South Carolina is actively engaged in building cyberinfrastructure connections with Tennessee to support life sciences research and advanced materials research with Vanderbilt, ORNL, and the U. Tenn for access to electron microscopy, the Spallation Neutron Source, and the new petaflop computer. Via the NSF EPSCoR Track 2 mechanism, SC State University plans to establish an externship program whereby SCSU computer science students train on the petaflop computer system in Knoxville. This RII proposal includes resources specifically to support the ATB Center and the participating faculty. Funds (NSF and institutional) are budgeted to develop an entry-level infrastructure that includes programmer/developer staff (middleware personnel), 16-server research cluster, and related software. Faculty can access additional cyberinfrastructure resources for research. For example, the Clemson University Genomics Institute maintains a 128-server cluster to support genomic research, and Clemson has a 20 Teraflop computing facility available to researchers statewide. Computational support for this RII proposal includes the following: (1) Computational resources on CRU campuses for use by all researchers including clusters meeting minimum requirements for modeling and sufficient storage. (2) Applications software libraries for various forms of modeling including industry standard software as well as open source software for niche research applications. (3) Applications developers with expertise in programming software for the various research applications as well as developing novel approaches for software use.

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G.

OUTREACH AND COMMUNICATION PLAN Based on recommendations from NSF site visits, surveys, and evaluations, the SC EPSCoR/IDeA Office will administer the following activities to promote efficient sharing of RII project results, communicate with the public and K-12 sector, facilitate technology commercialization, and promote opportunities for SC’s comprehensive research universities (CRUs), Historically Black Colleges and Universities (HBCUs), predominantly undergraduate institutions (PUIs), and Technical Colleges (TCs) to make high impact research infrastructure improvements. Annual Statewide Research Conference. Based on an 85% positive response to a recent needs assessment survey of SC faculty, the State Committee will host an annual statewide research conference to encourage faculty collaboration, broaden participation in research and create a forum for strategic planning. The format will mimic that of a “Gordon Conference” and coincide with the annual review by the RII External Advisory and Review Board. Roundtable sessions will provide a forum to initiate collaborative research discussions. Students and postdoctoral fellows will present posters during an informal session. Moderated breakout sessions will address topics such as federal and state funding opportunities, cyberinfrastructure developments and diversity activities. Science Journalism Fellows. This new program is designed to develop the capacity of professional journalists in SC to report on science and offer informal science education to the general public. Dr. Sonya Duhe’ from USC’s School of Journalism and Mass Communications will conduct annual 2-day reporting workshops that target non-specialist journalists, including newspaper and television reporters. The 10-12 participants, named Science Journalism Fellows, will receive a $1,000 stipend to cover travel, room and board. Journalism students with an interest in science reporting will be invited. The participants will have access to RII project scientists and be paired with postdoctoral fellows, graduate students or undergraduates from the South Carolina Project. Participants will visit the ATBC and other labs for first-hand demonstrations. SC Educational Television (SCETV). SC EPSCoR/IDeA will partner with SCETV to produce 40, 3-5 minute video segments highlighting The South Carolina Project and related EPSCoR activities. The content will address specific K-12 curriculum standards and be produced and uploaded by SCETV to the StreamlineSC video-on-demand system for access by South Carolina’s K-12 teachers. StreamlineSC was created by ETV with the SC Department of Education and the SC K-12 Technology Initiative in 2004 to improve and manage learning resources. The service engages teachers and students through the interactivity of the Internet by providing access to a high-resolution video and image library, interactive quizzes, an assignment builder, and teachers’ guides. This EPSCoR/SCETV partnership will broaden communication of the quality and scope of ongoing research in the state by creating the first series of SC-specific science videos. StreamlineSC is being used in all school districts within the state with >40,000 teachers (80%) holding an account. StreamlineSC had 2,174,580 total views and downloads in FY08. SBIR/STTR Phase 0 Program. This highly successful program provides seed grants to SCbased companies to help submit federal SBIR or STTR Phase I or II proposals. In the past three years, 25 small businesses have received Phase-0 support leading to $2,536,079 in federal SBIR/STTR awards and a return on investment of 10:1. The program has also led to workforce development. For example, Innegrity, LLC, a 2004 Phase 0 recipient with subsequent Phase I and II awards totaling $1.1M, recently announced a $15M expansion creating 150 new jobs in SC over 3-5 years. The Phase 0 Program is a competitive, merit-reviewed program. Phase 0 companies who obtain Phase I awards are eligible for a 1:1 match from the SC Launch! Program administered by the SC Research Authority as an incentive to pursue Phase II funding. H.

