RELEASE DATE:  November 18, 2003
RFA Number:  RFA-DE-05-005  

Department of Health and Human Services (DHHS)
National Institutes of Health (NIH)

National Institute of Dental and Craniofacial Research (NIDCR)



o Purpose of this RFA
o Research Objectives
o Mechanism of Support 
o Funds Available
o Eligible Institutions
o Individuals Eligible to Become Principal Investigators
o Where to Send Inquiries
o Letter of Intent
o Submitting an Application
o Supplementary Instructions
o Peer Review Process
o Review Criteria
o Receipt and Review Schedule
o Award Criteria
o Required Federal Citations


Stem cells from a number of orofacial structures recently have been 
identified and the ability to use human embryonic stem cells is now 
scientifically possible. The National Institute of Dental and 
Craniofacial Research (NIDCR) invites applications to promote research 
on the use of stem cells derived from human embryos and adults. 

The source of human embryonic stem cells will be limited to federally 
approved stem cell lines listed on the NIH Human Embryonic Stem Cell 
Registry. Information on the lines and how to contact providers can be 
found on the NIH stem cell registry 
and bioengineering approaches for the repair and regeneration of 
orofacial tissues and organs.  In particular, this Request for 
Applications (RFA) encourages studies on: i) the understanding of the 
unique properties of embryonic and post-natal stem cells in orofacial 
tissues; ii) the development of methods to induce appropriate stem cell 
expansion, differentiation and in vitro assembly of a functional tissue 
prototype unit and iii) the design and development for new bio-inspired 
materials for cell transplantation. (Note: FDA regulations and 
requirements may restrict the selection of cells eligible for 

Collaborative projects involving interdisciplinary teams of 
investigators are strongly encouraged.




Stem cell and developmental biology have entered an exciting new era of 
opportunities.  The Human Genome Project and similar work in other 
species have provided novel ways of addressing the important biological 
problems of development of different tissues and organs from small 
founder populations of stem cells, the maintenance and potential 
regeneration of organs during adult life, and the effects of age and 
disease on this capacity. 

In the 21st century, the field of biomaterials is also one of the most 
exciting areas of bioengineering.  There is currently "fresh energy" in 
this field due to the availability of information from the genome 
project and the availability of human adult and embryonic stem cells.  
Such advantages allow scientists to design and fabricate new materials 
following upon, and even improving the work of nature to meet the 
challenges of repairing and restoring orofacial tissues and organs.

Recently, stem cells from a number of orofacial structures have been 
identified and the ability to use human embryonic stem cells is now 
scientifically possible.  Learning how to take advantage of the 
multipotent and pluripotent nature of stem cells, and how to 
predictably control their differentiation can now begin in earnest.  
Consequently, there is a real opportunity to use adult and embryonic 
stem cells in combination with new biomaterials to regenerate complex 
structures. (NOTE: Certain legal restrictions may apply to the types of 
projects allowable.)

The clinical utility of stem cells to engineer tissues depends upon the 
ability to direct cells to form specialized tissues with characteristic 
structural and mechanical properties across different hierarchical 
scales.  Therefore, for the effective use of stem cells, it is 
important to learn about the nature and action of the cues that 
regulate stem cell fate in the orofacial tissues and organs (i.e. their 
biological niche). A great deal can be learned from developmental 
biology studies on the origin of the orofacial tissues and organs. For 
example, in the case of the orofacial tissues derive from the cranial 
neural crest that differentiates into craniofacial cartilage, bone, 
dental pulp, neurons, glia and other connective tissues of the face. 
How neuronal crest cells perform this function and how these precursor 
cells differentiate into the various parts of the face is currently not 
well understood. Moreover, the biophysical interactions between stem 
cells and scaffolds that predictably result in appropriate tissue form 
and function, both ex vivo and in vivo also are not well characterized. 
Research Objectives and Scope

The main objective of this RFA is to encourage research projects that 
make use of human post-natal and embryonic stem cells in combination 
with new biomaterials to regenerate the complex structures of the 
orofacial system. This RFA especially targets the establishment and 
identification of the full repertoire and origin of stem cells in 
orofacial tissues and the microenvironmental cues in these tissues that 
regulate their fate.  We expect that this solicitation will encourage 
researchers from different scientific disciplines (e.g., cell and 
molecular biology, genetics, physics, engineering, computer and 
clinical sciences and other relevant fields) to work collaboratively.  
The following are some examples of research topics relevant to this 
RFA. These examples are not meant to be all-inclusive or restrictive.

