KOSEN 한인과학기술자네트워크

Functional Tissue Engineering for Disorders and Diseases Primary Sponsor: National Heart, Lung, and Blood Institute Deadline: 3/13/2001; 3/13/2002; 3/13/2003; 3/12/2004 KEYWORDS Complete Title: FUNCTIONAL TISSUE ENGINEERING FOR HEART, VASCULAR, LUNG, BLOOD, AND SLEEP DISORDERS AND DISEASES: SBIR/STTR INITIATIVE PA NUMBER: PAR-01-006 National Heart, Lung, and Blood Institute Application Receipt Dates: March 13, 2001 and March 13, 2002 for Phase I and II applications March 13, 2003 and March 12, 2004 for Phase II applications only PURPOSE This announcement is to encourage small businesses to participate in the research and development of new approaches, technologies, tools, methods, devices, cells, biomolecules and biomaterials that can be used to engineer functional tissues in vitro for implantation in vivo as a biological substitute for damaged or diseased tissues and organs or to foster tissue regeneration and remodeling in vivo for the purpose of repairing, replacing, maintaining, or enhancing organ function. Applications should address a significant cardiovascular, pulmonary, hematologic, or sleep problem and propose research that will significantly improve clinical therapies for heart, vascular, lung, blood, and sleep disorders and diseases. In addition, research plans should emphasize rapidly transferring products and services to the patient and should integrate scientific disciplines such as bioengineering, biology, clinical medicine, materials science, chemistry, and physics. This program will use the Small Business Innovation Research (SBIR) and Small Business Technology Transfer (STTR) funding mechanisms. The SBIR and STTR applications received in response to this program will undergo review by a Special Emphasis Panel (SEP) with the combined breadth of expertise necessary to review the broad range of proposals anticipated. Specific review criteria, which are included in this Program Announcement (PA), will be used in the review of all application received to ensure that the objectives of the solicitation are met. Because the length of time and cost of research involving advanced technology projects may exceed that normally awarded for SBIR/STTR grants, the NHLBI will allow well justified Phase I applications with a project period of up to two years and a budget not to exceed $100,000 per year direct costs (maximum of $200,000 direct costs for 2 years). Phase II applications in response to this PA will only be accepted as competing continuations of previously funded NIH Phase I SBIR/STTR awards. The previously funded Phase I award need not have been awarded under this PA but the Phase II proposal must be a logical extension of the Phase I research. The NHLBI will consider Phase II projects with a project period up to three years and a budget not to exceed $400,000 per year direct costs. The March 13, 2001 and March 13, 2002 receipt dates will be for Phase I and Phase II applications. Only Phase II applications will be accepted on the last two receipt dates, March 13, 2003 and March 12, 2004. After the initial four receipt dates, this initiative will be evaluated and a decision will be made as to whether or not to continue the initiative. This PA must be read in conjunction with the Omnibus Solicitation of the Public Health Service for Small Business Innovation Research Grant Applications (PHS 99-2), and the Omnibus Solicitation of the National Institutes of Health for Small Business Technology Transfer Grant Applications (PHS 99-3). All of the instructions within the Omnibus Solicitations apply with the following exceptions: o Special Receipt Dates; o Additional review considerations; o Opportunity for two years of Phase I support with a budget not to exceed $100,000 in direct costs per year; o Opportunity for three years of Phase II support with a budget not to exceed $400,000 in direct costs per year. HEALTHY PEOPLE 2010 The Public Health Service (PHS) is committed to achieving the health promotion and disease prevention objectives of "Healthy People 2010," a PHS led national activity for setting priority areas. This Program Announcement (PA), "Functional Tissue and Organ Engineering for Heart, Vascular, Lung, Blood, and Sleep Disorders and Diseases: SBIR/STTR Initiative", is related to the priority areas of cardiovascular, lung, blood, and sleep disorders and diseases as well as additional priority areas. Potential applicants may obtain a copy of "Healthy People 2010" at www.health.gov/healthypeople/. ELIGIBILITY REQUIREMENTS Eligibility requirements for SBIR and STTR are described in the NIH Omnibus Solicitation for SBIR/STTR grant applications which is available on the Internet at: grants.nih.gov/grants/funding/sbirsttr1/index.htm. A