Release Date: June 19, 1998 

RFA:  DE-98-009


National Institute of Dental Research
National Institute of Arthritis and Musculoskeletal and Skin Diseases

Letter of Intent Receipt Date:  September 5, 1998
Application Receipt Date:  November 19, 1998


The National Institute of Dental Research (NIDR) and the National Institute of
Arthritis and Musculoskeletal and Skin Diseases (NIAMS), invite applications
in support of both design directed and hypothesis driven research whose aim it
is to develop natural and novel approaches for the repair, restoration, and
replacement of oral, craniofacial, dental, skin and musculoskeletal tissues
and organs based on a comprehensive scientific understanding of biological
structures and their function.  The overall goal of this Request for
Applications (RFA) is to facilitate multidisciplinary research aimed at
development of a new generation of natural and synthetic oral, craniofacial
dental and skin/musculoskeletal biomaterials, including total biological
approaches for use in instances in which synthetic implants historically have
been used.  Because of the nature of biomimetics and tissue engineering
research, the NIDR and the NIAMS are particularly interested in supporting
research conducted by collaborative, interdisciplinary teams of scientists
from the fields of engineering, chemistry, physics, mathematics, and biology.


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 RFA, Biomimetics and Tissue
Engineering in the Restoration of Orofacial Tissues, is related to the
priority areas oral health.  Potential applicants may obtain a copy of
"Healthy People 2000" (Full Report:  Stock No. 017-001-00474-0 or Summary
Report: Stock 017-001-00474-1) through the Superintendent of Documents,
Government Printing Office, Washington, DC 20402-9325 (telephone


Applications may be submitted by domestic and foreign, for-profit and non-
profit organizations, public and private, such as universities, colleges,
hospitals, laboratories, units of State and local governments and eligible
agencies of the Federal government.  Collaborative projects with foreign
scientists conducting unique research on biomimetics and tissue engineering
are encouraged. Also encouraged are applications that include investigators
who are racial/ethnic minority individuals, women and persons with
disabilities.  Although an application must be submitted from a single
institution, collaborative arrangements with other institutions are strongly


Traditional research project grants (R01), and exploratory/developmental
grants (R21) may be submitted in response to this RFA.  The R21 awards will be
utilized to support highly innovative exploratory studies for which extensive
preliminary results may not be available.  Through this mechanism
investigators can explore new innovative research paradigms.  Applicants for
the R21 must limit their requests to $100,000 in direct costs per year for two
years. R21 grants are not renewable, but future project continuation is
possible through other grant mechanisms, such as the R01.

Applications for R01 grants may request up to five years of support.  This RFA
is a one-time solicitation.

Because of the nature of research involving biomimetics and tissue
engineering, the Institutes encourage interdisciplinary collaborative
research.  In the case of collaborative research projects, a group of
investigators may simultaneously submit a minimum of 3 and no more than 5
applications. Collaborative projects with a common theme may be from a single
institution or several institutions, may include shared resources, and must
demonstrate the interdependence of the individual components. All
applications, both collaborative and individual, must provide evidence that
the research will be multidisciplinary in nature and applicants are encouraged
to specify how the research will further the missions of the NIDR and/or the
NIAMS. The maximum total costs for the first year of a group of collaborative
projects is $1 million.

It is anticipated that support for this program will begin in FY 2000.
Administrative adjustments in project period and/or amount may be required at
the time of the award.


Pending receipt of sufficient numbers of highly scientifically meritorious
applications, the NIDR will allocate approximately $4 million in total costs
to support projects from this RFA during FY 2000. Although the NIAMS has an
interest in collaborative projects for this RFA only, NIAMS will allocate
$400,000 in direct costs (approximately $600,000 in total costs) for FY 2000
to support 2 to 3 individual R01s, provided the applications are of high
scientific merit.  It is possible that a collaborative project in a topic area
that overlapped the interests of NIDR and NIAMS could be co-funded by these
two Institutes if the project is of high scientific merit.  Although this
program is provided for in the financial plans of the NIDR and NIAMS, the
award of grants pursuant to this RFA is contingent upon the receipt of a
sufficient number of high quality applications and the availability of funds
for this purpose. Policies that govern research grant programs of the NIH will



Over the last few years biomimetics and tissue engineering have emerged as a
new vision in the field of tissue and organ repair and restoration.
Biomimetics and tissue engineering are interdisciplinary fields that combine
information from the study of biological structures and their functions with
physics, mathematics, chemistry and engineering for the generation of new
materials, tissues and organs. These approaches can offer new ways of:  (a)
developing biological solutions for future design and synthesis of composite
materials such as bone, cartilage, tendon, ligament, skin, dentin, enamel,
cementum and periodontal ligament; (b) replacing and assembling functional
tissues and organs; and (c) evaluating medical and dental implants.