o identify the full repertoire and origin of adult stem cells in 
orofacial tissues and their relationship(s) to one another; 

o elucidate the molecular programs that regulate self-renewal of stem 
cells in the oral epithelium, salivary gland, tooth structures, bone, 
cartilage, muscles and nerves;

o identify the conditions needed to expand stem cell numbers ex vivo, 
and retain their stem properties;

o identify the factors (both intrinsic and extrinsic) that are 
necessary to induce human embryonic stem cells to differentiate in a 
predictable fashion to orofacial cells and tissues;

o identify the optimal type of stem cell or stem cell derivative for 
specific assays and cell therapy for orofacial diseases and disorders;

o consider multiple scaffold designs that can promote stem cell 
assembly into multi-dimensional structures that mimic the architecture 
and/or function of native tissue; and
o develop relevant in vitro assays (e.g., utilization of bioreactors) 
to predict the in vivo performance of tissue engineered/stem cell 

This RFA will use the NIH individual research project grant (R01) award 
mechanism. The total requested project period for an application 
submitted in response to this RFA may not exceed five years for an R01. 
As an applicant you will be solely responsible for planning, directing, 
and executing the proposed project.  This RFA is a one-time 
solicitation.  Future unsolicited, competing-continuation applications 
based on this project will compete with all investigator-initiated 
applications and will be reviewed according to the customary peer 
review procedures. The anticipated award date is April 2005.  
Applications that are not funded in the competition described in this 
RFA may be resubmitted as NEW investigator-initiated applications using 
the standard receipt for NEW applications described in the instructions 
to the PHS 398 application.

This RFA uses just-in-time concepts. It also uses the modular as well 
as the non-modular budgeting formats (see 
Specifically, if an investigator is submitting an application with 
direct costs in each year of $250,000 or less, use the modular format. 
Otherwise follow the instructions for non-modular research grant 
applications. This program does not require cost sharing as defined in 
the current NIH Grants Policy Statement at


The NIDCR intends to commit approximately $3.0 million in FY 2005 or FY 
2006 to fund 6 to 8 new applications in response to this RFA.  An 
applicant may request a project period of up to five years.  Because 
the nature and scope of the proposed research will vary from 
application to application, it is anticipated that the size and 
duration of each award will vary. Although the financial plans of the 
NIDCR provide support for this program, awards pursuant to this RFA are 
contingent upon the availability of funds and the receipt of a 
sufficient number of meritorious applications. 


You may submit (an) application(s) if the institution has any of the 
following characteristics:

o For-profit or non-profit organizations
o Public or private institutions, such as universities, colleges, 
hospitals, and laboratories
o Units of State and local governments
o Eligible agencies of the Federal government
o Domestic or foreign institutions/organizations
o Faith-based or community-based organizations


Any individual with the skills, knowledge, and resources necessary to 
carry out the proposed research is invited to work with their 
institution to develop an application for support. Individuals from 
underrepresented racial and ethnic groups as well as individuals with 
disabilities are always encouraged to apply for NIH programs.


We encourage inquiries concerning this RFA and welcome the opportunity 
to answer questions from potential applicants.  Inquiries may fall into 
three areas:  scientific/research, peer review, and financial or grants 
management issues:

o Direct your questions about scientific/research issues to:

Eleni Kousvelari, DDS, D.Sc.
Chief, Cellular & Molecular Biology, Physiology 
& Biotechnology Branch
Division of Basic and Translational Sciences
National Institute of Dental and Craniofacial Research
National Institutes of Health
Natcher Building 45, Room 4AN 12K
Bethesda, MD  20892-6402
Telephone:  (301) 594-2427
FAX:  (301) 480-8318

o Direct your questions about peer review issues to:

H. George Hausch, Ph.D.
Division of Extramural Activities
National Institute of Dental and Craniofacial Research
National Institutes of Health
Natcher Building 45, Room 4AN-44F 
Bethesda, MD 20892-6402
Telephone: (301) 594-2904 
FAX: (301) 480-8303 

o Direct your questions about financial or grants management matters 

Mary Daley, Chief
Grants Management Branch, 
Division of Extramural Activities
National Institute of Dental and Craniofacial Research
National Institutes of Health
Natcher Building 45, Room 4AN-44B
Bethesda, MD  20892
Telephone: (301) 594-4808
FAX: (301) 480-3562
Prospective applicants are asked to submit a letter of intent that 
includes the following information:

o Descriptive title of the proposed research
o Name, address, and telephone number of the Principal Investigator
o Names of other key personnel 
o Participating institutions
o Number and title of this RFA 

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 allows NIDCR staff to estimate the potential review 
workload and plan the review.
The letter of intent is to be sent by the date listed at the beginning 
of this document (March 23, 2004).  The letter of intent should be sent 

Eleni Kousvelari, DDS, D.Sc.
Chief, Cellular & Molecular Biology, Physiology 
& Biotechnology Branch
Division of Basic and Translational Sciences
National Institute of Dental and Craniofacial Research
National Institutes of Health
Natcher Building 45,Room 4AN 12K
Bethesda, MD  20892-6402
Telephone:  (301) 594-2427
FAX:  (301) 480-8318


Applications must be prepared using the PHS 398 research grant 
application instructions and forms (rev. 5/2001). Applications must 
have a DUN and Bradstreet (D&B) Data Universal Numbering System (DUNS) 
number as the Universal Identifier when applying for Federal grants or 
cooperative agreements. The DUNS number can be obtained by calling 
(866) 705-5711 or through the web site at The DUNS number should be entered on 
line 11 of the face page of the PHS 398 form. The PHS 398 document is 
available at in 
an interactive format.  For further assistance contact GrantsInfo, 
Telephone (301) 710-0267, Email:


requesting up to $250,000 per year in direct costs must be submitted in 
a modular grant format. The modular grant format simplifies the 
preparation of the budget in these applications by limiting the level 
of budgetary detail. Applicants request direct costs in $25,000 
modules. Section C of the research grant application instructions for 
the PHS 398 (rev. 5/2001) at includes step-
by-step guidance for preparing modular grants. Additional information 
on modular grants is available at

USING THE RFA LABEL: The RFA label available in the PHS 398 (rev. 
5/2001) application form must be affixed to the bottom of the face page 
of the application. Type the RFA number on the label. 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, the RFA title and number must be typed on line 2 of the face 
page of the application form and the YES box must be marked. The RFA 
label is also available at:

SENDING AN APPLICATION TO THE NIH: Submit a signed, typewritten 
original of the application, including the Checklist, and three signed, 
photocopies, in one package to:

Center for Scientific Review
National Institutes of Health
6701 Rockledge Drive, Room 1040, MSC-7710
Bethesda, MD 20892-7710 Bethesda, MD 20817 (for express/courier 

At the time of submission, two additional copies of the application and 
all copies of the appendix material must be sent to:

H. George Hausch, Ph.D.
Division of Extramural Activities 
National Institute of Dental and Craniofacial Research 
National Institutes of Health 
Natcher Bldg. 45, Room 4AN-44F, 
MSC 6402 
Bethesda, MD 20892-6402 

APPLICATION PROCESSING: Applications must be received on or before the 
application receipt date listed in the heading of this RFA.  If an 
application is received after that date, it will be returned to the 
applicant without review. 

Although there is no immediate acknowledgement of the receipt of an 
application, applicants are generally notified of the review and 
funding assignment within 8 weeks.
The Center for Scientific Review (CSR) will not accept any application 
in response to this RFA that is essentially the same as one currently 
pending initial review, unless the applicant withdraws the pending 
application.  However, when a previously unfunded application, 
originally submitted as an investigator-initiated application, is to be 
submitted in response to an RFA, it is to be prepared as a NEW 
application.  That is, the application for the RFA must not include an 
Introduction describing the changes and improvements made, and the text 
must not be marked to indicate the changes from the previous unfunded 
version of the application.  