limited number of hard copies of the NIH Omnibus SBIR/STTR Solicitation are available from: PHS SBIR/STTR Solicitation Office 13685 Baltimore Avenue Laurel, MD 20707-5096 Telephone: (301) 206-9385 FAX (301) 206-9722. Email: a2y@cu.nih.gov. MECHANISM OF SUPPORT This PA will use the National Institutes of Health (NIH) SBIR/STTR award mechanisms. Responsibility for the planning, direction, and execution of the proposed project will be solely that of the applicant. A. INDIVIDUAL PHASE I APPLICATIONS Phase I applications in response to this PA will be funded as Phase I SBIR Grants (R43) or Phase I STTR Grants (R41) with modifications as described below. Applications for Phase I grants should be prepared following the directions for Phase I SBIR/STTR applications as described in the Omnibus Solicitation which is available at: grants.nih.gov/grants/funding/sbirsttr1/11instructions.htm. Well-justified Phase I applications with a project period up to two years and a budget not to exceed $100,000 per year direct cost (maximum of $200,000 direct costs) will be allowed. B. INDIVIDUAL PHASE II APPLICATIONS Phase II applications in response to this PA will be awarded as Phase II SBIR Grants (R44) or STTR Grants (R42) with modifications as described below. Phase II applications will only be accepted as competing continuations of previously funded NIH Phase I SBIR/STTR awards. The Phase II application must be a logical extension of the Phase I research and must be responsive to this PA. Applications for Phase II awards should be prepared following the instructions for NIH Phase II SBIR/STTR applications. The Phase II SBIR instructions and application may be found on the Internet at: grants.nih.gov/grants/funding/sbir2/index.htm. The Phase II STTR instructions and application may be found on the Internet at: grants.nih.gov/grants/funding/sttr2/index.html. Well-justified Phase II applications with a project period up to three years and a budget not to exceed $400,000 in direct costs per year will be allowed. RESEARCH OBJECTIVES Every day thousands of people of all ages are admitted to hospitals because of the malfunction of some vital organ. Estimates of the total U.S. health care costs for patients with tissue loss or end-stage organ failure exceed four hundred billion dollars annually. Moreover, because of the dearth of transplantable organs, many of these people die. As an example, the American Heart Association reports only 2,300 of the 40,000 Americans who needed a heart transplant in 1997 received one. Existing prosthetic replacements for diseased or damaged tissue and organs are imperfect and subject patients to one or more ongoing risks including thrombosis, limited durability, increased susceptibility to infection, and need for re-operations. Taken together, these points illustrate the need for long-term, safe, and cost-effective solutions. Until very recently, most scientists and clinicians believed that damaged or diseased human tissue could be replaced only by donor transplants or with totally artificial parts. Today, however, tissue and organ engineering promises to revolutionize the treatment of patients who need new vital structures. It applies the principles of engineering and the life sciences in an effort to reach a fundamental understanding of structure-function relationships in normal and pathological tissues and to develop biological substitutes that can grow and remodel to restore, maintain, or improve tissue and organ function. The field has already made headway in the synthesis of structural tissues such as skin, cartilage, and bone. Furthermore, bladders have been successfully bioengineered and implanted in dogs. Thus, progress to date predicts future success in the bioengineering of more complex internal organs such as hearts, blood vessels, lungs, and blood and the field is now poised for moving ahead in that direction. However, the development of enabling tissue engineering technologies in a few critical areas, and the application of those technologies through an integrated systems approach, could serve as a catalyst for engineering functional cardiovascular, lung, and blood tissue and help lay the foundation for success that could impact tremendously on human health. Although more than a decade of research may be required before an entire heart, lung, or blood cell system is available, laboratory grown components of these organs, such as vascular grafts, heart valves, alveoli, and hematopoietic stem cells are currently being developed. Vascular grafts are critical for the treatment of peripheral vascular and coronary artery disease. Grafts currently in use for bypass surgery are obtained from the patients' own vessels or are constructed of