Release Date:  October 15, 2001

RFA:  RFA-HL-02-004

National Heart, Lung, and Blood Institute

Letter of Intent Receipt Date:  January 21, 2002
Application Receipt Date:       February 20, 2002



The intent of this solicitation is to encourage innovative research leading to 
the development of new approaches, technologies, tools, methods, devices, 
cells, biomolecules, and biomaterials that can be used to either engineer 
tissue in vitro as a biological substitute for implantation or to foster 
tissue regeneration in vivo, with the purpose of replacing, repairing, 
maintaining, or enhancing organ function.


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 Request for Applications (RFA), 
Innovative Concepts and Approaches to Developing Functional Tissues and Organs 
for Heart, Vascular, Lung, and Blood Applications: Exploratory/Developmental 
Awards (R21), is related to one or more of the priority areas.  Potential 
applicants may obtain a copy of "Healthy People 2010" at 


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.  Racial/ethnic minority individuals, 
women, and persons with disabilities are encouraged to apply as Principal 

Applications involving the use of stem cells may not include human embryonic 
stem cells.


This RFA will use the National Institutes of Health (NIH) Exploratory/ 
Developmental Research Grant (R21) award mechanism.  Responsibility for the 
planning, direction, and execution of the proposed project will be solely that 
of the applicant.  The total project period for an application submitted in 
response to this RFA may not exceed three years.  This RFA is a one-time 
solicitation.  The R21 cannot be renewed: if sufficient data are generated 
during the term of the award, investigators could apply for further funding 
through regular research grant mechanisms, e.g. the research project grant 
(R01) mechanism.  The anticipated award date is September 30, 2002.

Specific application instructions have been modified to reflect "MODULAR 
GRANT" and "JUST-IN-TIME" streamlining efforts that have been adopted by the 
NIH.  Complete and detailed instructions and information on Modular Grant 
applications have been incorporated into the PHS 398 (rev. 5/2001).  
Additional information on Modular Grants can be found at 


The NHLBI intends to commit approximately $6,750,000 in FY 2002 to fund 30 new 
grants in response to this RFA.  An applicant may request a project period of 
up to three years and a budget for direct costs of up to $150,000, or six 
modules, per year.  Because the nature and scope of the research proposed may 
vary, it is anticipated that the size of each award will also vary.  Although 
the financial plans of the NHLBI 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.  The new National 
Institute of Biomedical Imaging and Bioengineering (NIBIB) also has a strong 
interest in this area of research.  The NIBIB will consider support of 
applications submitted in response to this RFA after the Institute's 
accounting structures have been set up.   



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 $400 
billion annually.  Until very recently, most damaged or diseased human tissue 
could only be replaced by donor transplants or with totally artificial parts. 
Both of these solutions are imperfect, in part, because of the dearth of 
transplantable organs and the risks associated with prosthetic replacements.  
Today, tissue engineering and regenerative medicine promise to revolutionize 
the treatment of patients who need new vital structures.  These approaches 
apply 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, with 
the capacity to grow and remodel, to restore, maintain, or improve tissue and 
organ function.  The field has already made headway in the 
synthesis/regeneration 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 and the field is now poised for 
moving ahead in that direction.  However, high risk, innovative research in 
some critical areas could serve as a catalyst for engineering functional 
cardiovascular, lung, and blood tissues and help lay the foundation for 
success that could impact tremendously on human health. 


This RFA is being issued in recognition of the nascence of this scientific 
area for heart, lung, and blood applications, and the need for the development 
of novel concepts and approaches to engineering or regenerating functional 
tissues and organs.  The primary purpose of the solicitation is to provide 
investigators with the opportunity to explore entirely 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 
through fabrication of engineered constructs in vitro or by regeneration and 
remodeling in vivo.  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 regenerative 
medicine, it should be unusually imaginative or dramatically different from 
past paradigms, and it must have the potential for a broad impact on current 
efforts directed at growing tissues for repair or replacement.  To be eligible 
for consideration, proposals must be distinct from those traditionally 
submitted through the R01 mechanism.  For example, projects designed to 
produce incremental advances in knowledge will not be considered.  Proposals 
submitted under this mechanism should be limited to those with the potential 
for truly ground-breaking impact.

