Subject: NIH Guide-Vol.19, No. 39, November 2, 1990 - RFA HL-90-09-H
From: Dot Baker <[email-masked]>
To: [email-masked]
Date: Wed, 31 Oct 90 15:21 EST

Hi Paul,
   Please post this to the NIH Listserver as:
    RFAHL-90-09-H.110290
     Thanks.  dottie
 ---------------------------- Text of forwarded message -----------------------
 
REQUEST FOR APPLICATIONS:  RFA
RFA:  HL-90-09-H
CARDIOVASCULAR DEVICE-CENTERED INFECTIONS
 
P.T. 34; K.W. 0715040, 0740035, 0715125
 
NATIONAL HEART, LUNG, AND BLOOD INSTITUTE*
NATIONAL SCIENCE FOUNDATION
 
Letter of Intent Receipt Date:  December 3, 1990
Application Receipt Date:   January 14, 1991
 
PURPOSE
 
The Devices and Technology Branch (DTB), Division of Heart and
Vascular Diseases of the National Heart, Lung, and Blood
Institute (NHLBI), and the Section of Bioengineering and
Environmental Systems of the Engineering Directorate,
National Science Foundation (NSF), invite grant applications for
support of interdisciplinary research (Biomedical Sciences
and Bioengineering) on the mechanisms, prevention, and
treatment of infections developing in and around permanently
implanted cardiovascular devices in humans.
 
BACKGROUND
 
Foreign bodies have long been known to be infection-
potentiating, but mechanisms to explain this phenomenon are
not clearly defined.  Infection in close proximity to a valve
(endocarditis) occurs in 1-4% of patients with
mechanical or bioprosthetic heart valves.  One to 6% of
patients with prosthetic vascular grafts develop a graft-
associated infection.  However, in patients with total
artificial hearts (TAHs) or ventricular assist devices (VADs)
implanted for periods longer than 3 months, the incidence of
infection has been reported as 25-100%.  It is likely that
this high incidence stems in part from the existence of
external drive-lines which serve as portals of entry for
microorganisms despite all efforts at prevention.  Some of
the newer VAD systems currently undergoing preclinical
testing will require no external drive-lines.  This advance
is expected to reduce but not eliminate the risk of implant-
related infections in patients receiving these new devices.
 
Infection in patients with TAHs or VADs is commonly
associated with thromboembolism, and there is evidence that
these two complications are interrelated.  Ultrastructural
studies of TAHs examined following autopsy in several human
subjects have demonstrated failure of tissue integration and
diffuse adhesive bacterial colonization of biomaterial
surfaces.  At device retrieval, thrombotic material has been
observed, especially in the region of the valve struts and at
the connections between the device and the great vessels.  In
addition, patients have suffered embolic stroke, and
thromboembolic material has been observed in other organs,
especially the kidney.  These thrombi and emboli are
frequently infected.  An association between thrombosis and
infection has long been observed in a number of clinical
conditions, which include implanted prosthetic heart valves
and prosthetic vascular grafts, and several mechanisms have
been proposed for this. A thrombus forms an ideal nidus for
bacteria to adhere and multiply in a nutrient environment.
Conversely, certain bacteria can induce activation and
aggregation of platelets or leukocytes, and activation of
factors in the coagulation and complement cascades, thus
favoring thrombosis.  These mechanisms may result in a
vicious cycle between thrombosis and infection, each
increasing the likelihood of the other, especially in a
chronic setting.  Proteins that mediate adhesion of certain
cells, such as platelets and endothelial cells, to one another
and to other surfaces include fibronectin, laminin,
vitronectin, von Willebrand factor, and certain collagen
types.  The role of these and other proteins in bacterial
adhesion has not been fully defined.  Finally, TAH
implantation has been associated with alterations in
complement and leukocyte functions, perhaps contributing to
the high risk of periprosthetic and intraprosthetic infection
in these patients.
 
OBJECTIVES AND SCOPE
 
This special grant program is for support of
interdisciplinary research approaches to the problem of
infections associated with implanted prosthetic
cardiovascular devices.  Molecular, structural, and
computational biology approaches to the life and medical
sciences are encouraged:  these may deal with the nature of
the interaction between bacterial surface components, the
biomaterial surface, and molecules mediating bacterial
adhesion, growth, and colonization on biomaterials.  Other
approaches, especially employing the concepts and methods of
modern cell and molecular biology, are encouraged.
Applications should have a substantive content in
engineering.  This may include the development of new
engineering techniques or the novel application of existing
ones. Research projects involving human subjects, animal
models, or other experimental approaches may be focused on:
(1) the etiology, pathogenesis, and natural history of
device-centered infections, including the relationship to
thromboembolism; (2) elucidation of possible predisposing
factors for their development; and/or (3) potential
approaches to improved prevention, monitoring, and treatment
of such infections.
 