In the area of craniofacial, oral and dental principles from biomimetics and
tissue engineering are applied to developing dental and facial implants, new
polymers for guided tissue regeneration used in treating periodontal disease
and bone and connective tissue defects, coral-based hydroxyapatite replicas
for reconstruction of alveolar ridges and other osseous defects,
temporomandibular joint (TMJ) and other joint prostheses, formation of bone
matrix substitutes, and artificial replicas of bone, skin, and mucosa.


There is a need to develop the next generation of restorative materials and
medical implants.  New avenues of scientific inquiry may enable the
development of biomaterials that are safe, reliable, "smart", long-lasting,
and perform ideally in their respective biological environments. In order to
determine how best to facilitate development in the areas of biomimetics and
tissue engineering, the National Institute of Dental Research convened a 2-day
workshop entitled "Biomimetics, Tissue Engineering and Biomaterials" on
September 24-26, 1996 which brought together experts in the fields of
biomaterials, biomimetics, tissue engineering, cellular and molecular biology
as well as representatives from several NIH Institutes, other federal agencies
and industry.  These experts were charged with developing recommendations that
would provide a foundation for a research program in those areas having
specific application to the mission of the Institute. This RFA is issued in
accordance with the recommendations of workshop participants' along with those
of the National Advisory Dental Research Council (NADRC).

One intent of this RFA is to encourage and promote multidisciplinary research
on tissue engineering and biomimetics in the development of biomedical
implants as they apply to the repair, regeneration and maintenance of
craniofacial, oral and dental tissues and structures. Applicants for both
individual and collaborative projects are therefore encouraged to include
teams of individuals whose expertise broadens the scope of the scientific
approach of the team. An additional intent of the RFA is to encourage new
investigators to enter this area of research. These may be senior
investigators who have no previous experience in this field, or scientists
from any field who are at the beginning stages of their research careers.
Applicants are encouraged to include either category of new investigator on
their research team. In addition, applications are encouraged from new
investigators of either category.

Objective and Scope

The following research topics are provided as examples. They are not listed in
any priority order and are not intended to be inclusive or restrictive.

o  development and/or refinement of methods for the exploration and evaluation
of the dynamic natural state of tissues and cells (i.e., mechanisms and timing
of cell fate, cell spatial orientation) and of hierarchical levels of
craniofacial, oral and dental tissues and organs for the design and
development of new biologically-based materials;

o  development of methodologies and molecular probes to digitally record and
track events during craniofacial, oral and dental normal embryogenesis, and
diseases states; and development of virtual models of cellular and tissue
behavior to enable testing of theories before in vitro and in vivo

o  development of methodologies for accurate protein and cellular positioning
on biomaterial matrices, and development of biopolymers with the ability to
deliver signals to cells within the interstices of three dimensional matrices;

o  design of matrices that would promote the formation of facial musculature,
neurological pathways, bone, connective tissues, and skin for use in the
repair of orofacial tissues and musculoskeletal tissues;

o  development of practical systems for site-specific targeting (i.e.,
salivary glands, oral epithelium, tooth apparatus) of cells, genes and/or

o  advancement of the fundamental knowledge of biomineralization including
biomineralization precursor phases, microstructure formation, templating
growth and morphogenesis of bone and teeth, and development of effective
substitutes or replacements for these structures;

o  development of effective biomimetic routes to enhance the function of the
oral soft and hard tissues and salivary glands which may be lost due to
acquired or congenital abnormalities;

o  development of research strategies to advance the understanding of the
mechanisms of repair and maintenance of intraoral soft tissue injury and
engineering of artificial oral soft tissues;

o  development of artificial salivary glands through studies which include
identification of salivary stem cells, cell-based therapies, and synthesis of
appropriate classes of matrix materials that support the physiology of a
salivary secretory cell;

o  establishment of novel approaches to promote nerve outgrowth, through the
improvement of models at the organ/tissue level as well as at the molecular

o  transplantation of undifferentiated genetically modified cells and gene-
based therapies to assist nerve cells to regenerate;

o  development and use of high resolution imaging techniques to evaluate the
interfaces between biomimetically derived biomaterials and their biological
environment (i.e., enamel, dentin, cementum, bone, periodontal and other
ligaments); and

o  development of measurement systems that will evaluate short- and long-term
safety, efficacy, utility, economy and applicability of biomimetic and tissue
engineering-based materials.


It is the policy of the NIH that women and members of minority groups and
their subpopulations must be included in all NIH supported biomedical and
behavioral research projects involving human subjects, unless a clear and
compelling rationale and justification are provided that inclusion is
inappropriate with respect to the health of the subjects of the purpose of the
research.  This policy results from the NIH Revitalization Act of 1993
(Section 492B of Public Law 103-43).  All investigators proposing research
involving human subjects should read the "NIH Guidelines for Inclusion of
Women and Minorities as Subjects in Clinical Research", which have been
published in the Federal Register of March 28, 1994 (FR 59 14508-14513) and
the NIH Guide for Grants and Contracts, Vol. 23, No. 11, March 18, 1994.


