This Program Announcement expires on October 5, 2004, unless reissued.
FUNCTIONAL TISSUE ENGINEERING OF MUSCULOSKELETAL TISSUES
Release Date: October 18, 2001
PA NUMBER: PA-02-014
National Institute of Arthritis and Musculoskeletal and Skin Diseases
National Institute of Child Health and Human Development
National Institute of Dental and Craniofacial Research
THIS PA USES "MODULAR GRANT" AND "JUST-IN-TIME" CONCEPTS. MODULAR
INSTRUCTIONS MUST BE USED FOR RESEARCH GRANT APPLICATIONS UP TO $250,000 PER
YEAR. MODULAR BUDGET INSTRUCTIONS ARE PROVIDED IN SECTION C OF THE PHS 398
(REVISION 5/2001) AVAILABLE AT
http://grants.nih.gov/grants/funding/phs398/phs398.html.
PURPOSE
The purpose of this Program Announcement (PA) is to encourage the submission
of applications for research to enhance our understanding of functional
tissue engineering of musculoskeletal tissues (articular cartilage,
ligaments, tendons, bone, meniscus, intervertebral disc and skeletal muscle).
Innovative approaches to these scientific areas will be stressed.
HEALTHY PEOPLE 2000
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 Program
Announcement(PA), Functional Tissue Engineering of Musculoskeletal Tissues,
is related to one or more of the priority areas. Potential applicants may
obtain a copy of "Healthy People 2010" at http://www.health.gov/healthypeople.
ELIGIBILITY REQUIREMENTS
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
investigators.
MECHANISM OF SUPPORT
The Research Project (R01) grant mechanism will be used to support projects
under this PA. Under this mechanism, the applicant will plan, direct, and
carry out the research plan. The proposed project period during which the
research will be conducted should adequately reflect the time required to
accomplish the stated goals and be consistent with the policy for grant
support. For R01s, the total requested project period may not exceed five
years and applicants should apply for the length of time appropriate for the
work proposed, typically three to five years. NIDCR will allocate funds to
support 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 the NIAMS, NICHD and NIDCR could be co-funded by
any combination of these three Institutes, if the project is of high
scientific merit.
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
http://grants.nih.gov/grants/funding/modular/modular.htm.
Consistent with recommendations from the NIH Bioengineering Consortium,
applications with a bioengineering perspective that are submitted in response
to this PA may be either design/technology-driven, hypothesis-driven, or a
combination of the two.
RESEARCH OBJECTIVES
Background
The goal of tissue engineering is to repair or replace tissues and organs by
delivering implanted cells, scaffolds, DNA, proteins or protein fragments to
areas where they are needed. Despite early success, tissue engineers have
faced challenges in repairing or replacing injured or diseased tissues that
serve a predominantly biomechanical function, such as bone and articular
cartilage. An evolving discipline, functional tissue engineering seeks to
address these challenges [Butler, et al, Functional Tissue Engineering: The
Role of Biomechanics, Journal of Biomechanical Engineering, December 2000
122(6), pages 570-575]. Principles of functional tissue engineering include
the following: (1) In vivo stress/strain histories need to be measured for a
variety of activities. Such data provide mechanical threshholds that tissue
repairs/replacements will likely encounter, (2) Mechanical properties of the
native tissues must be established for sub-failure and failure conditions.
These baseline data provide parameters within the expected threshholds for
different in vivo activities and beyond these levels if safety factors are to
be incorporated, (3) A subset of these mechanical properties must be selected
and prioritized. This subset is important, given that the mechanical
properties of the designs are not expected to completely duplicate the
properties of native tissues, (4) Standards must be set when evaluating the
repairs/replacements after surgery to determine how good is enough? New
and improved methods must also be developed for assessing the function of
engineered tissues, (5) The effects of physical factors on cellular activity
must be determined in engineered tissues. Knowing these signals may shorten
the iterations required to successfully replace a tissue, and direct cellular
activity and phenotype toward a desired end goal, and (6) To effect a better
repair outcome, cell-matrix implants may benefit from being mechanically
stimulated using in vitro bioreactors prior to implantation. How
mechanical stress, as well as other physical factors, influences cell
activity in bioartificial matrices and bioreactors needs to be assessed.
