RESEARCH ON ORAL WOUND HEALING AND TISSUE REGENERATION NIH GUIDE, Volume 23, Number 4, January 28, 1994 PA NUMBER: PA-94-031 P.T. Keywords: National Institute of Dental Research PURPOSE The National Institute of Dental Research (NIDR) invites investigator-initiated grant applications to conduct multidisciplinary basic and clinical research on wound healing and tissue regeneration associated with the orofacial region. Applications that address the healing, regeneration and repair of oral tissues following periodontal diseases, trauma, and surgical treatment of birth defects such as cleft lip and palate and cancer are sought through this Program Announcement (PA). HEALTHY PEOPLE 2000 The Public Health Service (PHS) is committed to achieving the health promotion and disease prevention objectives of "Healthy People 2000," a PHS-led national activity for setting priority areas. This PA, Oral Wound Healing and Tissue Regeneration, is related to the priority area of oral health. Potential applicants may obtain a copy of "Healthy People 2000" (Full Report: Stock No. 017-001-00474-0) or "Healthy People 2000" (Summary Report: Stock No. 017-001-00473-1) through the Superintendent of Documents, Government Printing Office, Washington, DC 20402-9325 (telephone 202-783-3238). ELIGIBILITY REQUIREMENTS Applications may be submitted by domestic and foreign, non-profit and for-profit, public and private organizations, such as dental or medical schools, universities and research institutions. Foreign institutions are not eligible for the First Independent Research Support and Transition (FIRST) Award (R29). Applications from minority individuals and women are encouraged. MECHANISM OF SUPPORT The mechanisms available for the support of research in response to this PA include the traditional research project grant (R01), FIRST (R29) Award, small grant (R03), and Interactive Research Project Grants. Responsibility for the planning, direction, and execution of the projects will be solely that of the applicants. RESEARCH OBJECTIVES Background Wound healing is a complex process in which a variety of cellular and matrix components act in concert to reestablish the integrity of injured tissue. The complexity of this process may be simplified into four broad categories of the healing response that coincide with the temporal sequence of normal healing: hemostasis; inflammation; cell proliferation (repair); and tissue remodelling. The problems of repair and regeneration of orally related tissues, however, have certain unique features. For example, materials used in osseous reconstruction of the jaw must withstand extreme physical stresses. Moreover, the presence of teeth in the wound area can expose the underlying tissues of the oral environment and thus complicate the healing process. In addition, microorganisms and the host response to microorganisms in the oral cavity can prevent or significantly prolong healing of damaged tissues. The purpose of this PA is to further both basic and clinical research relevant to wound healing and tissue regeneration following periodontal diseases as well as various types of orofacial trauma, such as surgical treatment of cleft lip and palate, ablation and reconstructive treatment for cancer of the orofacial area, and regeneration of functional salivary glands following chemotherapy and radiation. A brief description of the relevant portions of the three major NIDR program areas covered by this PA follows. Craniofacial Injuries and Disorders The craniofacial region is especially susceptible to injuries and wounds resulting from motor vehicle crashes, motorcycle and bicycle related accidents, injuries associated with sports and recreation, and interpersonal violence. Additional sources of trauma include surgical correction of congenital craniofacial deformities. Successful management of injuries and wounds of the craniofacial structures presents unique challenges. The diversity of tissues and structures in close proximity to each other and the variety of functions in which they participate, including speech, hearing, breathing, mastication and swallowing, compound the problem of treating orofacial trauma. Wound healing following reconstructive surgery must often accommodate tissue deficits, such as large bony defects, thus compounding problems of the wound healing process. Oral Cancer The management of cancer of the orofacial complex similarly presents a unique challenge to the health care profession. Cancer therapy may involve surgery, chemotherapy, radiation therapy, or any combination of the three. The variety of tissues that comprise the orofacial complex (e.g., glandular secretory tissues, connective and mucosal tissues) respond in select fashion to ablative and reconstructive treatment of tumors of the head and neck. Restoration of optimal function and normal appearance is a principal goal