It is the policy of NIH that children (i.e., individuals under the age of 21)
must be included in all human subjects research, conducted or supported by the
NIH, unless there are scientific and ethical reasons not to include them. This
policy applies to all initial (Type 1) applications submitted for receipt
dates after October 1, 1998.  All investigators proposing research involving
human subjects should read the "NIH Policy and Guidelines on the Inclusion of
Children as Participants in Research Involving Human Subjects" that was
published in the NIH Guide for Grants and Contracts, March 6, 1998, and is
available at the following URL address:


Prospective applicants are asked to submit, by September 5, 1998, a letter of
intent that includes a descriptive title of the overall proposed research, the
name, address and telephone number of the Principal Investigator(s), the
identities of other key personnel and participating institutions, and the
number and title of the RFA in response to which the application may be
submitted.  Although a letter of intent is not required, is not binding, and
does not enter into the review of a subsequent application, the information
that it contains is helpful in planning for the timely review of the
applications.  It helps NIDR and NIAMS staff to estimate the potential review
workload and to avoid possible conflicts of interest in the review.

The letter of intent is to be addressed to Dr. Eleni Kousvelari at the address
listed under INQUIRIES.


Prospective applicants are encouraged to communicate with program and grants
management staff of the sponsoring Institutes as early as possible in the
planning phase of application preparation.  Advice and suggestions by staff
may materially assist applicants to ensure that the objectives and structure
and the budget format are acceptable.  Applicants are also encouraged to
obtain a copy of the NIDR workshop report either from the NIDR Home Page
( or from Dr. Eleni Kousvelari at the address listed

The research grant application form PHS 398 (rev. 5/95) is to be used in
applying for these grants.  These forms are available at most institutional
offices of sponsored research and may be obtained from the Division of
Extramural Outreach and Information Resources, National Institutes of Health,
6701 Rockledge Drive, MSC 7910, Bethesda, MD 20892-7910, telephone 301/710-0267, email:  The forms are also available on the NIH
homepage at

The RFA label available in the PHS 398 application form kit must be affixed to
the bottom of the face page of the original and the original must be placed on
top of the entire package.  Failure to use this label could result in delayed
processing of the application such that it may not reach the review committee
in time for review.  In addition, in order to identify the application as a
response to this RFA, the RFA title (Biomimetics and Tissue Engineering in the
Restoration of Orofacial Tissues) and number (DE-98-009) must be typed in item
2 of the face page of the application form and the YES box must be checked.

Applicants from institutions that have a General Clinical Research Centers
(GCRC) funded by the NIH National Center for Research Resources may wish to
identify the Center as a resource for conducting the proposed research.  If
so, a letter of agreement from the GCRC Program Director must be included in
the application material.

Submit a signed, typewritten original of the application, including a cover
letter, the checklist and three signed photocopies in one package to:

6701 ROCKLEDGE DRIVE, ROOM 1040 - MSC 7710
BETHESDA, MD  20892-7710
BETHESDA, MD  20817 (for express/courier service)

At the time of submission, two additional copies of the application must also
be sent to:

Dr. George Hausch
Scientific Review Section
Division of Extramural Research
National Institute of Dental Research
Natcher Building, Room 4AN-38D
Bethesda, MD 20892-6402

Applications must be received by November 19, 1998.  If an application is
received after that date, it will be returned to the applicant without review.


Upon receipt, applications will be reviewed for completeness by the Center for
Scientific Review (CSR) and responsiveness by the NIDR and NIAMS.  Incomplete
and/or non-responsive applications will be returned to the applicant without
further consideration.  Applications that are complete and responsive will be
evaluated for scientific and technical merit by an appropriate peer review
group convened by the sponsoring Institutes.  As part of the initial merit
review, a process will be used by the initial review group in which
applications will be determined to be competitive or non-competitive based on
their scientific merit relative to other applications received in response to
the RFA.  Applications judged to be competitive will be discussed and be
assigned a priority score.  Applications determined to be non-competitive will
be withdrawn from further consideration and the Principal Investigator and the
official signing for the applicant organization will be notified. 
Applications will receive a secondary level of review by NIDR's and NIAMS'
Advisory Council.

Review Criteria

The goals of NIH-supported research are to advance our understanding of
biological systems, improve the control of disease, and enhance health. The
reviewers will comment on the following aspects of the application in their
written critiques in order to judge the likelihood that the proposed research
will have a substantial impact on the pursuit of these goals. Each of these
criteria will be addressed and considered by the reviewers in assigning the
overall score and weighting them as appropriate for each application. Note
that the application does not need to be strong in all categories to be judged
likely to have a major scientific impact and thus deserve a high priority
score. For example, an investigator may propose to carry out important work
that by its nature is not innovative but is essential to move a field forward.