Incorporating each of these principles of functional tissue engineering
should result in safer and more efficacious repairs and replacements for the
patient. In addition, these principles outline scientific research
opportunities that could vastly improve the scientific knowledge base and the
result in tissue engineering applications for musculoskeletal injuries and
diseases that involve musculoskeletal tissues (articular cartilage,
ligaments, tendons, bone, meniscus, intervertebral disc and skeletal muscle).
This PA is an outgrowth of the NIAMS, NICHD and NIDCR continued interest in,
and support of, musculoskeletal tissue engineering research, and the National
Institutes of Health BECON 2001 Symposium on Reparative Medicine: Growing
Tissues and Organs. Further information on this meeting can be found at:
http://www.becon.nih.gov/becon.htm.
Scope
The following are examples of research topics that are appropriate for this
PA, however, they are not to be considered as all inclusive or limiting:
Better understand and define the normal mechanical properties of the
musculoskeletal tissues (i.e., the micro-environment) that we are trying to
repair or replace.
Develop new and/or improved methods for the non-invasive measurement of
mechanical function at the cell level and/or micro-environmental level.
Better understand the interactions between mechanical force and inflammatory
processes with specific reference to musculoskeletal tissue engineered
applications.
Better understand the intrinsic properties of extracellular musculoskeletal
matrices (synthesis, characterization, fabrication, cell responsiveness,
adaptation to the environment, and ways to improve marginal, inter-fascial
attachments).
Better understand how mechanical stress, as well as other physical factors,
influence cell activity in musculoskeletal bioartificial matrices and
bioreactors.
Better understand the mechanical events that occur during rehabilitation
following musculoskeletal tissue-engineered repair.
Identify and validate a minimum set of tests (in vitro and in vivo) to
functionally validate engineered musculoskeletal tissues.
Develop and validate constitutive models of scaffold degradation and fatigue
for use in musculoskeletal tissue engineering.
Develop and validate better mathematical (non-linear, time dependent) and
computational (robust, finite element) models for use in musculoskeletal
tissue engineering.
Better understand mechanical factors and their interaction with construct
design parameters in musculoskeletal tissue engineering.
Develop and/or validate minimally-invasive imaging modalities to assess the
progress/success of musculoskeletal tissue-engineered constructs.
Develop and/or validate other non-imaging-related, minimally-invasive
modalities (i.e, biochemical, serologic, ultrasound, etc.) to assess the
progress/success of musculoskeletal tissue-engineered constructs.
As science in this area advances, ultimately develop randomized, controlled
outcome studies of the use of tissue-engineered constructs for the reparative
medical treatment of musculoskeletal injuries and diseases.
INCLUSION OF WOMEN AND MINORITIES IN RESEARCH INVOLVING HUMAN SUBJECTS
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
(http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-048.html),
a complete copy of the updated Guidelines is available at
http://grants.nih.gov/grants/funding/women_min/guidelines_update.htm. 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.
INCLUSION OF CHILDREN AS PARTICIPANTS IN RESEARCH INVOLVING HUMAN SUBJECTS
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: http://grants.nih.gov/grants/guide/notice-files/not98-024.html.
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.
REQUIRED EDUCATION ON THE PROTECTION OF HUMAN SUBJECT PARTICIPANTS
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:
http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-039.html.
URLS IN NIH GRANT APPLICATIONS OR APPENDICES
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.
PUBLIC ACCESS TO RESEARCH DATA THROUGH THE FREEDOM OF INFORMATION ACT
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:
http://grants.nih.gov/grants/policy/a110/a110_guidance_dec1999.htm.
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.
APPLICATION PROCEDURES
The PHS 398 research grant application instructions and forms (rev. 5/2001)
at http://grants.nih.gov/grants/funding/phs398/phs398.html are to be used in
applying for these grants and will be accepted at the standard application
deadlines (http://grants.nih.gov/grants/dates.htm) as indicated in the
application kit. This version of the PHS 398 is available in an interactive,
searchable format. Although applicants are strongly encouraged to begin using
the 5/2001 revision of the PHS 398 as soon as possible, the NIH will continue
to accept applications prepared using the 4/1998 revision until January 9,
2002. Beginning January 10, 2002, however, the NIH will return applications
that are not submitted on the 5/2001 version. For further assistance contact
GrantsInfo, Telephone 301/710-0267, Email: GrantsInfo@nih.gov.
