OPERATION OF SENSORS IN VIVO RELEASE DATE: October 21, 2002 RFA: EB-03-001 National Institute of Biomedical Imaging and Bioengineering (NIBIB) (http://www.nibib1.nih.gov/) National Institute on Deafness and Other Communication Disorders (NIDCD) (http://www.nidcd.nih.gov/) LETTER OF INTENT RECEIPT DATE: January 6, 2003 APPLICATION RECEIPT DATE: January 21, 2003 THIS RFA CONTAINS THE FOLLOWING INFORMATION 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 PURPOSE OF THIS RFA The National Institute of Biomedical Imaging and Bioengineering (NIBIB) and the National Institute on Deafness and Other Communication Disorders seeks investigator-initiated applications for research grant awards (R01) or exploratory/developmental research grant awards(R21) for the development of innovative technologies designed to increase the utility of a sensor in vivo. In particular, novel sensing modalities need to be developed that operate in vivo or that alter the healing dynamics at the sensor insertion point. A team-based approach is strongly encouraged to capitalize upon the talents from sensor engineers, pathologists, histologists, cell biologists, immunologists and biomaterial scientists. Contributions from molecular and cellular biology, implant pathology, and immunology will help advance knowledge of the tissue reaction to sensor implantation in vivo. Materials science, engineering design changes, pharmaceutical adaptations, and novel transduction mechanisms are needed to improve sensor performance in vivo. Special emphasis will be placed on the validation of the sensor output to give a clinically relevant endpoint. RESEARCH OBJECTIVES The NIH's Bioengineering Consortium (BECON) held a two-day symposium titled "Sensors for Biological Research and Medicine" on June 24-25, 2002, at the Natcher Conference Center Bethesda, Maryland. Specific goals of the meeting were to provide a forum to showcase current advancements in biomedical sensor technology and applications, to identify future biomedical needs and the emerging technologies that can meet them, and to provide advice to the NIH concerning opportunities and needs in the field of biomedical sensors. One concern was the utility of a sensor in vivo. The invasion of a sensor into tissue creates a wound. The wound healing response in the presence of a biomaterial has certain abnormal traits compared to a sham wound healing response lacking an implant. Sensor biocompatibility is defined by this response, beginning with the first encounter of the sensor surface with host proteins, subsequent encounters with immune cells, inflammatory cytokine cascades, and fibroblasts with their fibrotic response locally around the implant. This abrogated healing response is a continuum of dynamic histological events influencing the sensing. The sensing surface constitutes one component of the sensing environment in this wound site. The surrounding tissue, responding also to the local trauma and inflammatory sequelae, constitutes the other half of this sensing environment. Mutual physiological influences, biochemical crosstalk, and signaling between the two halves are poorly characterized, poorly understood, and poorly controlled in most, if not all, sensor designs to date. Nonetheless, it is this complex environment in which implantable sensor performance and reliability is demanded. Implanted sensors must not necessarily avoid the encapsulation response to be successful. Various capsule reactions are tolerable to permit sensing function; some can be temporally modulated, perhaps eliminated. Yet, reliable, predictable capsule response yielding reliable, predictable sensor response is required. Site-to-site implant response, and species-to-species variability, must be seriously considered as well as other design, materials, and microenvironmental influences. These include certain performance enhancing biomaterial features (porous texture, surface shielding from adsorbed proteins, drug delivery, low inflammatory potential); advanced electronic signal processing algorithms to accommodate complex in situ sensing dynamics (and signal:noise limits); and novel designs with requisite new, improved sensing properties in an implantable context. To solve the long-standing challenges preventing practical realization of a long-term implantable sensor, new innovative technical and scientific approaches must exploit recent advances and yet-undiscovered principles governing the behavior of materials implanted into wound sites. The sensor implant site must be considered as a wound bed with compromised, abnormal healing cascades that resolve acutely but persist chronically. These healing dynamics, their physiological consequences, and their impact on in vivo sensing must be appreciated, and to whatever extent possible, controlled. The next phase of research in this area must directly resolve the problem of encapsulation by either processing sensor signals regardless of the encapsulation, or adapting methods to alter it. To address this problem, a team approach is strongly encouraged. The sensor and the tissue it affects can be separated into two separate, intimately related problems. Research addressing these problems may include, but not be limited to: o New knowledge of the foreign body response