Building Complex 3-Dimensional in Vitro Human Musculoskeletal and Skin Tissue Models (R43)

Current biomedical research is frequently carried out in a 2-dimensional (2-D) tissue culture environment, despite the fact that human tissues are 3-dimensional (3-D) structures that require the interactions of multiple cell types with one another and with the environment to maintain their shape and function. Most primary cells in 2-D cultures quickly lose in vivo properties such as tissue-specific gene expression, cell polarity, and cell-cell and cell-matrix contacts. Increasing knowledge about cell biology, materials science, and microfabrication technologies enables scientists to engineer functional units of human tissues (i.e., 3-D human tissue models). Further development of these highly controllable in vitro model systems would allow them to more closely mimic functions of human tissues or organs so that they could be used to study normal developmental biology or disease pathogenesis, or for drug screening. For example, patient-specific models could be generated to study rare diseases or diseases where animal models are not available. They would go beyond the “flat biology” to increase the complexity and diversity of in vitro models and assays, and bridge the gap between simple cell cultures and the full complexity of animal models. They also have the potential to minimize and/or replace animal testing, and may be a better alternative than animal models to study humans.

In 2011, the NIH, collaborating with the U.S. Food and Drug Administration and Defense Advanced Research Projects Agency, launched a Common Fund Program “Tissue Chip for Drug Screening” to develop 3-D human tissue chips that accurately model the structure and function of human organs. The program now resides in the NCATS (http://www.ncats.nih.gov/tissuechip).

In November of 2014, the NIAMS invited a group of leading scientists for a roundtable discussion on the “Opportunities and Challenges in Developing 3-Dimensional Human Tissue Models to Study Musculoskeletal and Skin Physiology and Pathophysiology” to assess this area of research. That discussion, as well as input received from participants before the meeting, helped us identify common as well as NIAMS-specific opportunities and challenges (http://www.niams.nih.gov/News_and_events/Meetings_and_Events/Roundtables/2014/3-D_models.asp).

The NIAMS seeks to fund Phase I R43 SBIR grant applications from small businesses to develop novel complex 3-dimensional in vitro human musculoskeletal and skin tissue models that fit into the NIAMS mission (http://www.niams.nih.gov/About_Us/Mission_and_Purpose/mission.asp). These engineered 3-D human tissue or organ models would provide alternatives to animal models of diseases and animal testing, and enable the study of human tissue physiology and disease pathophysiology in vitro and ultimately lead to better therapies that prevent or cure diseases. Applicants may propose to engineer novel in vitro models and/or develop novel technologies to meet some of the specific challenges in building these models.

Proposed technology and/or product developement needs to use human cells in the context of in vitro 3-D culture, and must be directly relevant to NIAMS mission areas. This FOA is not intended to support research using non-human cells or animals..

Examples of applications that are responsive to this FOA include, but are not limited to, the following:

• Tissue model systems that do not currently exist, including disease models for osteoarthritis (OA), rheumatoid arthritis (RA), and rare diseases
• Add complexity to existing model systems, such as mechanical/electrical stimuli or inflammatory components
• Mineralized bone models that include osteoblasts, osteoclasts, osteocytes, and the bone marrow compartment and their response to various physiological stimuli to advance the development and testing of potential osteoporosis therapies
• Functional skeletal muscle-bone models that are important for exercise and muscle-disease-related research
• Sophisticated skin models that incorporate multiple skin components such as hair follicles, vasculatures, nerves, sweat glands, immune cells, and fat
• Models to study innate and adaptive immune responses in the presence and absence of different cell types or triggers
• Models to elucidate gene regulatory networks and signaling pathways that modulate stem cell in vivo behavior during development and tissue repair
• Universal culture media that mimic the blood’s ability to transport a wide variety of peptides, proteins, and other molecules
• Alternative to polydimethylsiloxane (PDMS) which address considerations of adsorption of hydrophobic moieties
• Development of efficient scalable differentiation protocols that allow the creation of complex musculoskeletal and skin 3-D models from patient-specific iPS cells
• Engineering functional stem cell niches in 3-D musculoskeletal and skin models

See Section VIII. Other Information for award authorities and regulations.