In order for applicants to be responsive to this Request for
Applications (RFA), the
research should have a strong interdisciplinary component.
NSF support is contingent on a strong bioengineering
contribution.  This may include mathematical modeling,
instrumentation, tissue engineering, or any novel engineering
technique that may help characterize or understand the
mechanisms.  The routine use or modification of state-of-the-
art technology by itself will not qualify.  In addition, the
investigative approach should include one or more of the
following areas:  microbiology, immunology, infectious
diseases, cardiovascular diseases, molecular biology, cell
biology, pathology, and rheology.
 
Applications might include, but are not limited to, the
following:
 
o  Investigation of mechanisms for monitoring, producing, or
enhancing the development of a biological (cellular or
acellular) layer on the inner and outer surfaces of a
circulatory support device with the object of inhibiting
device-centered infections; with available methods for gene
transfer and expression, attempt the alteration of the
functions of leukocytes, endothelial cells, or other cells
with the object of making them more resistant to infection.
 
o  Examining the role of the bacterial cell surface
glycocalyx or other surface molecules in the specificity of
the adhesion of certain bacteria to certain polymers or
metals.
 
o  Investigation of bacterial adhesion to cardiovascular
implants by delineating binding sites on the surface of
biomaterials for bacteria or for extracellular molecules
mediating bacterial adhesion; determine the specificity of
binding sites for specific types of bacteria or proteins;
investigate techniques for saturating these binding sites or
synthesizing new materials, which have fewer binding sites for
bacteria, or for molecules mediating their adhesion.
 
o  Examination and defining the molecular basis of plasma and
extracellular matrix proteins in bacterial adhesion and
colonization   on biomaterials.  These proteins include
fibrinogen, fibronectin, laminin, vitronectin, von
Willebrand factor, and various collagen types.
 
o  Investigating the relation between infection and
thrombosis by studying the basic mechanisms whereby certain
microorganisms activate blood coagulation, fibrinolysis, and
complement.
 
o  Evaluating the changes in T- and B- lymphocytes,
macrophages, neutrophils, lymphokines, complement, and other
components of the immune system in response to interaction
between well-characterized biomaterials and blood or tissues
under controlled conditions; evaluate the role these
abnormalities may play in device-related infections.
 
o  Examining the production and possible effect on
susceptibility to infection of oxygen-free radicals released
following contact of biomaterials with blood and other
tissues.
 
o  Using in vitro, ex vivo, or in vivo models plus monitoring
and visualization, evaluation of the role of physical
properties (e.g., smoothness vs. roughness, porosity,
compliance, surface-free energy) or chemical composition of
various biomaterials, as elements influencing adhesion and
proliferation of microorganisms on a biomaterial or device
and in the development of an intraluminal and extraluminal
layer of host cells formed in response to device
implantation.
 
o  Evaluation of the use of new monitoring techniques,
including in-vivo visualization, to characterize changes in
surface phenomena.
 
o  Evaluation of mass transport and fluid mechanical factors
(e.g., shear stress, stasis, recirculation) in the adhesion,
colonization, and localization of bacteria on devices in
contact with blood.
 
Applicants are not required to include the above-mentioned
topics and are encouraged to consider other avenues of
investigation that have the potential of yielding
significant information regarding mechanisms of biomaterial-
centered infections.  To be responsive to this RFA,
applications must describe experimental conditions that
simulate those encountered by implanted cardiovascular
devices.  Attention should be given to appropriate
statistical design of the study.  Although not a
requirement, the inclusion of NHLBI-DTB primary reference
materials (low-density polyethylene and silica-free
polydimethylsiloxane) in the research plan is encouraged.
Arrangements for procuring these materials may be made by
contacting Dr. Paul Didisheim at the address and phone number
listed at the end of this announcement.  Also, if the
research involves infectivity or adhesiveness of specific
strains of microorganisms, these should be known to play
significant roles in device-related infections in man.
Engineering approaches proposed should have general
applicability.
 
