HHS SBIR RFA-HL-15-017

The SBIR/STTR Programs were recently reauthorized by the United States Congress with the SBIR/STTR Reauthorization Act of 2011(P.L. 112-81).  One change that was made to the SBIR program in this reauthorization was the authority for certain participating federal agencies to ‘issue a Phase II award to a small business concern that did not receive a Phase I award for that research/research & development.  This is a so-called ‘Direct-to-Phase II’ SBIR award.  This authority would permit SBCs to submit Direct-to-Phase-II SBIR applications, if the small business had performed the Phase I stage-type of research through other funding sources.  The legislative rationale for permitting the Direct-to-Phase II  award is to allow a SBC that has already built a technology prototype  and tested its feasibility (i.e. completed Phase-I-type R&D) to move directly into a Phase-II-type R&D that tests the functional viability of the prototype according to scientific methods and potential for commercial development. The Direct-to-Phase-II SBIR mechanism eliminates the need for the SBCs to propose additional small feasibility studies, if the technology is ready for the Phase II stage of development.  The Direct-to-Phase II authority is not available to the STTR program.

Background

Recent trends have created a large potential market for breakthrough medical solutions led by tissue engineered medical products.  For example, bioengineered trachea, vascular grafts, and other hollow-organ tissues have made entry into clinical studies, so sophisticated and more standardized bioreactors are critical for testing of complex, neo-organ technologies.  Additionally, considerable progress in the tissue engineering and regenerative medicine field has increased the demand for reliable tissue-specific bioreactors.   It is expected that biotech companies and academic partners involved in regenerative medicine strategies would leverage their existing knowledge base to apply to this FOA and its companion FOAs, RFA-HL-15-004 and RFA-HL-15-008.

Bioreactor technology is an essential part of the research and development pathway; however, existing devices lack necessary features for tissue engineered constructs to function clinically.  Research successes for a variety of simple bioreactor systems have shown sustained, but limited, in vivo function.  Systematic and validated analyses of tissue-specific growth and remodeling capacity are needed for advancing bioreactor systems, especially for those using stem cell technologies.  For example, devices for the growth of stem cells (SCs) should integrate SC expansion with subsequent mechanical stimulation to enhance functional differentiation for use in complex tissues.  Another challenge for cellular propagation is to establish stable protocols that do not require feeder layers and conditioned medium.  At the organ level, tailored lung tissue bioreactor design plans are needed for gas and blood exchange interfaces, whereas design of cardiac tissue bioreactors might emphasize electrical and mechanical forces.  Additionally, it may be possible to engineer 3D bone marrow organs that permit extensive blood stem cell self-renewal and hematopoiesis in vitro.  Given the complexity of engineered constructs, often containing a combination of cells, scaffolds, and other factors, special challenges exist for tissue engineered product characterization, which may affect its eventual manufacturing protocol and clinical utility.  Hence, there is an ongoing need for design innovation and parameter refinement of bioreactor systems, along with accepted protocols for standardization.

NIBIB joins this announcement consistent with its mission to lead the development and accelerate the application of biomedical technologies, through integration of engineering with the physical and life sciences, to advance basic research, and medical care.

Research Objectives

This program aims to support multidisciplinary small business teams in the development of complex, three-dimensional engineering systems for growing heart, lung, or bone marrow tissue.  Integrated devices will require a diverse array of scientific principles and technologies.  Ultimately, bioreactor designs should provide the most physiologically relevant environment to promote correct 3-dimensional tissue growth and maintenance, which is also efficient, safe and economical.  Such devices should be made commercially available and widely disseminated to researchers for application in the translational setting.

Specific Areas of Research Interest

Device design for research applications will likely be different from designs for clinical applications.  For research requirements, the bioreactor should provide for adaptability to the type and number of experimental conditions.  Whereas in contrast, clinical application designs need to meet GMP guidelines, which require robust production conditions and scale-up. 

Research examples appropriate for this FOA include, but are not limited to, those listed below:

• Bioreactors that incorporate optical imaging biomarkers and probes to effectively detect and measure cellular processes during tissue growth, remodeling and stabilization
• Approaches that incorporate microparticle materials to significantly reduce the expense in growing 3D cell aggregates, and which allow greater control over the kinetics of cell differentiation
• Systems that integrate controlled mechanical and electrical loading without compromise to sterility conditions
• Devices that robustly couple natural and/or artificial polymer synthesis to material formation and function for additive 3D tissue printing
• Bioreactors for lung research that incorporate multiple cell types, mimic mechanical forces (breathing), and provide air/liquid interfaces
• GMP standards for the bioreactor device, production process, scale-up, and test methods to characterize engineered tissue
• Methods to grow human tissues in a suitable animal model using human non embryonic pluripotent or multipotent progenitor cells (e.g., induced pluripotent stem cells)
• Tissue stasis technologies to support preservation of tissue following injury or to support extended storage or transport of transplant tissues or engineered tissues
• Use of new or improved bioreactor technology for more efficient and less costly clinical production of human blood cells from pluripotent or hematopoietic stem cells or progenitors

Areas of research that will not be considered responsive to this FOA include incremental refinement of mature technologies for cell production.  Applicants are strongly encouraged to discuss the proposed approach, concept, or strategy with Scientific/Research staff listed under Agency Contacts, to determine responsiveness to this FOA.

Metrics for Program Success

The majority of small businesses are developing tissue growth technologies devices primarily for the skin, cartilage, and bone, and tumor biology communities.  Movement of small companies into producing standardized tissue bioreactors for heart, lung, and blood tissue systems is an overarching programmatic goal.  The success of Phase I applications will be measured by evidence of the completion of developmental milestones.  Success of Phase II and Fast-Track applications will be measured by development of bioreactor systems that are either suitable for FDA-approved clinical studies or standardized devices that provide for long-term sterile matrix development and tissue maturation for use in the translational research setting.  Well-designed devices should markedly reduce the need and cost for expensive biologics.  Completed Phase II projects ought to show evidence of either licensing of their technology, merging with another business, product sales or submission of a Phase IIB application.