Applicants planning to submit an investigator-initiated new (type 1),
competing continuation (type 2), competing supplement, or any amended/revised
version of the preceding grant application types requesting $500,000 or more
in direct costs for any year are advised that he or she must contact the
Institute or Center (IC) program staff before submitting the application,
i.e, as plans for the study are being developed. Furthermore, the applicant
must obtain agreement from the IC staff that the IC will accept the
application for consideration for award. Finally, the applicant must
identify, in a cover letter sent with the application, the staff member and
Institute or Center who agreed to accept assignment of the application.
This policy requires an applicant to obtain agreement for acceptance of both
any such application and any such subsequent amendment. Refer to the NIH
Guide for Grants and Contracts, March 20, 1998 at
http://grants.nih.gov/grants/guide/notice-files/not98-030.html.
SPECIFIC INSTRUCTIONS FOR MODULAR GRANT APPLICATIONS
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
http://grants.nih.gov/grants/funding/phs398/phs398.html is to be used in
applying for these grants, with modular budget instructions provided in
Section C of the application instructions. Applicants are permitted,
however, to use the 4/1998 revision of the PHS 398 for scheduled application
receipt dates until January 9, 2002. If you are preparing an application
using the 4/1998 version, please refer to the step-by-step instructions for
Modular Grants available at
http://grants.nih.gov/grants/funding/modular/modular.htm. Additional
information about Modular Grants is also available on this site.
The title and number of the program announcement must be typed on line 2 of
the face page of the application form and the YES box must be marked.
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)
REVIEW CONSIDERATIONS
Applications will be assigned on the basis of established PHS referral
guidelines. Applications will be evaluated for scientific and technical
merit by an appropriate scientific review group convened in accordance with
the standard NIH peer review procedures. 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 applications under review, will
be discussed, assigned a priority score, and receive a second level review by
the appropriate national advisory council or board.
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. 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.
(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
support?
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
evaluated.
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.
o The adequacy of the proposed plan to share data, if appropriate.
AWARD CRITERIA
Award criteria that will be used to make award decisions include:
o scientific merit
o availability of funds
o programmatic priorities.
INQUIRIES
Inquiries are encouraged. The opportunity to clarify any issues or questions
from potential applicants is welcome.
Direct inquiries regarding programmatic issues to:
James S. Panagis, MD, MPH
Director, Orthopaedics Program
National Institute of Arthritis and Musculoskeletal and Skin Diseases
45 Center Drive, Room 5AS-37K
Bethesda, MD 20892-6500
Telephone: (301) 594-5055
FAX: (301) 480-4543
Email: jp149d@nih.gov
Louis A. Quatrano, Ph.D.
Behavioral Sciences and Rehabilitation Engineering Program
National Center for Medical Rehabilitation Research, NICHD
6100 Executive Blvd. Rm. 2A-03
Bethesda, MD 20852
Telephone: (301)402-4221
FAX: (301) 402-0832
Email: lq2n@nih.gov
Eleni Kousvelari, DDS, D.Sc.
Chief, Cellular and Molecular Biology
National Institute of Dental and Craniofacial Research
45 Center Drive, Room 4AN-18A
Bethesda, MD 20892-6500
Telephone: (301) 594-2427
FAX: (301) 480-8318
Email: kousvelari@de45.nidr.ni.gov
Direct inquiries regarding fiscal matters to:
Ms. Melinda Nelson
Grants Management Office
National Institute of Arthritis and Musculoskeletal and Skin Diseases
45 Center Drive, Room 5AS-49F
Bethesda, MD 20892-6500
Telephone: (301) 594-3535
FAX: (301) 480-5450
Email: nelsonm@mail.@nih.gov
Christopher Myers
Grants Management
NICHD
6100 Executive Blvd. Rm. 8A17
Bethesda, MD 20852
Telephone: (301)435-6966
FAX: (301) 402-0915
Email: myersc@mail.nih.gov
Martin R. Rubenstein
Chief Grants Management Officer
National Institute of Dental and Craniofacial Research
Telephone: (301) 594-4800
FAX: (301) 480-8301
Email: Martin.Rubenstein@NIH.GOV
AUTHORITY AND REGULATIONS
This program is described in the Catalog of Federal Domestic Assistance No.
93.846, 93.929 and 93.158. 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, and 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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