of the care and management of tumors of the head and neck. Because of the recurring nature of many types of cancers, therapy frequently must be repeated, often complicating the healing process. A serious side effect of therapy, especially that involving radiation or chemotherapy, is damage to the salivary glands and the immune system, which can in turn lead to a general impairment of healing, repair, and regeneration of the oral tissues. Periodontal Diseases Periodontal diseases comprise a group of related microbial- induced chronic inflammatory disorders that destroy the tissues supporting the teeth. These diseases can result in loss of substantial bone and soft tissue around the affected teeth, which challenges the clinician's efforts to restore full structure and supporting function to the periodontium. Periodontal healing is complicated by microbial recolonization of the subgingival sulcus, systemic diseases (e.g., diabetes), conditions in which there is direct bone contact with the root cementum (ankylosis), and the downward migration of epithelial cells, which prevents the reattachment of the fibrous periodontal ligaments to the cementum and alveolar bone. Major goals of periodontal therapy are, therefore, to inhibit microbial recolonization, prevent epithelial interference with proper integration of the soft and hard tissues, accelerate complete reformation of the lost alveolar bone without ankylosis or root resorption, reestablish a complete periodontal ligament network, and restore healthy gingival soft tissues. Major gaps exist in our understanding of the mechanisms by which healing of the periodontium can be accelerated and or enhanced by the clinician. Guided tissue regeneration of the periodontium, for example, while no longer considered experimental, remains an evolving technology requiring further research. Scope A selection of research topics appropriate for this PA is identified below. This list is illustrative and not exclusive, restrictive or in priority order. Investigators are encouraged to submit scientifically meritorious applications in any area of research responsive to the overall research objectives of this PA. Projects should be founded on a strong hypothesis as evidenced by preliminary data. Prior experience of the investigative team is an important element in demonstrating the likely success of the research proposed. o Molecular and Cellular Basis of Healthy Tissues Investigations that address the molecular and cellular characteristics of healthy oral tissues and their mechanisms for regeneration are central to understanding the goals of successful wound healing therapy. These studies include the role of cell adhesion molecules, isolation and characterization of tissue progenitor cells, normal gene expression in oral tissues, and molecular basis of homeostatic tissue cell replacement. In addition, studies of the influence of anatomical features, such as tooth root furcations, on proper healing of the oral tissues are needed. Investigations that identify cell lineages (e.g., cementoblasts) associated with periodontal wound healing are also appropriate. Also, studies that would advance an understanding of the molecular and cellular basis of periodontal guided tissue regeneration, as well as improve the methodology involved, are strongly encouraged. o Cytokines, Growth Factors, and Biological Response Modifiers Cytokines and polypeptide growth factors, including angiogenic growth factors and bone morphogenetic proteins, have been shown to regulate many of the processes involved in wound healing both in vitro and in animal models. The precise role of these factors in wound healing in the orofacial area requires further delineation. As some growth factors affect specific stages of healing and cell types in a temporal manner, it may be necessary to combine certain growth factors for complex wounds and to determine the optimal time for delivery of the factors. Furthermore, biological response modifiers that can control the activities of cytokines and growth factors need to be identified and characterized. The use of genetic therapies to deliver the genes for these proteins to the injured or defective sites represents an exciting contemporary approach for enhancing orofacial wound healing. o Biomaterials Development of new bone-derived, metallic, and synthetic materials for osseous reconstruction is central to the advancement of repair and regeneration of craniofacial and periodontal tissues. Moreover, the use of bone-inductive techniques with appropriate biodegradable and non-biodegradable scaffolding materials appears to offer new modalities for the treatment of congenital or acquired bone defects. Also, studies are needed to develop methods to evaluate the long-term performance of biomaterials, such as hydroxyapatite, ceramic, and coral implants, which are used in the repair