EVALUATION AND ASSESSMENT PLAN The SC EPSCoR/IDeA State Committee and Office fully endorse implementation of an integrated multi-year evaluation plan to measure progress toward the goals and objectives of the proposed NSF RII project. The State Committee makes professional development opportunities in evaluation available to the staff and other personnel involved with SC EPSCoR/IDeA projects, including the RII. The Project Administrator, T. Scott Little, PhD, is Certified in Evaluation Practice

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and Quantitative Methods by the Center for Evaluation Effectiveness at The George Washington University and has extensive experience evaluating NSF RII, NIH INBRE, NSF HBCU-UP and other federal programs. Dr. Little and his staff are responsible for implementing the Evaluation Plan for the proposed RII. Dr. Little is assisted by Gray H. Ladd, Project Assistant for Evaluation. Mr. Ladd has extensive training in the use of statistical analysis software, including Statistical Profiles for the Social Sciences (SPSS). He has developed a comprehensive quantitative dataset of inputs and outcomes for EPSCoR/IDeA programs in SC. For the duration of this project, the staff will collect and analyze data and generate reports for the State Committee, RII Management Team and other stakeholders. The staff regularly participates in data collection and analyses, produces detailed evaluation reports of outreach activities, and develops and implements participant tracking procedures. An External Advisory and Review Board will annually review progress, make recommendations for improvements, and contribute to the annual progress report, including evaluation of the role and accomplishments of each participating institution and initiative. Because infrastructure improvements are designed to support transformative results, SC EPSCoR/IDeA will collect longitudinal data with the expectation that many achievements will occur after the award period. Process evaluation will assess program implementation and help identify barriers to meeting stated objectives. Outcome evaluation will assess the long term effectiveness of the program. Data will be obtained through participant observation, surveys and other instruments. Clearly defined roles and responsibilities for evaluation extend across the staff including: recording minutes for the State Committee, External Advisory and Review and I3 Boards; developing evaluation methodologies and procedures; coordinating mail and on-site reviews; creating customized web pages for reporting and maintaining evaluative data; and preparing financial reports. Metrics. Specific outcomes to assess RII accomplishments and progress toward competitiveness include: number of studies funded; number of research publications and presentations with special attention to peer-reviewed journals and high impact meetings; number of patent applications and licenses; number of collaborations established, with special attention to teams from 2 or more institutions or disciplines; utilization of facilities, materials and services, with special attention to shared use by faculty of multiple institutions; institutional support for RII-funded operations (space, faculty, staff, etc.); amount of additional research funding and diversity of funding sources; number of additional scientists with expertise in the RII thematic areas participating in RII activities; number of trainees associated with RII activities and their subsequent career path; and number of courses, seminars and workshops offered. Platforms of competitiveness extend across the institutions proposing the faculty hiring initiatives of this RII. Archived data from prior RII projects allow empirical evaluation. Expected outcomes include essentially doubling the number of research active faculty members engaged in tissue biofabrication research. Notably, the number of active research faculty engaged in biomedical engineering research at USC grew from 1 in 2004 to 12 in 2007 as a result of the 2004 RII program. At full development (i.e., at time of promotion/tenure decisions), junior faculty hired within the PhD granting institutions will be expected to generate at least $200K/yr in external research funding. New senior hires will be expected to operate a research program with at least $300K/yr in external research funding. A 3- to 5-fold increase is expected in the number of PhD students having expertise in tissue biofabrication, as well as in the number of peer-reviewed journal publications. Metrics for the Workforce Development Plan include enrollment in new courses and programs and degrees conferred. For example, the inaugural MS program at SCSU is scheduled for Fall 2011 with an entering class projected to be 20 African American students. Graduate student support from the RII at Claflin is expected to generate 9 Masters in Biotechnology degrees to African Americans. Through the proposed undergraduate research programs, Claflin, Furman, Voorhees, and USC-Beaufort will provide training for more than 80 African American students. An additional 25 African American high school students will participate in a summer research program at Claflin. The state office of the SC EPSCoR/IDeA program has put in place a student tracking database to ensure accountability, relevance and effectiveness of the proposed programs. Other metrics of success will include stable or improved standings in departmental rankings.