Upon receipt, applications will be reviewed for completeness by the CSR 
and responsiveness by the NIDCR.  Incomplete and/or non-responsive 
applications will be returned to the applicant without further 

Applications that are complete and responsive to the RFA will be 
evaluated for scientific and technical merit by an appropriate peer 
review group convened by the NIDCR in accordance with the review 
criteria stated below. As part of the initial merit review, all 
applications will:

o Undergo a process in which only those applications deemed to have the 
highest scientific merit, generally the top half of the applications 
under review, will be discussed and assigned a priority score
o Receive a written critique
o Receive a second level review by the National Advisory Dental and 
Craniofacial Research Council. 


The goals of NIH-supported research are to advance our understanding of 
biological systems, improve the control of disease, and enhance health.  
In the written comments, reviewers will be asked to evaluate the 
application in order to judge the likelihood that the proposed research 
will have a substantial impact on the pursuit of these goals. The 
scientific review group will address and consider each of the following 
criteria in assigning the application’s overall score, weighting them 
as appropriate for each application. 

o Significance 
o Approach 
o Innovation
o Investigator
o Environment
The application does not need to be strong in all categories to be 
judged likely to have 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 field?

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 

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)?

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?  

ADDITIONAL REVIEW CRITERIA: In addition to the above criteria, the 
following items will be considered in the determination of scientific 
merit and the priority score:

human subjects and protections from research risk relating to their 
participation in the proposed research will be assessed. (See criteria 
included in the section on Federal Citations, below)
of plans to include subjects from genders, all racial and ethnic groups 
(and subgroups), and children as appropriate for the scientific goals 
of the research. Plans for the recruitment and retention of subjects 
will also be evaluated. (See Inclusion Criteria in the sections on 
Federal Citations, below).

are to be used in the project, the five items described under Section 
of the PHS 398 research grant application instructions (rev. 5/2001) 
will be assessed.


SHARING RESEARCH DATA: Applicants requesting more than $500,000 in 
direct costs in any year of the proposed research must include a data 
sharing plan in their application. The reasonableness of the data 
sharing plan or the rationale for not sharing research data will be 
assessed by the reviewers. However, reviewers will not factor the 
proposed data sharing plan into the determination of scientific merit 
or priority score. 

BUDGET: The reasonableness of the proposed budget and the requested 
period of support in relation to the proposed research.


Letter of Intent Receipt Date: March 23, 2004  
Application Receipt Date: April 23, 2004       
Peer Review Date: October 2004                
Council Review: January 2005                  
Earliest Anticipated Start Date: April 2005 


Award criteria that will be used to make award decisions include:

o Scientific merit of the proposed project as determined by peer review
o Availability of funds
o Programmatic priorities.


HUMAN SUBJECTS PROTECTION: Federal regulations (45CFR46) require that 
applications and proposals involving human subjects must be evaluated 
with reference to the risks to the subjects, the adequacy of protection 
against these risks, the potential benefits of the research to the 
subjects and others, and the importance of the knowledge gained or to 
be gained.

SHARING RESEARCH DATA:  Starting with the October 1, 2003 receipt date, 
investigators submitting an NIH application seeking $500,000 or more in 
direct costs in any single year are expected to include a plan for data 
sharing or state why this is not possible. Investigators should 
seek guidance from their institutions, on issues related to 
institutional policies, local IRB rules, as well as local, state and 
Federal laws and regulations, including the Privacy Rule. Reviewers 
will consider the data sharing plan but will not factor the plan into 
the determination of the scientific merit or the priority score.

policy of the NIH that women and members of minority groups and their 
sub-populations must be included in all NIH-supported clinical research 
projects unless a clear and compelling justification is provided 
indicating that inclusion is inappropriate with respect to the health 
of the subjects or the purpose of the research. This policy results 
from the NIH Revitalization Act of 1993 (Section 492B of Public Law 

All investigators proposing clinical research should read the AMENDMENT 
"NIH Guidelines for Inclusion of Women and Minorities as Subjects in 
Clinical Research - Amended, October, 2001," published in the NIH Guide 
for Grants and Contracts on October 9, 2001
a complete copy of the updated Guidelines are available at 
The amended policy incorporates: the use of an NIH definition 
of clinical research; updated racial and ethnic categories in 
compliance with the new OMB standards; clarification of language 
governing NIH-defined Phase III clinical trials consistent with the new 
PHS Form 398; and updated roles and responsibilities of NIH staff and 
the extramural community. The policy continues to require for all NIH-
defined Phase III clinical trials that: a) all applications or 
proposals and/or protocols must provide a description of plans to 
conduct analyses, as appropriate, to address differences by sex/gender 
and/or racial/ethnic groups, including subgroups if applicable; and b) 
investigators must report annual accrual and progress in conducting 
analyses, as appropriate, by sex/gender and/or racial/ethnic group 

