RELEASE DATE:  December 30, 2002 
RFA: EB-03-010 
National Institute of Biomedical Imaging and Bioengineering (NIBIB)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)



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


The National Institute of Biomedical Imaging and Bioengineering (NIBIB) 
and the National Institute of Diabetes and Digestive and Kidney 
Diseases (NIDDK) issue this Request for Applications (RFA) to address 
key research challenges in the field of tissue engineering.  The full 
promise of tissue engineering as a means to develop functional tissue 
or organ substitutes in vitro for implantation in vivo, or to remodel 
and regenerate tissue in vivo for the purpose of repairing, replacing, 
maintaining, or enhancing organ function, is only beginning to be 
realized.  Tissue engineering also offers a potential source of human 
tissues for use as biosensors or for the development of drugs including 
screening for novel drug candidates, identifying novel genes as drug 
targets or therapeutic agents, and testing for drug toxicity.  As an 
emerging multidisciplinary field in which ideas, concepts, and 
techniques are developing at an exceedingly rapid pace, there is 
significant interest and demand for government agencies to provide 
additional resources in this and related areas for fostering the basic 
and applied science needed for this field to mature and important 
breakthroughs to transition from basic and pre-clinical research to 
clinical studies. The overall goal of this solicitation is to provide 
resources to address the issues that must be overcome in order to 
continue to move this field forward rapidly. It is structured to 
provide an opportunity where clinicians, engineers, and scientists from 
a variety of disciplines can establish research collaborations that 
will hasten the development of tissue engineering.    


Tissue engineering is a rapidly growing area that seeks to create, 
repair and/or replace tissues and organs by using combinations of 
cells, biomaterials, and/or biologically active molecules.  It is an 
interdisciplinary field that integrates aspects of engineering, and 
other quantitative sciences, with biology and medicine. Research and 
technology development in tissue engineering promises to revolutionize 
current methods of health care treatment and significantly improve the 
quality of life for millions of patients.  As one indication of the 
scope of the problem that tissue engineering addresses, worldwide organ 
replacement therapies utilizing standard organo-metallic devices 
consume 8 percent of medical spending, or approximately $350 billion 
per year.  Organ transplantation is another option for replacing 
damaged or diseased tissue, but one that is severely limited by donor 
availability.  Tissue-engineered products hold the promise for true 
functional replacement at affordable cost.  However, despite early 
successes, few functional tissue engineered products are currently 
available for clinical use.  

As described in the January 2002 World Technology Evaluation Center 
(WTEC) report, "Tissue Engineering Research", it is clear that critical 
advances in engineering and design are needed and key regulatory issues 
must be addressed if the promises of this field are to be fulfilled.  
The report is based on findings of the WTEC study supported by member 
agencies of the Multi-Agency Tissue Engineering Science (MATES) Working 
Group  These include the National 
Institutes of Health (NIH), National Science Foundation (NSF), National 
Institute of Standards and Technology (NIST), National Aeronautics and 
Space Administration (NASA), Defense Advanced Research Projects Agency 
(DARPA), and the Food and Drug Administration (FDA).  The research 
areas covered and described in this solicitation represent a collective 
effort of the MATES Working Group.  In addition, as discussed in 
several other recent forums such as the 2001 NIH/BECON sponsored 
meeting on "Reparative Medicine: Growing Tissues and Organs" and the 2001 NIST sponsored 
workshop on "Standards for Biomedical Materials and Devices," there are 
a number of areas in tissue engineering requiring additional research.  
These include: improved methods for the identification and 
characterization of cells; development of novel biomaterials; new 
approaches to the design and delivery of three dimensional constructs; 
and development of enabling technologies and methods to ensure the 
safety and quality assurance of engineered tissues as well as methods 
for the stable storage of these products prior to clinical use.  As the 
field evolves from initial proof-of-principle demonstrations of 
feasibility to the development of products intended for widespread 
clinical use, the NIBIB and the NIDDK are in a unique position to 
foster developments in this area by providing resources to ensure that 
these obstacles are successfully overcome and that these revolutionary 
products move from the research bench to the clinic. 

Strengthening research programs of relevance to tissue engineering and 
eventual clinical utilization of products developed by this field are 
important areas of emphasis for the NIBIB and NIDDK.  Areas in which 
such scientific opportunities exist include, but are not limited to:

1.  Identification/Characterization of Cells and Development of Novel 

The identification of an optimal cell source for a particular tissue 
engineering application will depend on rigorous characterization with 
regards to plasticity, propagation, and control of differentiation both 
in vitro and in vivo. To guide the organization, growth, and 
differentiation of cells in tissue engineered constructs, a variety of 
biomaterials are needed to provide mechanical support as well as 
physical, chemical, and mechanical cues in forming functional tissues. 
These materials and their degradation products must be non-toxic and 
non-immunogenic, as well as possess other properties specific for a 
given tissue construct and the site of implantation.  It is clear that 
the continued development of this field will depend upon identification 
and characterization of additional sources of cells as well as the 
development of new biomaterials and increased understanding of their 
interactions with cells. 