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Education, outreach, communication, diversity and collaborative initiatives require individual logic models with quantitative and qualitative input, process and outcome metrics. Maintaining tracking records for participants in new academic or science workforce positions, receipt of nonEPSCoR/IDeA support, and numbers of publications are examples of quantitative data used to attribute achievements to the RII project. Examples of maintained qualitative data that reflect an improved research culture are: increased credit for interdisciplinary research and entrepreneurship in tenure/promotion criteria, and creation of new courses or degree programs. Resources and Tools. The SC EPSCoR/IDeA staff will maintain quantitative and qualitative data in mainstream statistical and analytical software packages, as indicated below. Mixed method analysis yields data mined to assess progress toward achieving delineated goals and objectives, and guide implementation of research and education activities.  Statistical Profiles for the Social Sciences (SPSS) is a software package with complex data management and analysis capabilities as well as presentation and reporting tools. The SC EPSCoR/IDeA dataset includes variables for quantitative measures of research productivity (e.g., proposal submissions and awards, publications, presentations, patents and licenses). Select qualitative data are entered through coding. Data may be selected for analysis according to values of one or more variables and filtered to determine impact at the individual, outreach program, institutional, or entire project level.  Zarca Interactive is an online survey module that enables design, collection and analysis of needs assessment and other large scale participant surveys, as well as outreach and other project progress reports. Data collected in Zarca can be exported directly to SPSS.  ATLAS.ti, a leading qualitative data analysis software package, will be implemented and tested in the 1st year of the RII project as a tool for cataloging qualitative data. Examples of data sources to be imported include minutes, progress reports and site review summaries. I. SUSTAINABILITY PLAN I1. Offer Grants for Exploratory Academic Research (GEAR). The SC EPSCoR/IDeA Office will administer the GEAR program that provides flexible funds to support projects with high potential for significant short-term impact. GEAR is open to all SC institutions of higher education. Grants are non-renewable, 12-24 mo. in duration with $100,000 maximum award. GEAR support can be for new faculty startup, graduate fellowships, shared equipment, collaborations, etc. Proposals will be evaluated based on specific criteria including: technical merit; potential to generate mainstream, extramural support and peer-reviewed publications; likelihood of impact on institutional research culture; and significant broader impact on the state’s research enterprise. Activities with access to traditional sources of support would not have funding priority. I2. Formalize statewide center status for the Advanced Tissue Bioengineering Center. The process for attaining official statewide center status has been initiated, with final approval to be obtained from the State Commission on Higher Education. Center status will enhance organization of graduate courses, multi-investigator applications, communications, and data sharing. The center will have a high profile physical presence in the collaborative Bioengineering Building in Charleston. Its planned completion in 2010 is a significant milestone for long term sustainability of the ATB Center. Allocation of funds for this building indicates the priority and commitment that the research universities have made to enhance NSF-style transformative and NIH-style translational research. I3. Support the long term commitment and career development of the new faculty to be hired. The proposed project calls for recruitment of 22 new faculty who will receive competitive startup packages (salaries, technical support and equipment). They will have tenure-track appointments in appropriate departments, demonstrating the institutions’ long term commitment beyond the RII funding period. Junior faculty recruited through this program are expected to achieve a proper level of nationally competitive research funding within 3-5 years. Targeted faculty mentoring programs will enable junior faculty to obtain preliminary data and develop collaborations. Teams of

