Collagen turnover-stimulated gene delivery to enhance tissue repair

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1605130 - SullivanThis project will develop new materials that can ultimately improve the speed and efficacy of healing in chronic wounds and other injured tissues. Many treatment approaches for difficult-to-heal wounds involve the topical application of healing factors such as growth factor (GF) proteins. However, GF proteins are needed at specific concentrations over a well-defined time course, and topical delivery regimens often fail to produce desired delivery profiles leading to incomplete repair. Accordingly, this project will develop and evaluate a fundamentally new gene delivery approach that will enable improved control over GF delivery. To accomplish this effect, the project will produce biomaterials in which gene particles are integrated into the fibers of collagen gels that are designed to degrade and release GFs at the right time at the local tissue healing site. Completion of the project will result in the acquisition of new scientific understanding at the interface of tissue repair biology and biomaterials engineering by illuminating the ways in which cellular repair mechanisms may be altered when cells encounter engineered materials that mimic native tissues. Ultimately, these material platforms can be applicable in multiple tissue engineering applications such as wound repair and implant functionalization. The efforts will also have broad impacts on bioengineering education and career development of underrepresented students, through new research, classroom, and career development opportunities to graduate students, undergraduates, and high school students. These activities will be facilitated through integration and leadership from the PIs in a variety of on-campus training and mentoring programs.Aberrant extracellular matrix (ECM) synthesis and turnover processes define the success or failure of healing in a wide variety of regenerative medicine applications. Accordingly, improved strategies to understand and manipulate ECM-driven cell growth and growth factor signaling would have enormous benefits in multiple tissue repair technologies. The investigators are developing an innovative approach to improve control over the dynamics and location of growth factor delivery by harnessing ECM remodeling to stimulate growth factor gene release and expression. In particular, investigators will exploit their expertise in designing collagen-mimetic peptide (CMP) nanostructures to engineer DNA polyplex-modified collagen scaffolds that induce localized, high efficiency GF expression coordinated with tissue repair kinetics. The development of CMP-linked gene delivery technologies has transformative potential through its ability to both harness as well as enrich and orchestrate the highly dynamic cellular repair cascades underlying healing. Furthermore, the studies provide unique opportunities to ask fundamental questions at the interface of regenerative biology and biomaterials engineering: (1) Does CMP-mediated integration of gene nanostructures within collagen scaffolds permit gene retention over time periods commensurate with the stability vs. turnover of the scaffold? Are native endocytic collagen processing pathways altered when nanostructures are integrated via triple-helical interactions with CMPs? and (2) Does integration of gene nanostructures within collagen enhance the stability of the genes in a manner akin to ECM-based stabilization of protein factors and viruses? These questions are addressed through two objectives aimed at (1) optimizing the localization and activity of CMP/polyplex-linked collagens for sequestration and delivery of active gene constructs over prolonged time periods, using both in vitro and in vivo repair models to express model genes; and (2) elucidating key design parameters controlling polyplex retention, CMP/polyplex/collagen processing, and improved activity of expressed growth factors such as PDGF. These approaches will ultimately be useful as a versatile biomaterials platform able to stimulate improved healing in a variety of regenerative medicine applications. The project will advance the use of collagen-mediated gene delivery in multiple tissue engineering applications such as wound repair and implant functionalization. The research activities will also serve as a catalyst to provide new research, classroom, and career development opportunities to graduate students, undergraduates, and high school students, particularly through integration and leadership from the investigators in a variety of on-campus training and mentoring programs.