synthetic materials. In either case, problems with vessel availability and complications due to thrombosis, infection, intimal hyperplasia, and occlusion make these grafts less than optimal. Efforts to develop tissue-engineered vascular grafts with improved long-term patency are needed. Another promising area for cardiovascular tissue engineering involves cardiac valves. Congenital and acquired diseases of the heart valves and great arteries are leading causes of morbidity and mortality. Current prosthetic or bioprosthetic replacement implants do not grow or remodel with the patient and are associated with risks including thrombosis, limited durability, infection, and the need for re- operations. Through a tissue-engineering approach, progress has been made in growing heart valves that function short- term in animals. These types of studies need to be expanded. Cell engineering and cell transplant procedures have the potential to treat heart failure. After a myocardial infarct, scar tissue might be replaced with muscle by transplanting cardiac cells or stem cells directly into the scar area. Another concept could be to grow a living tissue patch that could be applied to the scarred tissue or sewn into the heart after removal of the infarcted tissue. For the treatment of sleep disorders, transplantation of engineered cells to replace missing hypocretin/orexin-producing neurons in the brain may reverse some of the symptoms of narcolepsy. Growing blood and blood product-producing cells in the laboratory is another area of considerable interest. The ability to expand stem cells in culture would assure adequate reconstitution of patients, supply cells for gene therapy of blood diseases such as hemophilia, and allow for the production of patient-specific blood products or products with minimal antigenicity. To date, the expansion of transplantable stem cells in culture has not been possible. Additional studies to develop this field would be an important step forward in making stem cell technologies a therapeutic choice for more patients. Creating venous valves for the treatment of deep venous thrombosis is another area of opportunity. Acute and chronic anticoagulation are the only existing treatments for the valvular dysfunction associated with this disease. Bioengineering of functional replacements for diseased venous valves would provide an important treatment option in an area where no other options exist. Lung researchers have been able to propagate the lung bud in culture up to the stage of branching morphogenesis and have demonstrated augmentation and inhibition of alveolization with various compounds that function as morphogens and/or negative regulators. The implantation of a primitive lung bud that could grow in vivo might circumvent the existing problems of transplantation rejection and shortage of organs. In addition to laboratory grown tissues, more immediate returns may be realized in the area of regenerating functional structures in vivo. There is increasing evidence that lung may be capable of regeneration. Unilateral pneumonectomy in animals results in growth of new alveoli in the remaining lung tissue. Other studies have demonstrated that retinoic acid leads to lung growth and increased numbers of alveoli in neonatal animals and in a rodent model of emphysema. Future studies are needed to assess the functional significance of these changes in lung structure, and the potential of other agents to regenerate lung tissue in diseases such as emphysema or bronchopulmonary dysplasia. Another important goal for the future is to develop the ability to assemble extracellular matrix in emphysema or rebuild lung structure damaged by pulmonary fibrosis. Rebuilding lung regions or fostering repair of lung injury incurred in conjunction with inflammatory processes, interruption of normal development, or proteolytic degradation will significantly impact treatment for lung disease. In the quest to develop laboratory or in vivo grown tissues and organs, partners are needed in many disciplines including physics, mathematics, chemistry, computer sciences, engineering, biology and medicine. It is anticipated that the creativity of interdisciplinary teams will result in new understandings, novel products, and innovative technologies. It is thus the intention of this PA to encourage close interactions among researchers working in different fields. The NHLBI also recognizes that applications for tissue engineering projects may be either design- directed toward technology development, or hypothesis-driven and either type of application is acceptable under the SBIR/STTR mechanism. This PA was developed because of the nascence of this scientific area, and the need for the development