Specific areas of interest include but are not limited to: 

o  Isolation of stem and progenitor cells and methods to promote 
targeted stimulation of proliferation and controlled 
differentiation, including evaluation of signaling pathways in 
differentiation and dedifferentiation.
o  Development of novel scaffolds and delivery vehicles that combine 
bioactive molecules, such as growth factors or DNA, to coordinate 
the temporal and spatial distribution of biomolecules in relation to 
the desired cellular response.
o  Incorporation of new biomaterials and polymer classes of interest to 
tissue engineering into material libraries as reference standards or 
tools for validation purposes.
o  In addition to the above the NIDDK is specifically interested in 
engineering tissues to replace the function of pancreatic beta 
cells, liver, kidney and bladder.  

2.  Engineering Design and Functional Assessment of Constructs:

Advances are needed in the application of rational engineering design 
principles to tissue engineered constructs and the design must span 
multiple hierarchical scales, from the macroscopic level, directed at 
satisfying the clinical requirements of the product, to the microscopic 
level, directed at satisfying the cell and molecular requirements for 
long-term functional success.  Determining the fate and function of 
implanted constructs is also of critical importance.

Specific areas of interest include but are not limited to:

o   Novel approaches to materials processing to create scaffolds, which 
allow composition variation to accommodate divergence in evolving 
tissue structures.  
o   Development of strategies to promote vascularization and/or 
innervation within engineered tissues or in vivo. 
o   Model systems to understand physical, chemical and biomechanical 
aspects of cell signaling 
o   Consideration of multiple design and delivery approaches for in 
vitro tissue preparations and in situ tissue regeneration, such as 
methods to direct self assembly/maturation of bioscaffolds leading 
to in situ generation of constructs
o   Achievement of immunological tolerance for engineered constructs 
o   Increased understanding of the basic principles governing tissue 
formation, function, and failure, including the assembly of multiple 
cell types and biomaterials into multi-dimensional structures that 
mimic the architecture and/or function of native tissue.
o   Methodologies, such as various imaging modalities, to track the fate 
and allow the assessment of implanted engineered constructs in a 
non-invasive or minimally invasive manner.
3.  Enabling Technologies

If the benefits of tissue engineering are to be realized, the field 
must deliver products that can be commercialized. Therefore, a wide 
range of enabling technologies, such as techniques for use in growing 
tissues/organs on a commercially relevant scale; new, relevant, pre-
clinical models; methods to establish biosafety, quality assurance and 
performance; strategies for preserving living-cell products with off-
the-shelf availability and determining the fate of the implanted 
constructs will be required. 

Specific areas of interest include but are not limited to:

o   New sensitive and rapid test methods to address biosafety, function 
and stability of the final engineered construct.
o   Development of appropriate in vitro and in vivo pre-clinical models 
to address biocompatibility, toxicity, immunogenicity and 
inflammatory responses. 
o   Development of relevant in vitro tests to predict the in vivo 
performance of tissue engineered medical products, both for product 
development and quality control in manufacturing.
o   Cost effective approaches for the production of tissues and organs, 
that can meet regulatory requirements for good manufacturing 
practices (GMP).
o   Techniques and technologies for preserving both cells and engineered 
tissues to permit the stable storage of these products prior to 
clinical utilization.
o   Three-dimensional tissue production including development of 
bioreactor and organ support systems.

This RFA will use the NIH research grant award mechanism (R01) and the 
development/exploratory grant award mechanism (R21).  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 R01 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 September 30, 2003.

The R01 mechanism is recommended for applications that emphasize basic 
discovery or crosscutting research that addresses specific aspects of 
tissue engineering.   Research periods associated with the R01 
proposals are limited to five years with no cap on budget amount.   

The R21 Exploratory/Developmental Award supports exploratory or 
developmental research aimed at proof-of-principle for high-risk 
projects where no or very little preliminary data is available.  An R21 
application can be for up to two years with a maximum budget request of 
$275,000 direct costs for the 2-year period and a maximum page limit of 
15 pages.  R21 applications are not renewable.  Investigators are 
encouraged to use data generated from the R21 application to apply for 
further funding through the R01 mechanism (or other appropriate 
This RFA uses just-in-time concepts.  It also uses the modular as well 
as the non-modular budgeting formats
Specifically, if you are submitting an application with direct costs 
(including total costs of consortium arrangements) in each year of 
$250,000 or less, use the modular format.  Otherwise follow the 
instructions for non-modular research grant applications.

The NIBIB intends to commit a total of approximately $8,000,000, and 
the NIDDK intends to commit a total of approximately $350,000 in FY 
2003 to fund 20 to 30 new and/or competitive continuation grants in 
response to this RFA. An applicant may request a project period of up 
to 5 years for an R01 and a project period of up to 2 years for an R21.  
Budgets for direct costs of up to $275,000 for the 2-year period will 
be accepted for an R21.  There is no budget limitation for R01 

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 also vary. Although the financial plans of 
the NIBIB and the NIDDK 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 your 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 

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.   


