Engineering Composite Nanofibrous Scaffolds for Repairing Segmental Bone Defect

Project: Research project

Project Details

Description

Large extremity bone defects resulting from blast injuries are common among active duty military personnel. These defects are responsible for about 64% of Soldiers' inability to return to duty, permanent disability, and amputation. Currently, autografts and metal implant procedures are a gold standard for bone defect replacement; however, they suffer from limited availability and a mismatch in mechanical and biological properties, resulting in failure or incomplete bone healing. Thus, there is a great need for developing biological graft substitutes with enhanced biological properties that allow for accelerated bone regeneration.

Strategies used to heal complex large bone defects rarely result in a mechanically stable bond between the graft and the bone. Various approaches allow for a small variety of bone-stimulating molecules to be incorporated into the graft, resulting in improper bone growth. The knowledge gap in synthetic graft development is the precise understanding of which cell-derived biomaterials will best stimulate infiltrating cells to deposit a mechanically strong bone. Also, the limited understanding of the influence of inner structure of a graft on bone deposition has significantly hindered the development of bone grafts. Previous studies suggest that the architecture and the osteogenic cue composition of synthetic grafts are vital to their integrity, bone fusion, and the healing process. Thus, optimization of a graft's inner architecture promises to accelerate bone growth within the graft and produce a mechanically stable bone. A strategy that uses cell-derived biomaterials can vastly exceed the number of bone-stimulating molecules found in demineralized bone preparations.

The proposed research will focus on the Topic Area of Nanomaterials for Bone Regeneration. The technology addresses three Areas of Encouragement: (1) promoting neovascularization and bone ingrowth, (2) recruitment of endogenous cells to facilitate bone regeneration and osseointegration, and (3) regeneration of segmental/large bone defect in a load-bearing femur. The primary objective of this work is to design and characterize a novel structured nanocomposite (bone graft substitute) as an alternative to biological bone grafts. The nanocomposite scaffold offers mechanical strength and bioactivity though cell-derived extracellular matrix (dECM) that contains a myriad of morphogenic cues to promote neovascularization, recruitment of endogenous cells to enhance mineralized matrix deposition, and osseointegration of the synthetic bone graft substitute. This work will be carried out under three specific aims. Studies outlined under Aim 1 are to optimize and characterize nanocomposite for its dECM content, in vitro mineralization, and mechanical strength. Aim 2 will identify two best conditions and compositions of dECM resulting from various cell sources in promoting osteogenic differentiation of bone marrow derived stromal cells (BMScs). The efficacy of these nanocomposites in bridging critical sized long bone defects in rat femurs will be evaluated over a period of 12 weeks under Aim 3. This approach combines the benefits of engineered biodegradable scaffold properties with bioactivity of the cell derived ECM to promote bone healing. Additionally, studies are deigned to characterize and optimize this approach for any potential biocompatibility issues arising from dECM processing in preclinical models.

The research findings from this work can ultimately be applied towards the development of synthetic grafts for patients and combat personnel with significant bone loss. Soldiers that sustain injuries to their lower extremities in the battlefield are in great need of these grafts. The synthetic bone grafts have a potential to heal bone damage without the need for additional surgeries to harvest autografts, thus eliminating serious complications such as infection and chronic pain. The improved synthetic grafts will help these patients heal, return to duty quicker, and bypass extensive rehabilitation protocols and revision surgeries.

Additionally, the composite nanofibrous scaffold design in this project will help in creating tissue engineered grafts that better mimic native bone composition and enhance the graft's capacity to fully integrate with patients' bones. The project is expected to validate the concept of reducing the presence of inhibitory polymers in the graft while designing its architecture to direct organization of bone tissue deposition to increase its mechanical strength. The research will establish a foundation for further refinement of biomolecules responsible for greater mineral deposition and complete bone healing. The novel concept of combining cell-derived biomaterials from multiple cell sources can find its applications in many tissue reconstructive procedures. If proven effective, these concepts can have a tremendous benefit for injured Soldiers and civilians with complex multi-tissue injuries by helping them regain functionality faster.

StatusActive
Effective start/end date1/01/19 → …

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