Date of Completion


Embargo Period



Biomaterials, collagen-hydroxyapatite composites, drug delivery, tissue engineering, coating, intrafibrillar

Major Advisor

Mei Wei

Associate Advisor

Mark Aindow

Associate Advisor

Xiuling Lu

Associate Advisor

David W. Rowe

Associate Advisor

Puxian Gao

Field of Study

Materials Science and Engineering


Doctor of Philosophy

Open Access

Open Access


Collagen, the most abundant protein, and hydroxyapatite, the main component in natural bone, are usually used as a biomimetic composite in many biomedical applications due to their excellent biocompatibility, great biodegradability, and flexible structural and compositional alterability. In this dissertation, a systematic study was conducted to design, develop and characterize collagen-hydroxyapatite-based (Col-HA-based) composite materials and explore their wide biomedical applications.

First, the biomeralization mechanism of collagen was investigated. The degree of intrafibrillar mineralization of Col-HA fibrils was enhanced by the employment of carboxyl-rich brushlike polymers, which is believed to be capable of replicating the sequestration functions of non-collagenous proteins (NCPs) that regulate collagen mineralization. This will substantially broaden the application of Col-HA composites by providing a great flexibility to adjust the mineral content. The composites can be as rigid as bone, as compliant as tendon, or demonstrate a gradient from rigid to compliant like cartilage.

Second, collagen-based nanoworms (NWs) with different sizes were self-assembled from collagen triple helices by precisely controlling the polymerization process of collagen molecules to be used as long circulation drug delivery vehicles for tumor treatment applications. Intrafibrillar mineralized Col-HA nanoworms were developed with tailored stiffness and surface properties. As a result, the mineralized Col-HA nanoworms with appropriate stiffness and size demonstrated significantly prolonged blood circulation time (> 5 days) that is one of the key factors influencing the therapeutic payload delivery efficacy to the tumor site. More importantly, such developed NWs are pH-sensitive material. It was found that over 80% loaded drugs (doxorubicin) were released within 24 h at the tumor environment (pH 5). In comparison, only ~35% of loaded drugs were released within the same period at the biological pH (7.4). Moreover, magnetic nanoparticles (NPs)were grafted onto the NWs to grant the materials with magnetic targeting administration ability in the presence of external magnetic forces.

Third, novel intrafibrillar mineralized Col-HA-based scaffolds, constructed in either cellular or lamellar microstructures, were established through a biomimetic method to enhance the new bone regenerating capability of tissue engineering scaffolds. Moreover, two essential elements, Fe and Mn, were substituted into intrafibrillar mineralized Col-HA lamellar scaffolds to improve the osteogenic ability of the material. Enhanced MC3T3 cell adhesion and proliferation were observed with the incorporation of ions. It was revealed that the incorporation of the Fe/Mn ions significantly promoted the osteogenic differentiation of mouse bone marrow mesenchymal stem cells (BMSCs) through fluorescence-activated cell sorting (FACS), fluorescent microscopy and RT-PCR analysis. The in vivo new bone formation potential of these materials was also compared using a mouse calvarial defect model. The results demonstrated that these scaffolds are in favor of new bone formation and the groups with ion incorporation exhibited better new bone forming ability. This provides a simple but meaningful strategy to create smart Col-HA-based scaffolds for bone tissue regeneration.

Last, a Col-HA composite coating was deposited onto Ti-6Al-4V, the most widely used metal implant material, using a novel one-step biomimetic process to grant the inert substrate with excellent bioactivity. The cross-sectional characteristics of the coating were thoroughly investigated and reconstructed in 3D using focused ion beam (FIB) and Avizo. By further analyzing the porosity distribution along the coating depth through RStudio, it was revealed that the adhesive strength is more associated with the average pore volume, rather than the total pore volume, at the coating interfaces. Moreover, by observing the cross-sectional characteristics of the cell-coating-substrate, it was found that large number of relatively big pores at the coating surfaces favored osteoblast adhesion and proliferation. The addition of collagen molecule further promoted the biocompatibility of hydroxyapatite coating but with slight sacrifice of mechanical properties.

In summary, the Col-HA-based composite materials have been successfully developed as either NWs for targeted drug delivery and tumor therapy, or micro fibrils and scaffolds for tissue engineering (bone, cartilage, tendon), or biomimetic coating for hard tissue replacement.