In any studies involving human subjects, women and minority
individuals must be included in the study population;
otherwise a clear rationale for their exclusion must be
provided in the application.  Minority institutions are
encouraged to apply, and other institutions are encouraged to
establish collaborative arrangements with minority
institutions.
 
EXCLUSIONS
 
Applications aimed primarily at examining the biological
problem of infections with non-cardiovascular implants (e.g.,
orthopedic, dental, eye, ear) will not be considered
responsive to this RFA.
 
This solicitation will not support large-scale clinical
trials.  While interdisciplinary research is required, this
should not be in the form of a large number of projects which
would constitute a program project.  Applicants may request
equipment; however, funds will not be provided to equip a
laboratory or for major, expensive items.  Specifically,
funds will not be provided for the purchase of expensive
cardiovascular devices.
 
MECHANISM OF SUPPORT
 
The support mechanism for this program will be the
traditional, individual research grant as administered by the
NHLBI and NSF.  A committee comprised of NHLBI and NSF staff
will determine which agency will fund the most highly rated
applications.  Although approximately $1.0 million total
costs (direct plus indirect) for this program is included in
the financial requests for fiscal year 1991, award of grants
pursuant to this RFA is contingent upon receipt of funds for
this purpose.  The hope is to award up to five grants under
this program.  The specific amount to be funded, however,
will depend on the merit and scope of the applications
received and the availability of funds.  Since a variety of
approaches would represent valid responses to this
announcement, it is anticipated that there will be a range of
costs among individual grants awarded.  If collaborative
arrangements involve sub-contracts with other institutions,
the NHLBI Grants Operations Branch should be consulted
regarding procedures to be followed (tel:  301-496-7255).
 
Following initiation of the program, NHLBI and NSF will
jointly sponsor annual meetings to encourage exchange of
information among investigators who participate in this
program.  In the budget for the grant application, applicants
should request ADDITIONAL TRAVEL FUNDS for a one-day meeting
each year, to be held in the Washington, D.C. area.
Applicants should also include a statement in their
applications indicating their willingness to participate in
these meetings.  Applicants, who will plan and execute their
own research programs, are requested to furnish their own
estimates of the time required to achieve the objectives of
the proposed research project.  Up to FIVE YEARS of support
may be requested.
 
At the end of the official award period, renewal applications
may be submitted through the regular grant programs of the
NIH or NSF.  It is anticipated that support for the present
program will begin in July 1991.  Administrative adjustments
in project period and/or amount of support may be required at
the time of the award.
 
All current policies and requirements that govern the
research grant programs of NIH and NSF will apply to grants
awarded under this RFA.  Awards to foreign institutions will
be made only for research of very unusual merit, need and
promise, and in accordance with Public Health Service and NSF
policy governing such awards.
 
REVIEW PROCEDURES AND CRITERIA
 
Review Method:  Upon receipt, applications will be reviewed
for their responsiveness to the objectives of this RFA by NIH
and NSF staffs.  If an application is judged unresponsive,
the applicant will be contacted and given the opportunity to
withdraw the application, or have it considered for the
regular NIH or NSF grant programs.  If an application
submitted in response to this RFA is substantially similar
to a research grant application already submitted to the NIH
or NSF for review, but has not yet been reviewed, the
applicant will be asked to withdraw either the pending
application or the new one.  Simultaneous submission of
identical applications will not be allowed, nor will
essentially identical applications be reviewed by different
review committees.  Therefore, an application cannot be
submitted in response to this RFA that is essentially
identical to one that has already been 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.
 
Those applications that are judged to be responsive will be
reviewed for scientific and technical merit by an invited
review group convened by the Division of Extramural Affairs,
NHLBI.  The review group will be composed of mostly
nonfederally employed reviewers with expertise that will
include the disciplines represented by the applications.
Applications will be reviewed in competition with each other
on a nation-wide basis.  This RFA solicitation is a single
competition and has one specific deadline for receipt of
applications.
 
Review Criteria:  The factors to be considered in the
evaluation of scientific and engineering merit of each
application will be similar to those used in the review of
traditional research project grant
applications, including:
 
     o the novelty, originality and feasibility of the
approach and the merit of the experimental design
 
     o clear indication of an interdisciplinary approach
encompassing a substantive and innovative bioengineering
component
 
     o the competence of the principal investigator and
collaborators to accomplish the proposed research, and the
commitment and time they will devote to the project
 
     o the suitability of the facilities to perform the
proposed research, including laboratories, instrumentation,
and data management systems
 
     o the appropriateness of the requested budget for the
work proposed.
 