of novel concepts and approaches to engineering functional tissues and organs, The primary purpose of the solicitation is to provide investigators with the opportunity to explore new approaches and test imaginative new ideas in areas that will have a significant impact on developing functional cardiovascular, lung, and blood tissues and organs. In addition, it is intended to encourage the development of substantial and meaningful changes to existing technology. The proposed research should be at the frontiers of tissue engineering and it must have the potential for an impact on current efforts directed at growing or regenerating tissues for repair or replacement. Cardiovascular, lung and blood tissuegenesis/organogenesis share some common scientific challenges and can all benefit from some common technological approaches. At the same time, each application area also presents its own challenges that relate to specific clinical problems and the unique biology and physiology of the tissue. Thus research should proceed along two parallel fronts: cross-cutting science and technology, and focused approaches aimed at well-defined clinical problems. This solicitation is open to all innovative approaches to engineering tissues and organs for heart, vascular, lung, blood, and sleep disorders and diseases. Possible applications, listed below for illustrative purposes only, are to develop: o functional heart, vascular, lung, or blood tissues or organs; o cell culture systems for optimal growth and maintenance of tissue- engineered constructs with differentiated cellular functions. These constructs might include vascular grafts, heart valves, myocardial patches, lung buds, or bone marrow; o techniques for creating scaffolds with the complex architecture and chemistry necessary to elicit differentiated phenotypes of cardiovascular, lung and blood cells and tissues grown in vitro; o bioreactors that simulate physiologically relevant biomechanical and biological environments for growing heart, vascular, lung and blood tissues; o ways to create vascular networks, ranging from capillaries to arteries/veins, that are capable of anastomosing with vessels at the site of implantation for those constructs grown in vitro; o ways to engineer immunologically-tolerant autologous tissue; o cellular markers to distinguish progenitor cells of the heart, blood vessels, lung and blood; o methods for cell sourcing including isolation, expansion and differentiation of stem and progenitor cells for cardiovascular, lung and blood tissues; o quantitative analyses and modeling of how signals are presented physically and temporally to cells and how cells integrate multiple signals to generate a response which could provide a design basis for the manipulation of the environment to achieve tissuegenesis; o quantitative methods for non-invasively assessing or monitoring the function of engineered tissues; o animal models for in vivo testing of engineered tissue or for in vivo tissue engineering; o techniques for in vivo regenerative medicine using cells and/or polymer delivery of genes, molecules or drugs; o technology for preservation of engineered tissues; o technology to support large-scale manufacturing of engineered tissues. INCLUSION OF WOMEN AND MINORITIES IN RESEARCH INVOLVING HUMAN INQUIRIES Inquiries are encouraged. The opportunity to clarify any issues or questions from potential applicants is welcome. Direct inquiries regarding programmatic issues to: Cardiovascular Christine A. Kelley, Ph.D. Division of Heart and Vascular Diseases National Heart, Lung, and Blood Institute Rockledge II, Room 9142 Bethesda, MD 20892 Telephone: (301) 435-0513 FAX: (310) 480-1336 Email: kelleyc@nhlbi.nih.gov Blood Carol H. Letendre, Ph.D. Division of Blood Diseases and Resources National Heart, Lung, and Blood Institute Rockledge II, Room 10140 Bethesda, MD 20892 Telephone: (301) 435-0080 FAX: (301) 480-0867 Email: letendre@nhlbi.nih.gov Lung Mary Anne Berberich, Ph.D. Division of Lung Diseases National Heart, Lung, and Blood Institute Rockledge II, Room 10102 Bethesda, MD 20892 Telephone: (301) 435-0222 FAX: (301) 480-3557 Email: berberim@nhlbi.nih.gov Sleep Michael Twery, Ph.D. National Center on Sleep Disorders Research National Heart, Lung, and Blood Institute Rockledge II, Room 10038 Bethesda, MD 20892 Telephone: (301) 435-0199 FAX: (301) 480-3451 Email: twery@nih.gov Direct inquiries regarding fiscal matters to: Mr. David Reiter Division of Extramural Affairs Grants Operations Branch National Heart, Lung, and Blood Institute Rockledge II, Room 7154 Bethesda, MD 20892 Telephone: (301) 435-0177 FAX: (301) 480-3310 Email: reiterd@nhlbi.nih.gov National Heart, Lung, and Blood Institute (www.nhlbi.nih.gov)