EAGER: (ST2) Engineering Biomaterials that Integrate in the Native ECM of Cells.

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Non-technical abstract:Biomaterials are materials that interact with biological systems, and are therefore an essential component for fundamental biology studies, medical applications, and engineering tissues. However, current biomaterials are designed to interface and interact with cells and tissues, and cells cannot actively remodel and incorporate biomaterials into the final cell generated tissue. Inspired by the Square-Table-2 meeting, this project proposes to design Integrative Synbio-Materials (ISMs) as a novel class of biomaterials that cells recycle and integrate into newly built tissue. The researchers hypothesize that ISMs can lead to engineered tissues with novel properties. To test this hypothesis, the research team aims to apply recently developed synthetic biology approaches to incorporate non-standard amino acids in extracellular matrix proteins, which serve as linker molecules to synthetic biomaterials and as such introduce novel chemistry into engineered tissue. Success from this project brings about a paradigm shift from ‘materials that interface with tissues’ to ‘materials that integrate into tissues’ and provides a new platform to study cell-extracellular matrix interactions in their native tissue environment in vivo, to engineer tissues and organs, and to deliver drugs. This research, conducted at the Biological Design Center at Boston University, is tightly coupled to a strong education plan. The project trains students at graduate and undergraduate levels, across the fields of synthetic biology, tissue engineering, and material science, for productive careers in the 21st century scientific workforce. Students will have ample opportunities to learn state-of-the-art technologies, present at international conferences, and connect with research communities in the greater Boston area. Technical abstract:Recent advances in soft biomaterials such as polyacrylamide and polyethylene glycol with highly tunable biophysical properties, controllable degradation characteristics, and release kinetics of biochemical signals have provided unprecedented insights in cellular mechano-transduction and cell signaling. Despite these major advances, all biomaterials share one common limitation; that is cells cannot actively remodel and incorporate that material into the final cell generated tissue. Indeed, when adherent to a material surface, cells degrade the material while depositing new extracellular matrix (ECM) on the cell-material interface, but the biomaterial itself is not incorporated in the de novo tissue matrix. Thus, as cells remodel the cell-material interface, the biophysical or biochemical cues delivered by the material to control cell behavior are progressively lost. This limitation constrains the function of the engineered tissue that can be achieved. To overcome this fundamental limitation of biomaterials, this project proposes to develop Integrative Synbio-Materials (ISMs) as a novel class of biomaterials that cells recycle and use to assemble their ECM. Taking advantage of new insights in fibronectin remodeling, a ubiquitous ECM protein that is critical for the assembly of tissues during embryonic development and after injury, and the development of recoded E. coli strains that incorporate non-standard amino acids in proteins, this project aims to engineer synthetically modified fibronectin fragments that are tagged with azido residues, which provide reactive sites for crosslinking with polymeric materials such as dextran. Using synthetically modified fibronectin fragments as building blocks for ISMs, this project pursues the hypothesis that synthetic control of ISMs, such as tuning stiffness, is retained upon the incorporation of ISMs in de novo assembled ECMs. When successful, this project brings about a paradigm shift from ‘biomaterials that interface with cells’ to ‘biomaterials that integrate into the native ECM of cells’. This Division of Materials Research (DMR) grant supports research to develop Integrative Synbio-Materials (ISMs) as a novel class of biomaterials that cells recycle and use to assemble their extra-cellular matrix (ECM) managed by the Condensed Matter Physics (CMP) Program in DMR of the Mathematical and Physical Sciences (MPS) Directorate.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.