Since the R21 mechanism is intended to encourage exploratory research, no 
preliminary data are required.  However, the application should make clear 
that the proposed research is scientifically sound, the qualifications of the 
investigators are appropriate, and the resources available to the 
investigators are adequate.  Applications from both individuals and groups 
interested in developing suitable novel approaches are encouraged, however 
team approaches to these efforts are especially encouraged in the belief that 
a synergistic blend of expertise and resources may be needed.  It is expected 
that this research will require expertise from a variety of disciplines, 
including engineering, chemistry, physics, materials science, biology, and 
Efforts in cardiovascular, lung, and blood tissue engineering and regenerative 
medicine share many common scientific challenges and can 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.  Research under this program 
should thus proceed along one, or both, of two parallel fronts; cross-cutting 
basic science and technology and/or focused approaches aimed at well-defined 
clinical problems.  The NHLBI anticipates the receipt of applications 
addressing, but not limited to, the following areas:  

1.  Basic Science and Technology Common to Heart, Lung, and Blood

A.  Stem/Progenitor Cell Biology (excluding human embryonic stem cells) B 
Studies focused on heart, vascular, lung, and blood stem/progenitor cells is 
needed including: 1) molecular identification of stem/progenitor cells; 2) 
development of cellular markers to distinguish stem/progenitor cells; 3) study 
and improvement of stem/progenitor cell homing; 4) understanding growth 
factors, matrix molecules, and signaling pathways involved in stem/progenitor 
cell growth and differentiation; 5) development of standard protocols for 
culturing stem/progenitor cells   

B.  Vascular Assembly in Engineered and Natural Tissues - Research in at least 
two major areas is needed: 1) for cells or patches of tissue implanted 
directly into a site in vivo or for tissue regenerated in vivo; analysis of 
the spacial and temporal interplay of multiple genetic and environmental 
signals involved in the development, regeneration, and regression of vascular 
networks; 2) for tissues grown in vitro; methods to create vascular networks 
ranging from capillaries to arteries/veins that are capable of anastomosing 
with vessels at the site of implantation.

C.  Signaling and Remodeling B Knowledge of the interplay between 
environmental factors and intrinsic cell factors that together regulate 
renewal of cardiovascular, lung, and blood tissues is needed including: 1) 
understanding what environmental cues, including growth factors and matrix 
molecules, attract the cells that ultimately lead to repopulation of sites of 
injury and identification of where such cells originate;  2) understanding the 
factors that prevent regeneration of injured structures; and 3) developing 
quantitative analyses and modeling of how signals are presented physically and 
temporally to cells and how cells integrate multiple signals to generate a 
response.  This knowledge could provide a design basis for the manipulation of 
the environment to achieve tissuegenesis.

D.  Scaffold Fabrication and Control of Cellular Behavior - Techniques for 
creating 3D scaffolds with complex architecture and chemistry must be 
developed significantly beyond current stages to address the needs of 
vascularized and innervated tissues.  This includes development of novel 
molecular design strategies, materials fabrication processes, and methods for 
functional analysis of biomaterials.

Highly novel research focused on genetic approaches to tissue engineering, 
regeneration, and repair, innervation of tissue-engineered/regenerated tissue, 
functional assessment of engineered/regenerated tissue, issues related to the 
immune response to engineered tissues and cells, and bioreactors and 
bioprocessing, will also be considered responsive. 

2.  Functional Applications of Science and Technology to Clinical Problems  

A.  Heart B Engineer cells, myocardial patches, or heart ventricles for 
implantation to restore, renew or replace the contractile function of the 
failing heart.  Tissue engineer valves to treat congenital or acquired 
diseases of the heart valves and great arteries.  Develop biomechanical 
environments for engineering cardiac tissues in vitro.  Design methods to 
foster cardiac tissue regeneration in vivo.

B.  Vascular B Efforts to develop tissue-engineered vascular grafts with 
improved long-term patency need to be undertaken particularly with the 
addition of physiologically relevant mechanical forces to the growing tissue. 
 Design methods to foster vascular regeneration in vivo.

C.  Lung B Novel approaches such as using progenitor cells or patches of 
cultured primordial lung tissue to replace gas exchange areas destroyed by 
injury and replaced by dysfunctional tissue.  Effects of mechanical factors on 
function of newly generated or transplanted tissues will need to be assessed. 

