Tissue Engineering and Dental and Craniofacial Regenerative Medicine Research AND Immunology and Immunotherapy Programs
Center for Integrative Biology and Infectious Diseases
OBJECTIVE
The goal of this initiative is to develop novel concepts and paradigms for patterning of tissue inflammatory microenvironments as a means to reconstruct of damaged oral and craniofacial tissues. To this end, this initiative will support multidisciplinary and interdisciplinary research on the development of biotechnology-driven strategies to promote resolution of acute and chronic inflammation, to inhibit tissue fibrosis and scarring, and to enhance endogenous healing and regeneration of oral and craniofacial tissues. Supported research will integrate advances in cell and developmental biology, stem cell biology, immunology, and signal transduction with those in material science, drug delivery, nanotechnology, tissue engineering and other bioengineering disciplines. Specifically, this initiative seeks to stimulate research that will augment inflammation resolution and reconstruction of oral and craniofacial tissues on topics such as: 1) identification and validation of biomarkers, signaling pathways, and gene networks defining acute and chronic inflammation, and predicting success vs. failure of inflammation resolution; 2) discovery and validation of therapeutic agents, including small molecule therapeutics, that specifically target different steps of the inflammatory process, and tissue regeneration; 3) design of precise temporal, spatial and combinatorial delivery and release to tissues of therapeutic molecules, genes, gene products, and cells to promote inflammation resolution and enhance tissue regeneration; 4) development of approaches for controlling inflammatory cell adhesion, migration, and homing to the site of injury to promote inflammation resolution and tissue regeneration; 5) development of in vitro and in vivo assay systems, including high throughput assay systems, for robust screening of functional endpoints of inflammation resolution and tissue regeneration; and 6) development of non-invasive imaging and cell tracking methodologies to aid in the assessment of tissue inflammatory and regeneration status.
BACKGROUND
Inflammation is a highly regulated physiological response that had evolved to provide protection and to promote healing in the setting of infection and injury. However, unresolved acute inflammation can progress into chronic inflammation, a process hallmarked by a continuous cycle of tissue destruction, as well as fibrosis, and scarring. Many clinical syndromes, including those of the oral and craniofacial tissues, such as periodontitis, pulpitis, mucositis, and some forms of temporomandibular joint disorders, share underlying chronic inflammatory mechanisms. In order to develop effective therapeutic strategies for prevention, diagnosis, and treatment of these conditions it will be important to understand the molecular and cellular mechanisms of inflammation resolution, and to develop effective approaches for its precise and predictable control.
Important insights have already been made into the mechanisms of inflammation resolution. For example, it has been found that resolution of inflammation is not a passive process of simple inflammatory suppression, but is rather an active multistage sequence of temporally and spatially regulated events controlled by inflammatory cells, cytokines, chemokines, extracellular matrix (ECM) molecules, proteases, as well as by the newly identified endogenous ‘‘pro-resolving’’ lipid mediators called lipoxins, resolvins and protectins. These lipid mediators have recently become the focus of intense investigation as promising molecular targets for new drug discovery to augment inflammation resolution and combat chronic inflammation. Unlike the traditional anti-inflammatory drugs, which inhibit inflammation, the emerging “pro-resolving” drugs are designed to mimic physiological resolution of inflammation.
Given the temporal, spatial and combinatorial complexity of normal inflammatory response and inflammation resolution, predictable control of these processes represents a formidable challenge. It is unlikely that this control can be achieved using traditional therapeutic modalities and traditional modes of biomolecule delivery to tissues. On the other hand, the tools of modern bioengineering and nanotechnology are capable of providing powerful means to predictably shape the composition, three-dimensional architecture and the dynamics of tissue microenvironments. As such, these tools are uniquely suited to control inflammation resolution and reconstruction of diseased oral and craniofacial tissues. Important examples of such new tools include, but are not limited to: cell-instructive ECM-like materials that can communicate multiple regulatory signals to the tissues in a temporally and spatially defined fashion and display specific cell-adhesive and homing signals, “smart” self-assembling biomaterials that can alter their properties in response to specific microenvironmental cues, material fabrication technologies that allow creation of tissue-like structures with defined 3-dimensional architectures mimicking normal tissue organization, and new drug delivery methodologies allowing targeted delivery to tissues of multiple biomolecules with defined kinetics.
The NIDCR recognizes the exciting window of opportunity for advancing reconstruction of diseased oral and craniofacial tissues created by these advances in basic biological sciences and bioengineering. Taking full advantage of these new advances will require a strong multidisciplinary and interdisciplinary effort. Fostering this cooperation is at the center of this initiative.
Examples of research topics that would fill the current gaps of knowledge include, but are not limited to:
- Development of biomarkers predictive of successful vs. unsuccessful inflammation resolution and transition of acute inflammation into chronic inflammation
- Elucidation of signaling pathways and gene networks that control transition of acute inflammation into chronic inflammation
- Elucidation of signaling pathways and gene networks that promote regeneration of functional oral and craniofacial tissues vs. fibrosis and scarring
- Identification and characterization of cytokines, chemokines, ECM and inflammatory cells controlling inflammation resolution, chronic inflammation, tissue regeneration, fibrosis and scarring
- Identification and characterization of cell types responsible for oral and craniofacial tissue regeneration and fibrosis
- Development of non-invasive and dynamic imaging of inflammatory tissue microenvironment
- Development of strategies for targeted controlled delivery and presentation to tissues of therapeutics and bioactive gene products that can predictably modify tissue microenvironment
- Development of strategies for targeted controlled delivery and release to tissues of multiple therapeutics and bioactive gene products with predetermined kinetics
- Development of strategies for directing cell migration and homing in vivo
- Development of strategies for guiding in vivo tissue self-assembly using scaffolds, including nanoparticle-based scaffolds
- Development of efficient high-throughput in vitro and in vivo assays for screening of functional endpoints of inflammation resolution and tissue regeneration