of orofacial bone defects. Recent advances in the use of modified collagen matrices for the reconstruction of oral soft tissue, including the mucosal surfaces of the mouth, promise improved materials for soft tissue regeneration. Resorbable barrier materials, such as those used in guided tissue regeneration, are needed to prevent migration of tissues that interfere with structural and functional repair of the oral tissues. o Nutrition Wound healing is affected by a wide variety of metabolic and nutritional factors. Their effects on reparative and defense mechanisms are complex, additive and often synergistic. Studies are needed to determine the effects of nutritional factors on the regenerative process of oral tissues. Since metabolic and nutritional deficiencies can increase oral tissue susceptibility to injury and prolong the healing process, studies that will identify and establish effective treatment plans to prevent or correct the deficiencies are needed. o Aging, Systemic and Behavioral Conditions Studies are needed to clarify the mechanisms through which aging, systemic diseases (e.g., diabetes, Paget's disease), and behavioral practices (e.g., alcohol consumption, smoking) influence oral wound healing. Studies are also needed to develop improved means for promoting oral wound healing under such adverse conditions. o Radiation and Chemotherapy Radiation and chemotherapy have profound effects on the immune system, cell proliferation and tissue growth. These treatments appear to influence the healing process. Studies are therefore needed to define the effects of radiation and chemotherapy on, for example, production of cytokines and growth factors by oral tissues, the stability and integration of reconstructive biomaterials, and the molecular mechanisms involved in oral tissue damage. o Models of Oral Wounds The investigation of oral wound healing has been hampered by a lack of in vitro and suitable animal models. Furthermore, sensitive methods to quantify the histological, immunological, and biochemical events in the wound are needed. Models are needed in which it would be possible to study the effect of, for example, chronic inflammation, cytokines and growth factors, biomaterials, free radicals, aging, diabetes, or tobacco smoke on orofacial wound healing. The use of transgenic and gene knockout animals might provide important models for studying oral wound healing. o Technology Transfer and Clinical Application of Basic Science This PA encourages collaborative research efforts among clinicians, materials scientists, and basic scientists to transfer the knowledge gained in the laboratory to the clinical arena. Cooperative efforts between universities and for-profit as well as not-for-profit private organizations are encouraged in order to develop commercial applications that promote oral wound healing. STUDY POPULATIONS SPECIAL INSTRUCTIONS TO APPLICANTS REGARDING IMPLEMENTATION OF NIH POLICIES CONCERNING INCLUSION OF WOMEN AND MINORITIES IN CLINICAL RESEARCH STUDY POPULATIONS NIH policy is that applicants for clinical research grants and cooperative agreements are required to include minorities and women in study populations so that research findings can be of benefit to all persons at risk of the disease, disorder or condition under study; special emphasis should be placed on the need for inclusion of minorities and women in studies of diseases, disorders and conditions which disproportionately affect them. This policy is intended to apply to males and females of all ages. If women or minorities are excluded or inadequately represented in clinical research, particularly in proposed population-based studies, a clear compelling rationale must be provided. The composition of the proposed study population must be described in terms of gender and racial/ethnic group. In addition, gender and racial/ethnic issues should be addressed in developing a research design and sample site appropriate for the scientific objectives of the study. This information should be included in form PHS 398 (rev. 9/91) in items l-4 of the Research Plan and summarized in item 5, Human Subjects. Applicants are urged to carefully assess the feasibility of including the broadest possible representation of minority groups. However, NIH recognizes that it may not be feasible or appropriate in all such projects to include representation of the full array of United States racial, ethnic minority populations (i.e., Native Americans [including American Indians or Alaskan Natives], Asian/Pacific Islanders, Blacks, Hispanics). The rationale for studies on single minority population groups should be provided. For the purpose of this policy, clinical research is defined as human biomedical and behavioral studies of etiology, epidemiology, prevention (and preventive strategies), diagnosis, or treatment of diseases, disorders or