SUBJECTS:  The NIH maintains a policy 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, 

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 is available at

policy requires education on the protection of human subject 
participants for all investigators submitting NIH proposals for 
research involving human subjects. This policy announcement is in the 
NIH Guide for Grants and Contracts Announcement, dated June 5, 2000, at

HUMAN EMBRYONIC STEM CELLS (hESC): Criteria for federal funding of 
research on hESCs can be found at 
and at 
Only research using hESC lines that are registered in the 
NIH Human Embryonic Stem Cell Registry will be eligible for Federal 
funding (see  It is the responsibility of the 
applicant to provide, in the project description and elsewhere in the 
application as appropriate, the official NIH identifier(s) for the hESC 
line(s)to be used in the proposed research.  Applications that do not 
provide this information will be returned without review. 

The Office of Management and Budget (OMB) Circular A-110 has been 
revised to provide public access to research data through the Freedom 
of Information Act (FOIA) under some circumstances. Data that are (1) 
first produced in a project that is supported in whole or in part with 
Federal funds and (2) cited publicly and officially by a Federal agency 
in support of an action that has the force and effect of law (i.e., a 
regulation) may be accessed through FOIA. It is important for 
applicants to understand the basic scope of this amendment. NIH has 
provided guidance at

Applicants may wish to place data collected under this PA in a public 
archive, which can provide protections for the data and manage the 
distribution for an indefinite period of time. If so, the application 
should include a description of the archiving plan in the study design 
and include information about this in the budget justification section 
of the application. In addition, applicants should think about how to 
structure informed consent statements and other human subjects 
procedures given the potential for wider use of data collected under 
this award.

The Department of Health and Human Services (DHHS) issued final 
modification to the "Standards for Privacy of Individually Identifiable 
Health Information", the "Privacy Rule," on August 14, 2002.  The 
Privacy Rule is a federal regulation under the Health Insurance 
Portability and Accountability Act (HIPAA) of 1996 that governs the 
protection of individually identifiable health information, and is 
administered and enforced by the DHHS Office for Civil Rights (OCR). 
Those who must comply with the Privacy Rule (classified under the Rule 
as "covered entities") must do so by April 14, 2003  (with the 
exception of small health plans which have an extra year to comply).  

Decisions about applicability and implementation of the Privacy Rule 
reside with the researcher and his/her institution. The OCR website 
( provides information on the Privacy Rule, 
including a complete Regulation Text and a set of decision tools on "Am 
I a covered entity?"  Information on the impact of the HIPAA Privacy 
Rule on NIH processes involving the review, funding, and progress 
monitoring of grants, cooperative agreements, and research contracts 
can be found at

proposals for NIH funding must be self-contained within specified page 
limitations. Unless otherwise specified in an NIH solicitation, 
Internet addresses (URLs) should not be used to provide information 
necessary to the review because reviewers are under no obligation to 
view the Internet sites.   Furthermore, we caution reviewers that their 
anonymity may be compromised when they directly access an Internet 

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 RFA is related to one or more of the priority areas.  
Potential applicants may obtain a copy of "Healthy People 2010" at

AUTHORITY AND REGULATIONS:  This program is described in the Catalog of 
Federal Domestic Assistance at and is not subject 
to the intergovernmental review requirements of Executive Order 12372 
or Health Systems Agency review.  Awards are made under the 
authorization of Sections 301 and 405 of the Public Health Service Act 
as amended (42 USC 241 and 284) and under Federal Regulations 42 CFR 52 
and 45 CFR Parts 74 and 92.  All awards are subject to the terms and 
conditions, cost principles, and other considerations described in the 
NIH Grants Policy Statement.  The NIH Grants Policy Statement can be 
found at

The PHS strongly encourages all grant recipients to provide a smoke-
free workplace and discourage the 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.  This is consistent with the PHS mission to protect and 
advance the physical and mental health of the American people.

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