General Clinical Research Centers:  Applicants from institutions that 
have a General Clinical Research Center (GCRC) funded by the NIH 
National Center for Research Resources may wish to identify the GCRC as 
a resource for conducting the proposed research.  If so, a letter of 
agreement from either the GCRC program director or principal 
investigator should be included with the application.

Grantee Meetings:  Principal Investigators will be required to attend 
an annual meeting in the Bethesda, MD region organized by NIBIB.  
Investigators must include travel to this meeting as part of the budget 
request and state a willingness to participate in this meeting.


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

o Direct your questions about scientific/research issues to:

Christine A. Kelley, Ph.D.
Acting Director
Division of Bioengineering
National Institute of Biomedical Imaging and Bioengineering
Suite 200
6707 Democracy Blvd.
Bethesda, MD  20892-5469
Telephone:  (301) 451-4778
Fax: (301) 480-4973

Maren R. Laughlin, Ph.D.
Director, Metabolism Program
6707 Democracy Blvd, Rm. 6101, MSC 5460
Bethesda, MD  20892-5460
Telephone: (301) 594-8802 
Fax: (301) 480-3503 

o Direct your questions about financial or grants management matters 

Ms. Nancy Curling
Division of Extramural Activities
National Institute of Biomedical Imaging and Bioengineering
Suite 900
6707 Democracy Blvd. 
Bethesda, MD  20892
Telephone:  (301) 451-4782
Fax:  301-480-4974

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 IC 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.  The letter of intent should be sent to:

Meredith D. Temple, Ph.D.
Health Scientist Administrator
Division of Extramural Activities
National Institute of Biomedical Imaging and Bioengineering
Suite 200
6707 Democracy Blvd.
Bethesda, MD 20892
Telephone: (301) 451-4792
Fax: (301) 480-4973


Applications must be prepared using the PHS 398 research grant 
application instructions and forms (rev. 5/2001).  The PHS 398 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 five 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 service)
APPLICATION PROCESSING: 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. 

Please Note: As of November 27, 2001, all applications and other 
deliveries to the Center for Scientific Review must come via courier 
delivery or the USPS.  Applications delivered by individuals to the 
Center for Scientific Review will no longer be accepted.  For 
additional information, see the NIH Guide Notice

Upon receipt, applications will be reviewed for completeness by the CSR 
and responsiveness by the NIBIB. Incomplete applications will be 
returned to the applicant without further consideration.  And, if the 
application is not responsive to the RFA, CSR staff may contact the 
applicant to determine whether to return the application to the 
applicant or submit it for review in competition with unsolicited 
applications at the next appropriate NIH review cycle.

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 CSR in accordance with the review criteria 
stated below.  As part of the initial merit review, all applications 

o Receive a written critique
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 second level review by the appropriate National Advisory 

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 your application in order to judge the likelihood 
that the proposed research will have a substantial impact on the 
pursuit of these goals: 

o Significance 
o Approach 
o Innovation
o Investigator
o Environment
The scientific review group will address and consider each of these 
criteria in assigning your application's overall score, weighting them 
as appropriate for each application.  Your 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, 
you may propose to carry out important work that by its nature is not 
innovative but is essential to move a field forward. 
(1) SIGNIFICANCE:  Does your study address an important problem? If the 
aims of your application are achieved, how do they advance scientific 
knowledge?  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?  Do you acknowledge potential problem areas and 
consider alternative tactics?

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

(4) INVESTIGATOR: Are you appropriately trained and well suited to 
carry out this work?  Is the work proposed appropriate to your 
experience level as the principal investigator and to that of other 
researchers (if any)?

(5) ENVIRONMENT:  Does the scientific environment in which your 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, your 
application will be reviewed with respect to the following:

o TEAM-APPROACH:  The inclusion of researchers with divergent 
backgrounds, for example, the partnering of an engineer, a physiologist 
and/or a clinician.

o R21 REVIEW CRITERIA: Since the R21 mechanism is intended to
encourage exploratory/developmental research, proposals submitted as an 
R21 will also be reviewed based on their high risk/high impact 
potential and whether or not the proposal is significantly distinct 
from those traditionally submitted through the R01 mechanism.  For 
example, R21 projects designed to produce incremental advances in 
knowledge will not be considered.

o PROTECTIONS:  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.

o INCLUSION:  The adequacy of plans to include subjects from both 
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 included in the section on Federal Citations, below)

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


Letter of Intent Receipt Date: February 14, 2003
Application Receipt Date: March 14, 2003
Peer Review Date: May/June, 2003
Council Review: September, 2003
Earliest Anticipated Start Date: September 30, 2003


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.

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 103-43).

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.  You will find this policy 
announcement 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 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.

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 No. 93.286 & 93.287 (NIBIB) and 93.847, 
93.848 & 93.849 (NIDDK) and is not subject to the intergovernmental 
review requirements of Executive Order 12372 or Health Systems Agency 
review.  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 described at and under Federal 
Regulations 42 CFR 52 and 45 CFR Parts 74 and 92.

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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