conditions, including but not limited to clinical trials. The usual NIH policies concerning research on human subjects also apply. Basic research or clinical studies in which human tissues cannot be identified or linked to individuals are excluded. However, every effort should be made to include human tissues from women and racial/ethnic minorities when it is important to apply the results of the study broadly, and this should be addressed by applicants. For foreign awards, the policy on inclusion of women applies fully; since the definition of minority differs in other countries, the applicant must discuss the relevance of research involving foreign population groups to the United States' populations, including minorities. If the required information is not contained within the application, the application will be returned. Peer reviewers will address specifically whether the research plan in the application conforms to these policies. If the representation of women or minorities in a study design is inadequate to answer the scientific question(s) addressed or the justification for the selected study population is inadequate, it will be considered a scientific weakness or deficiency in the study design and will be reflected in assigning the priority score to the application. All applications for clinical research submitted to the NIH are required to address these policies. NIH funding components will not award grants or cooperative agreements that do not comply with these policies. APPLICATION PROCEDURES Applications are to be submitted on grant application form PHS-398 (rev. 9/91), which may be obtained from the Office of Grants Information, Division of Research Grants, National Institutes of Health, 5333 Westbard Avenue, Room 449, Bethesda, MD 20892, telephone 301-435-0714, and from the institution's office of sponsored research. To identify the application as a response to this PA, check "YES" on item 2a on the face page of the application and enter PA-94-031, "Wound Healing and Tissue Regeneration." Applications will be accepted at the standard application deadlines indicated in the application kits. Applications for the FIRST Award (R29) must include at least three sealed letters of reference attached to the face page of the original application. FIRST Award (R29) applications submitted without the required number of reference letters will be considered incomplete and will be returned without review. A signed, typewritten original of the application, and five signed photocopies, in one package must be submitted to: Division of Research Grants National Institutes of Health Westwood Building, Room 240 Bethesda, MD 20892** REVIEW CONSIDERATIONS Applications will be assigned on the basis of established PHS referral guidelines. Applications will be reviewed for scientific and technical merit by initial review groups of the Division of Research Grants, NIH, or by the review group of the relevant Institute in accordance with the standard NIH peer review procedures. Following scientific-technical review, applications will receive a second level review by the appropriate national advisory council or board. AWARD CRITERIA Applications will compete for available funds with all other approved applications assigned to that institute, center or division. The following will be considered in making funding decisions: o Quality of the proposed project as determined by peer review o Availability of funds o Program balance among research areas of the announcement. INQUIRIES Written and telephone inquiries concerning this PA are encouraged. The opportunity to clarify any issues or questions from potential applicants is welcome. Direct inquiries regarding programmatic issues to: Mohandas Bhat, M.D.S, Dr.P.H. Director, Craniofacial Development and Disorders Program Telephone: (301) 594-7648 Matthew A. Kinnard, Ph.D. Director, Oral Soft Tissue Diseases and AIDS Program Telephone: (301) 594-7641 Dennis F. Mangan, Ph.D. Director, Periodontal Diseases Program Telephone: (301) 594-7641 Extramural Program National Institute of Dental Research Westwood Building Room 509 Bethesda, MD 20892 Direct inquiries regarding fiscal matters to: Ms. Theresa Ringler Grants Management Office National Institute of Dental Research Westwood Building, Room 510 Bethesda, MD 20892 Telephone: (301) 594-7629 AUTHORITY AND REGULATIONS This program is described in the Catalog of Federal Domestic Assistance No. 93.121. Awards are made under authorization of the Public Health Service Act, Title IV, Part A (Public Law 78-410, as amended by Public Law 99-158,(42 USC 241 and 285) and administered under PHS grants policies and Federal Regulations 42 CFR 52 and 45 CFR Part 74. This program is not subject to the intergovernmental review requirements of Executive Order 12372 or Health Systems Agency review. .
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