METHOD OF APPLICATION
 
Letter of intent:  Prospective applicants are asked to submit
a letter of intent to apply to this RFA.  This letter should
include the names of any participating institutions and all
investigators, together with a descriptive title.  Such a
letter of intent is not binding and it will not enter into
the review of any application.  Letters of intent are
requested solely for planning purposes.  The NHLBI and NSF
Staff will not provide responses to such letters.  Letters of
intent to apply to this RFA should be received no later than
December 3, 1990, and should be addressed to:
 
                 Dr. Charles L. Turbyfill
                 Review Branch
                 Division of Extramural Affairs
                 National Heart, Lung, and Blood Institute
                 Westwood Building, Room 553
                 NIH, Bethesda, MD  20892
 
Format for Applications:  Submit applications on form PHS-398
(revised 10/88), the application form for the traditional NIH
research project grant.  Copies of this form are available in
the applicant institution's office of sponsored research, or
may be obtained from the following:
 
                 Office of Grants Inquiries
                 Division of Research Grants
                 Westwood Building, Room 449
                 NIH, Bethesda, MD  20892
 
Use the conventional format for research project grant
applications and ensure that points identified in the section
above on "Review Procedures and Criteria" are fulfilled.
Applications that contain prior work supported by the NSF
must include a "Results from prior support" statement. To
identify the application as a response to this RFA, CHECK
"YES" on item 2 of page 1 of the application and enter the
title "Cardiovascular Device-Centered Infections", and enter
the RFA number HL-90-09-H in the space provided.
 
THE RFA LABEL FOUND IN THE FORM PHS-398 APPLICATION KIT MUST
BE AFFIXED TO THE BOTTOM OF THE FACE PAGE OF THE ORIGINAL
COMPLETED APPLICATION FORM PHS-398.  FAILURE TO USE THIS
LABEL COULD RESULT IN DELAYED PROCESSING OF YOUR APPLICATION
SUCH THAT IT MAY NOT REACH THE REVIEW COMMITTEE IN TIME FOR
REVIEW.
 
Application Procedure:  Send or deliver the completed, signed
application and four (4) complete photocopies of it to the
following, making sure that the original application with the
RFA label attached is on top:
 
                 Division of Research Grants
                 Westwood Building, Room 240
                 National Institutes of Health
                 Bethesda, MD  20892**
 
SEND TWO ADDITIONAL COPIES OF THE APPLICATION TO DR. CHARLES
TURBYFILL AT THE ADDRESS LISTED UNDER "LETTER OF INTENT".  IT
IS IMPORTANT TO SEND THESE TWO COPIES AT THE SAME TIME AS THE
ORIGINAL AND FOUR COPIES ARE SENT TO THE DIVISION OF RESEARCH
GRANTS, OTHERWISE THE NHLBI CANNOT GUARANTEE THAT THE
APPLICATION WILL BE REVIEWED IN COMPETITION FOR THIS RFA.
 
Applications must be received by January 14, 1991.  An
application not received by this date will be considered
ineligible
 
Timetable:
 
Letter of Intent                   December 3, 1990
Application Receipt Date           January 14, 1991
Review by National Heart, Lung,
  and Blood Advisory Council
  and NSF Staff                    May 23-24, 1991
Anticipated Award Date             July 1, 1991
 
Inquiries:  Inquiries regarding this announcement may be
directed to the following:
 
Dr. Paul Didisheim               Norman Caplan
Head, Biomaterials Program       Section Head
Devices and Technology Branch    Bioengineering and
Division of Heart and Vascular      Environmental Systems
    Diseases                     National Science Foundation
National Heart, Lung, and        1800 G Street
    Blood Institute              Washington, D.C. 20550
Federal Building, Room 312       Telephone:  (202) 357-7955
7550 Wisconsin Avenue
Bethesda, MD  20892
Telephone:  (301) 496-1586
 
     *This program is described in the Catalog of Federal
Domestic Assistance number 93.837, Heart and Vascular
Diseases.  Awards will be made under the authority of the
Public Health Services Act, Section 301 (42 USC 241) and
administered under PHS grant policies and Federal
regulations, most specifically 42 CFR Part 52 and 45 CFR Part
74.  This program is not subject to the intergovernmental
review requirements of Executive Order 12372, or to Health