Significance:  Does this study address an important problem?  If the aims of
the application are achieved, how will scientific knowledge be advanced?  What
will be the effect of these studies on the concepts or methods that drive this

Approach:  Are the conceptual framework, design, methods, and analyses
adequately developed, well-integrated, and appropriate to the aims of the
project?  Does the applicant acknowledge potential problem areas and consider
alternative tactics?

Innovation:  Does the project employ novel concepts, approaches or methods? 
Are the aims original and innovative?  Does the project challenge existing
paradigms or develop new methodologies or technologies?

Investigator:  Is the investigator appropriately trained and well-suited to
carry out this work?  Is the work proposed appropriate to the experience level
of the principal investigator and other researchers (if any)?

Collaborative research: Is the degree to which the project will represent
collaborative research among investigators from different disciplines within
an individual R01 acceptable? Is the work proposed among individual R01s
interdisciplinary in nature? Is the likelihood of effective collaboration
among the investigators? What is the likelihood that the proposed research
will advance the knowledge in tissue engineering, biomimetics, and
biomaterials for application to craniofacial, oral and dental health?

Environment:  Does the scientific environment in which the work will be done
contribute to the probability of success?  Do the proposed experiments take
advantage of unique features of the scientific environment or employ useful
collaborative arrangements?  Is there evidence of institutional support?

The R21 mechanism encourages applications to explore new research paradigms in
biomimetics, and tissue engineering as applied to the objectives of this RFA.
In the case of R21 applications, comprehensive preliminary results
demonstrating feasibility are not required. It is, however, incumbent on the
applicant to provide a convincing rationale for the proposed studies and to
relate them to the focus of this RFA.

The availability of special opportunities for furthering research programs
through the use of unusual talent resources, populations, or environmental
conditions in other countries that are not readily available in the United
States or that provide augmentation of existing U.S. resources will be
considered in the review.

The initial review will also examine the appropriateness of proposed budget
and duration, the adequacy of plans to include both genders and minorities and
their subgroups as appropriate for the scientific goals of the research and
plans for the recruitment and retention of subjects, the provisions for the
protection of human and animal subjects, and the safety of the research


The earliest anticipated date of award is December 1999.  Applicants should be
aware that, in addition to scientific merit, program priorities and program
balance, the total cost of the proposed project and the availability of funds
will be considered in making funding recommendations.  In addition,
complementary funding from other public and private sources including
foundations and industrial concerns is encouraged.  In circumstances in which
applications have similar scientific merit, but vary in cost competitiveness,
the more cost competitive application is likely to be selected for funding.


Written and telephone inquiries concerning this RFA are encouraged. The
opportunity to clarify any issues or questions from potential applicants is

Direct inquiries regarding programmatic issues to:

Dr. Eleni Kousvelari
Division of Extramural Research
National Institute of Dental Research
Natcher Building, Room 4AN 18A
Bethesda, MD  20892-6402
Telephone:  (301) 594-2427
FAX:  (301) 480-8318

Dr. James S. Panagis
Orthopaedics Program
National Institute of Arthritis and Musculoskeletal and Skin Diseases
Natcher Building, Room 5AS 37K
Bethesda, MD  20892-6500
Telephone:  (301) 594-5055
FAX:  (301) 480-4543

Direct inquiries regarding grants management issues to:

Mr. Kevin Crist
Division of Extramural Research
National Institute of Dental Research
Natcher Building, Room 4AS 55
Bethesda, MD  20892-6402
Telephone:  (301) 594-4800
FAX:  (301) 480-8301

Ms. Vicki Maurer
Grants Management Branch
National Institute of Arthritis and Musculoskeletal and Skin Diseases
Natcher Building, Room 5AS 49A
Bethesda, MD  20892-6500
Telephone:  (301) 594-3504
FAX:  (301) 480-5450


Letter of Intent Receipt Date:  September 5, 1998
Application Receipt Date:       November 19,1998
Scientific Review:              April/May 1999
Advisory Council Date:          September/October 1999
Earliest Award Date:            December 1999


This program is described in the Catalog of Federal Domestic Assistance Nos.
Nos. 93.121 and 93.846.  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.

The PHS strongly encourages all grant and contract recipients to provide a
smoke-free workplace and promote the non-use of all tobacco products.  In
addition, Public Law 103-227, the Pro-Children Act of 1994, prohibits smoking
in certain facilities (or in some cases, any portion of a facility) in which
regular or routine education, library, day care, health care or early
childhood development services are provided to children.

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