D.  Blood B Hematopoietic stem cells: assays for stem cell products that 
predict engraftment in patients, transplant regimens with reduced toxicity, 
regimens that induce tolerance, methods to identify, purify, and expand 
specific populations of lineage committed cells, and generation of "generic" 
stem cell populations.  Transfusable blood components: culture-derived red 
blood cells, leukocytes, and platelets (or their precursors), artificial 
oxygen carrying solutions, methods to prevent immunization by such cells or 
artificial blood components, and large scale production and storage methods 
are needed.


Applications involving the use of human stem cells may not include human 
embryonic stem cells.

Grantees will meet annually to share results, to ensure that the NHLBI has a 
coherent view of the advances in the field, and to have an opportunity for 
collective problem solving among investigators.  Applicants should request 
travel funds in their budget for the principal investigator and one additional 
young investigator to attend this annual meeting. 


It is the policy of the NIH that women and members of minority groups and 
their sub-populations 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 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 103-43). 

All investigators proposing research involving human subjects should read the 
UPDATED "NIH Guidelines for Inclusion of Women and Minorities as Subjects in 
Clinical Research," published in the NIH Guide for Grants and Contracts on 
August 2, 2000
(; a 
complete copy of the updated Guidelines are available at  The 
revisions relate to NIH defined Phase III clinical trials and require: a) all 
applications or proposals and/or protocols to 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) all 
investigators to report accrual, and to conduct and report analyses, as 
appropriate, by sex/gender and/or racial/ethnic group differences.


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 

Investigators also may obtain copies of these policies from the program staff 
listed under INQUIRIES.  Program staff may also provide additional relevant 
information concerning the policy.


NIH 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 found in the NIH Guide for Grants and 
Contracts Announcement dated June 5, 2000, at the following website:


All applications and 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.  Reviewers are cautioned that their anonymity may 
be compromised when they directly access an Internet site.


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 RFA 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.


Prospective applicants are asked to submit a letter of intent that includes a 
descriptive title of the proposed research, the name, address, and telephone 
number of the Principal Investigator, 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 allows IC staff to 
estimate the potential review workload and plan the review.

The letter of intent is to be sent to Dr. Deborah Beebe, at the address listed 
under INQUIRES, by the letter of intent receipt date listed in the heading of 
this RFA.


The PHS 398 research grant application instructions and forms (rev. 5/2001) at must be used in 
applying for these grants.  This version of the PHS 398 is available in an 
interactive, searchable format.  For further assistance contact GrantsInfo, 
Telephone 301/710-0267, Email:


The modular grant concept establishes specific modules in which direct costs 
may be requested as well as a maximum level for requested budgets. Only 
limited budgetary information is required under this approach.  The 
just-in-time concept allows applicants to submit certain information only when 
there is a possibility for an award. It is anticipated that these changes will 
reduce the administrative burden for the applicants, reviewers and NIH staff. 
 The research grant application form PHS 398 (rev. 5/2001) at is to be 
used in applying for these grants, with modular budget instructions provided 
in Section C of the application instructions.

All application instructions outlined in the PHS 398 application kit are to be 
followed with the following modifications for R21 applications:

1.  R21 applications will use the "MODULAR GRANT" and "JUST-IN-TIME" concepts, 
with direct costs requested in $25,000 modules, up to the total direct costs 
limit of $150,000, or six modules, per year.

2.   Items a-d of the Research Plan for the R21 application may not exceed 15 
pages, including tables and figures.  The following information should be 
taken into account for items a, b and c:  

o   Item a, SPECIFIC AIMS--The instructions for this section suggest that the 
applicant state "the hypotheses to be tested".  Since some applications 
submitted in response to this RFA may also be design- or problem-driven (e.g., 
development of novel technologies), or need-driven (initial research to 
develop a body of data upon which future research will build), hypothesis 
testing per se may not be the driving force in developing such a proposal and, 
therefore, may not be applicable.  Thus, the application should state the 
hypotheses, design, problem and/or need which will drive the proposed 

o   Item b, BACKGROUND AND SIGNIFICANCE--In this section, it is important to 
identify clearly how the application addresses the specific objectives of this 
RFA and the purpose of the R21 mechanism.

o   Item c, PRELIMINARY STUDIES/PROGRESS REPORT-- Although preliminary data 
are not required for an R21 application, they may be included.  