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competitive, collaborative researchers can compete successfully for large scale grants like NSF’s ERC, MRSEC, STC, NIH’s P01, Center or BRP grants. I4. Develop educational and research training opportunities that build on the unique capabilities of the ATBC. The multi-disciplinary nature of the South Carolina Project positions SC to compete for new training initiatives at the interface of mathematics and biology. The emerging biofabrication field offers exciting opportunities for K-12 and public education as well as undergraduate and graduate training initiatives like SEPA awards, REU sites, GAANNs, and IGERTs. Minority candidates will be encouraged to apply for individual fellowships and supplements through NSF, NIH, and other programs such as the UNCF-Merck Fellowships. I5. Support technology transfer and commercialization of research. An aggressive approach will be taken to patent and license novel technologies for commercialization. University royalties generated from such activities will be reinvested in infrastructure maintenance and development. The SBIR Phase 0 program is designed to stimulate new SBIR/STTR proposals. SC Launch! facilitates SBIR/STTR Phase II proposals to provide sustainability at the next level of development. The universities’ respective technology transfer offices will help identify corporate sponsors for research support and licensing. The chart below is a timeline for implementation of the plan for building statewide capacity in biofabrication. Solid lines indicate accomplishments and dotted lines represent planned activities.

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J.

MANAGEMENT PLAN The South Carolina EPSCoR/IDeA Committee makes all policy and major programmatic decisions for the state’s portfolio of EPSCoR/IDeA programs. The Committee consists of provosts and vice presidents for research, health sciences and economic development from SC’s 3 PhD granting universities; a representative from the state’s 4-year institutions and HBCUs; the Deputy Director for Research at the Savannah River National Laboratory; an SC Department of Commerce representative; and the CEO of the SC Research Authority (SCRA). The current Chair, Dr. John R. Raymond, is Vice President for Academic Affairs & Provost at MUSC. The President and CEO of 3D Systems and the President of Health Sciences South Carolina will join the Committee in early 2009 to better align SC’s EPSCoR and IDeA programs with new state investments. The Committee has an annual strategic planning retreat to promote a unified vision for academic R&D in South Carolina. To expedite business, an Executive Committee meets in monthly conference calls with the State EPSCoR/IDeA Director (Dr. Jerome D. Odom) and Manager (Dr. T. Scott Little). The State Committee operates under a ratified set of Bylaws that delineate its Purpose, General Powers and Membership, Officers and Resource Allocation. Succession is a major programmatic decision under the purview of the State Committee. For example, in 2001 the Committee administered a smooth transition of Principal Investigator, inclusive of change in fiscal agent and novate of award. The State Committee appoints or proposes nominations for appropriate individuals to fill vacancies, as necessary. The designated PI/PD for a given EPSCoR/IDeA program has signatory authority for all project expenditures. The State Committee maintains a 1500 sq. ft. office with 5 full-time staff, including a State Manager (Dr. Little), financial and subcontracts manager, and 3 program assistants. The staff assists in centralized fiscal monitoring and program assessment, implementation of outreach activities, and liaison to university administrators, faculty and student participants. The staff collects and maintains project data for use in internal and external program reports and evaluation; manages subcontracts to participating organizations; disseminates program information and achievements through the website and quarterly newsletter; arranges logistics for conferences, workshops, and symposia; organizes site reviews; and prepares and/or provides presentations to members of the SC General Assembly and Congress. The staff has responsibilities across all federal agency EPSCoR and EPSCoR-like programs, including the 2004 SC NSF/EPSCoR RII and the SC NIH/IDeA INBRE program. The scope of responsibility with the mission-oriented agencies includes development and issuance of statewide program solicitations, identification of reviewers, and administration of panel logistics and review results. Management Team. The Committee proposes two of its Officers — the State Director (Dr. Odom) and Manager (Dr. Little) — as Principal Investigator and Project Administrator respectively, for the 2009 RII program. Dr. Roger Markwald, Professor and Chair of the Department of Cell Biology & Anatomy at MUSC, will serve as Scientific Director and Co-PI. Dr. Odom is an accomplished chemist and former provost, vice president for academic affairs, dean and department chair; he is ideally qualified to serve as PI for a statewide research initiative. Dr. Markwald is a Distinguished University Professor with an international reputation for contributions to the field of developmental biology; he has served as a department chair for 24 years and is an NIH Merit Awardee. Other members of the Management Team include individuals with the administrative capacity to accomplish the hiring and faculty development plans. Dr. Larry Dooley is Associate Dean for Engineering & Science at Clemson. Dr. Rosemarie Booze is Interim Vice President for Research at USC; her position will facilitate implementation of the proposed intercollegiate hiring plan at USC. Drs. Markwald and Odom will oversee the RII program's search and selection committees for the 22 proposed interdisciplinary tenure-track hires as well as faculty development activities across the institutions. The multi-institutional Management Team will provide leadership, monitor and evaluate program activities, oversee project reports, and ensure integration of program activities among the participating institutions. The SC Research Authority (SCRA), as fiscal agent for the State Committee, serves as fiscal agent for the RII program. The SCRA Administrative and Finance Group provides fiscal oversight and guidance in contractual, financial, security, legal, personnel and

