NIH GUIDE, Volume 23, Number 4, January 28, 1994

PA NUMBER:  PA-94-031



National Institute of Dental Research


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).


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).


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.


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.



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.


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.





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


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



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**


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



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.


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


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



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