mechanisms, their kinetics, dynamics, and details, including pathways leading to both foreign body giant cell formation and fibroblast recruitment in wound sites; o Methods to evaluate the influence of the inflammatory reaction and cytokine presence in a wound site with sensor response; o Design features for new sensors that enable accurate calibration throughout the wound healing including dynamic and complex signal processing algorithms to adapt signals logically and reliably over time; o Improved sensor designs that can anticipate the wound site dynamics and interface with tissue appropriately with multiple behaviors depending on the environment; o Understanding of site-to-site variability in sensing response and its relationship to wound site-site changes; o Understanding of species differences (histology, physiology, accuracy, and advantage) in animal models used to evaluate sensors intended for human application. In addition, the NIDCD is interested in translatable in vivo sensor systems specifically impacting the auditory, vestibular, olfaction, taste, voice, speech and language neural and sensory systems. Research addressing these interests may include, but not be limited to: o Enhanced development of the neural tissue and circuitry hardware interface(s) to improve amplification and transmission of sound and speech; o Development of electrosensors from biomimetic materials that will reduce or prevent biofouling when implanted into CNS tissue; o Development of hardware/tissue interfaces to improve the representation of speech and sound; o Development and enhancement of high throughput sensor technologies for the detection of middle ear infections; o Enhanced electrostimulatory prosthesis interfaces capable of sensing head acceleration forces using accelerometer and gyroscope technology for vestibular-deficient individuals; o Development and enhancement of taste and olfaction sensor technologies. MECHANISM OF SUPPORT This RFA will use the NIH investigator-initiated 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 cross-cutting research that addresses specific aspects of sensors operating in vivo. 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 very little or no preliminary data is available. An R21 application can be for up to two years with a maximum budget request of $150,000 direct costs per year and a maximum page limit of 10 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 mechanisms). This RFA uses just-in-time concepts. It also uses the modular as well as the non-modular budgeting formats (see https://grants.nih.gov/grants/funding/modular/modular.htm). 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. FUNDS AVAILABLE The participating Institutes intend to commit approximately $4.6M in FY 2003 to fund 10 to 16 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 $150,000 per year will be accepted for an R21. There is no budget limitation for R01 applications. Applications requesting up to $250,000 per year in direct costs must be submitted in a modular grant format. Since the total costs for a subcontract or consortium are included in the direct cost request, one additional module of $25,000 may be requested for the facilities and administrative costs associated with third party agreements. Under these guidelines, applications requesting $250,000 may request $275,000 to cover the facilities and administrative costs described above. A module requested for this purpose must be clearly identified in the budget justification section of the application, and will be restricted for this purpose only at the time of award. 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 NIDCD 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. At this time, it is not known if this RFA will be reissued. ELIGIBLE INSTITUTIONS 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 INDIVIDUALS ELIGIBLE TO BECOME PRINCIPAL INVESTIGATORS 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. SPECIAL REQUIREMENTS 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. WHERE TO SEND INQUIRIES We encourage inquiries concerning this RFA and welcome the opportunity to answer questions from potential applicants. Inquiries may fall into three areas: scientific/research, peer review, and financial or grants management issues: o Direct your questions about scientific/research issues to: Christine A. Kelley, Ph.D. Acting Director Division of Bioengineering National Institute of Biomedical Imaging and Bioengineering NIH/DHHS Suite 200 6707 Democracy Blvd. Bethesda, MD 20892-5469 Telephone: (301) 451-4778 Fax: (301) 480-4973 Email: kelleyc@mail.nih.gov Nancy L. Freeman, Ph.D. Scientific Program Director National Institutes of Health National Institute on Deafness and Other Communication Disorders NIH/DHHS Executive Plaza South-400C 6120 Executive Blvd. MSC-7180 Bethesda, MD 20892-7180 Telephone: (301) 402-3458 Fax: (301) 402-6251 Email: nancy_freeman@NIH.gov o Direct your questions about peer review issues to: David T. George, Ph.D. Chief, Office of Scientific Review Division of Extramural Activities National Institute of Biomedical Imaging and Bioengineering NIH/DHHS Suite 920 6707 Democracy Blvd. Bethesda, MD 20892-5469 Telephone: (301) 496-8633 FAX: (301) 480-0675 Email: georged@nih.gov o Direct