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administrative matters. Upon notice of award, the SC EPSCoR/IDeA staff will establish subcontract agreements with participating institutions. Ongoing tasks include technical assistance through preparation of annual reports; maintenance of project process, outcome and demographic data; establishing and monitoring all federal and non-federal accounts; identification and dissemination of funding opportunities; and arrangement of logistics for program activities. Weekly meetings among the PI, Project Leader and Project Administrator will allow for identification of significant achievements or concerns. External Advisory and Review Board. As authorized by the Bylaws, an External Advisory and Review Board will provide continuous oversight and external evaluation of progress toward attainment of the RII project goals and objectives. Proposed members of the EARB have scientific and technical expertise in biofabrication and knowledge of NSF’s education, outreach and diversity goals. Proposed members include: Willie Pearson (Chair), Professor, School of History, Technology and Society, Georgia Inst. of Technology; Arnold I. Caplan, Professor of Biology, Case Western Reserve Univ.; M. Gregory Forest, Professor and Associate Chair of Applied Mathematics, UNCChapel Hill; Todd McAllister, President and CEO, Cytograft Tissue Engineering; Robert Nerem, Professor and Director, Parker H. Petit Inst. for Bioengineering and Bioscience, Georgia Inst. of Technology; Laura Niklason, Associate Professor, Department of Biomedical Engineering, Yale U.; and Joan Reede, Dean for Diversity and Community Partnership, Harvard U. The EARB will hold its first meeting shortly after notice of award, and will meet thereafter on an annual basis. Implementation Team. Leadership from the alliance institutions will form an interinstitutional implementation team to ensure alignment of the faculty recruitment and development initiatives with the scientific theme of the RII. This team is composed of the 8 individuals named as Institutional Directors of the participating institutions (see Table A below) who can facilitate the new faculty search and selection processes at their respective institutions and other proposed activities. The Implementation Team also includes leadership from other RII components including science (V. Mironov); communication (R. Swaja); and cyberinfrastructure (W. Hogue). The Implementation Team will meet every 6 weeks by videoconference, and in person at least once per year in conjunction with the External Advisory and Review Board meeting. Affiliations and demographics for all committees/teams are provided in Supplement Doc. A.

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