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:

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

BETHESDA, MD  20892-7710
BETHESDA, MD  20817 (for express/courier service)

At the time of submission, two additional copies of the application, as well 
as all five collated sets of Appendix material, must be sent to Dr. Deborah 
Beebe at the address listed under Inquiries.  Applications must be received by 
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.
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.  The 
CSR will not accept any application that is essentially the same as one 
already reviewed.  This does not preclude the submission of substantial 
revisions of applications already reviewed, but such applications must include 
an Introduction addressing the previous critique.

Principal investigators should not sent supplementary material without first 
contacting the Scientific Review Administrator (SRA).  The SRA will be 
identified in the letter sent to you indicating that your application has been 
received.  If you have not yet received such a letter within three weeks after 
submitting the application, contact Dr. Deborah Beebe at the address listed 
under Inquiries.


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

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 NHLBI in accordance with the review criteria stated below.  As part of the 
initial merit review, all applications will receive a written critique and 
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, assigned a priority score, and receive a second level 
review by the NHLBI National 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.  In 
the written comments, reviewers will be asked to discuss the following aspects 
of the application 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 in assigning the overall score, 
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 major 
scientific impact and thus deserve a high priority score.

(1) 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?

(2) 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?

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

(4) 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)?

(5) 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 

In addition to the above criteria, in accordance with NIH policy, all 
applications will also be reviewed with respect to the following:

o  The adequacy of plans to include both genders, minorities and their 
subgroups, and children as appropriate for the scientific goals of the 
research.  Plans for the recruitment and retention of subjects will also be 

o  The reasonableness of the proposed budget and duration in relation to the 
proposed research.

o  The adequacy of the proposed protection for humans, animals or the 
environment, to the extent they may be adversely affected by the project  
proposed in the application.


Letter of Intent Receipt Date:    January 21, 2002
Application Receipt Date:         February 20, 2002
Peer Review Date:                 May/June 2002
Council Review:                   September 5-6, 2002
Earliest Anticipated Start Date:  September 30, 2002


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

o  scientific merit (as determined by peer review)
o  availability of funds
o  programmatic priorities.


Inquiries concerning this RFA are encouraged.  The opportunity to clarify any 
issues or answer questions from potential applicants is welcome.

Direct inquiries regarding programmatic issues to:


Christine A. Kelley, Ph.D.
Division of Heart and Vascular Diseases
National Heart, Lung, and Blood Institute
Rockledge II, Room 9142
Bethesda, MD  20892-7940
Telephone:  (301) 435-0513
FAX:  (301) 480-1335


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


Phyllis Mitchell, M.S.
Division of Blood Diseases and Resources
National Heart, Lung, and Blood Institute
Rockledge II, Room 10163
Bethesda, MD  20892-7950
Telephone:  (301) 435-0481
FAX:  (301) 480-1060

Send letter of intent and 2 copies of the application and direct inquiries 
regarding review issues to:

Deborah P. Beebe, Ph.D.
Division of Extramural Affairs
National Heart, Lung, and Blood Institute
6701 Rockledge Drive, Room 7178 (MSC 7924)
Bethesda, MD  20892-7924 (20817 for Courier)
Telephone:  (301) 435-0270
Fax:  (301) 480-3541

Direct inquiries regarding fiscal matters to:

Ms. Diane Drew
Grants Operations Branch
Division of Extramural Affairs
National Heart, Lung, and Blood Institute
6701 Rockledge Drive, Room 7157A, MSC 7926
Bethesda, Maryland  20892-7926
Telephone:  (301) 435-0177
FAX:  (301) 480-3310


This program is described in the Catalog of Federal Domestic Assistance No. 
93.837, 93,838, and 93.839.  Awards are made under authorization of Sections 
301 and 405 of the Public Health Service Act as amended (42 USC 241 and 284) 
and administered under NIH grants policies and Federal Regulations 42 CFR 52 
and 45 CFR Parts 74 and 92.  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 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.  This is consistent with the 
PHS mission to protect and advance the physical and mental health of the 
American people.

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