Date of Award

5-2013

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Legacy Department

Bioengineering

Advisor

Laberge, Martine

Committee Member

Zhang , Ning

Committee Member

Wen , Xuejun

Committee Member

Yao , Hai

Abstract

Bone tissue serves many functions, including structural support, protection of internal organs, and mineral and growth factor storage, to name a few. Moreover, human bone exhibits excellent mechanical properties, demonstrating superb compressive strength as well as significant elasticity, due to its collagen content. However, defects still occur at a relatively high rate in this tissue. Critical sized defects in bone are defined as defects that cannot form a union and heal on their own. These types of defects occur often, and typically require surgical intervention. The current gold standard treatment for critical sized defects in bone is the use of allografts and autografts. There are many issues associated with these methods, including donor site morbidity and the need for two surgeries. Recently, bone tissue engineering has emerged as a future alternative to bone grafting for treatment of long bone defects. Numerous strategies involving three basic components, biomolecules, stem cells, and engineered scaffolds, have shown promise in inducing sufficient bone regeneration. However, a common limitation of these strategies lies in their inability to generate bone tissue that mimics the organized microstructure of cortical bone. For this reason, the regenerated bone is often highly disorganized and possesses poor mechanical properties.
A relatively new concept in the field of tissue engineering is the concept of biomimicry. This approach aims to create a scaffold that mimics the natural tissue as closely as possible, including reproducing properties such as composition and microstructure. For bone tissue engineering, specifically, this most often achieved by fabricating highly porous ceramic constructs that resemble the structure of cancellous bone. These scaffolds have many excellent qualities including bioactivity, space for cells and new tissue ingrowth, and relatively decent mechanical properties. However, when utilizing these scaffolds, new tissue is often very disorganized and has poor mechanical properties.
Another biomimetic approach for bone tissue engineering, though not as popular, is to utilize nanofibers to mimic the cortical component of long bones. Aligned polymer nanofibril arrays are often used in tissue engineering applications due to their ability to mimic the aligned extracellular matrix of numerous tissues in the body, including bone. The hypothesis of this approach is that if a more organized bone structure is formed during the healing process, the time for the remodeling process to occur would be reduced. This is advantageous as it will allow cells to penetrate and migrate within the scaffold in order to regenerate the tissue. Aligned nanofibril arrays can easily be fabricated using a basic electrospinning device and a modified collection plate. This method does have a variety of advantages, including the ability to vary polymer types and tailor the degradation rate. However, this method isn't often utilized for bone tissue engineering due to the extremely poor mechanical properties of polymer nanofibers. Some researchers have investigated their use for bone tissue engineering, mineralized the surface of nanofibers to more closely mimic the structure while enhancing the bioactivity, though this does not help much with the mechanical properties.
To our knowledge, these approaches have not been used simultaneously in order to create a truly biomimetic construct that mimics the entire structure of the human long bone. Thus, the objective of this project was to optimize both of these techniques and then combine them in order to fabricate a bone tissue engineering construct that mimics the whole structure of human long bone. The first step was to create highly porous ceramic constructs that would mimic the structure of human cancellous bone. We did this by creating a composite structure composed of both hydroxyapatite and beta tricalcium phosphate. Using varying concentrations of both components, we were able to come up with a structure that suited our application. We then aimed to mimic the structure and arrangement of collagen fibrils in cortical bones' extracellular matrix by using a customized electrospinning apparatus that is paired with motorized collecting device developed in our lab, in order to spin small diameter, highly-aligned, loose nanofibril arrays. To further mimic the structure of cortical bone, we created a novel hydroxyapatite coating on the nanofibers surface to emulate the distinct relationship between collagen and hydroxyapatite in native bone. We then combined both structures in order to create a truly biomimetic long bone tissue engineering scaffold. These scaffolds were evaluated both separately and together in vitro for bone regeneration capabilities. Future studies include in vivo implantation into rabbit radial defects to assess regeneration and organization of new bone tissue.

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