your questions about financial or grants management matters to: Ms. Nancy Curling Division of Extramural Activities National Institute of Biomedical Imaging and Bioengineering NIH/DHHS Suite 900 6707 Democracy Blvd. Bethesda, MD 20892 Telephone: (301) 451-4786 Fax: 301-480-4974 Email: curlingn@nih.gov LETTER OF INTENT 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 David T. George, Ph.D. at the address listed under WHERE TO SEND INQUIRIES. SUBMITTING AN APPLICATION Applications must be prepared using the PHS 398 research grant application instructions and forms (rev. 5/2001). The PHS 398 is available at https://grants.nih.gov/grants/funding/phs398/phs398.html in an interactive format. For further assistance contact GrantsInfo, Telephone (301) 710-0267, Email: GrantsInfo@nih.gov. SPECIFIC INSTRUCTIONS FOR MODULAR GRANT APPLICATIONS: Applications 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 https://grants.nih.gov/grants/funding/phs398/phs398.html includes step- by-step guidance for preparing modular grants. Additional information on modular grants is available at https://grants.nih.gov/grants/funding/modular/modular.htm. 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: https://grants.nih.gov/grants/funding/phs398/label-bk.pdf. SUBMITTING AN APPLICATION: Submit a signed, typewritten original of the application, including the Checklist, and three signed, photocopies, in one package to: Center For Scientific Review National Institutes Of Health 6701 Rockledge Drive, Room 1040, MSC 7710 Bethesda, MD 20892-7710 Bethesda, MD 20817 (for express/courier service) At the time of submission, two additional copies of the application and all five collated sets of Appendix material must be sent to Dr. David T. George at the address listed under WHERE TO SEND INQUIRIES. 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. Principal investigators should not send 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 received such a letter within three weeks after submitting the application, contact Dr. David George at the address listed under WHERE TO SEND INQUIRIES. 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 https://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-012.html. PEER REVIEW PROCESS 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 NIBIB in accordance with the review criteria stated below. As part of the initial merit review, all applications will: 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 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 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 For both the R01 and R21 grant applications, 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 technologies? (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 MECHANISM ONLY: 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. RECEIPT AND REVIEW SCHEDULE Letter of Intent Receipt Date: January 6, 2003 Application Receipt Date: January 21, 2003 Peer Review Date: May/June, 2003 Council Review: September, 2003 Earliest Anticipated Start Date: September 30, 2003 AWARD CRITERIA 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. REQUIRED FEDERAL CITATIONS INCLUSION OF WOMEN AND MINORITIES IN CLINICAL RESEARCH: 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 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 (https://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-001.html); a complete copy of the updated Guidelines are available at https://grants.nih.gov/grants/funding/women_min/guidelines_amended_10_2001.htm. 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 differences. INCLUSION OF CHILDREN AS PARTICIPANTS IN RESEARCH INVOLVING HUMAN 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, 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 is available at https://grants.nih.gov/grants/funding/children/children.htm. 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. You will find this policy announcement in the NIH Guide for Grants and Contracts Announcement, dated June 5, 2000, at https://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-039.html. HUMAN EMBRYONIC STEM CELLS (hESC): Criteria for federal funding of research on hESCs can be found at https://grants.nih.gov/grants/stem_cells.htm and at https://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-005.html. Only research using hESC lines that are registered in the NIH Human Embryonic Stem Cell Registry will be eligible for Federal funding (see http://escr.nih.gov). 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. 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 https://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. 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. Furthermore, we caution reviewers that their anonymity may be compromised when they directly access an Internet site. 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 http://www.health.gov/healthypeople. AUTHORITY AND REGULATIONS: This program is described in the Catalog of Federal Domestic Assistance No. 93.286 (NIBIB), 93.287 (NIBIB), and No. 93.173 (NIDCD) 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 https://grants.nih.gov/grants/policy/policy.htm 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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