Self-assembled Rosette Nanotubes for Drug Delivery and Bone/Cartilage Tissue Regeneration.

摘要

Today, a variety of implants (such as bone cements, titanium fixative devices and artificial joints) are widely used in orthopedics, especially for bone and cartilage repair. However, conventional implant materials (like micron-rough, nano-smooth metals, ceramics and polymers) and traditional implantation techniques (such as invasive open surgeries) continuously result in high costs, long recovery times, unacceptable failure rates and significant inconvenience for patients. Therefore, research efforts are continuously seeking novel solutions including nanotechnology to more quickly and efficiently repair bone and cartilage. For example, rosette nanotubes (RNTs) are novel biomimetic self-assembled supramolecular structures whose basic building blocks are DNA base-pairs. They can dissolve in physiological environments and solidify into a viscous gel at body temperatures binding to severed tissue. Moreover, RNTs are similar in size to natural collagen in bone and cartilage and previous studies have found that they can enhance cell adhesive protein adsorption and improve cell attachment and long-term functions.;In this thesis, the potential of RNTs to serve as a new generation of implant materials was investigated. Importantly, the ability of RNTs to improve bone and cartilage repair was tested from three aspects: material properties, drug/growth factor delivery and biological functions. Specifically, from the material property and biological interaction point-of-views, RNTs presented excellent cyto- and bio-compatibilities as demonstrated in vitro and in vivo. Specifically, RNTs increased osteoblast (bone forming cells) functions and fibroblast-like type B synovial cell (cartilage precursor cells) chondrogenic differentiation by either coating them on titanium or mixing them with hydrogels. Moreover, RNTs enhanced the adhesive strength of hydrogels by binding to severed artificial tissue. For RNT drug/growth factor delivery and biological assays, several bioactive short peptides were investigated from bone morphogenetic protein-7 (BMP-7) to improve bone regeneration and dexamethasone was selected as a model drug for both bone and cartilage applications. In vitro and in vivo results showed that RNTs were able to be either chemically modified with such short peptides or physically incorporated with drugs. Especially, drugs released from RNTs extended over time and were bioactive.;In addition, to reduce the recovery time and limit the pain and inconvenience of orthopedic surgeries, in situ injection techniques were investigated here. The purpose of this effort was to inject RNT composites to heal bone or cartilage defects by combining the self-assembly properties of RNTs with polymer composites. In this manner, an electrospinning injection technique was designed for cartilage repair. In vitro results showed that RNTs could be directly electrospun into cartilage defects with fibroblast-like type B synovial cells or chondrocytes (cartilage forming cells) to bond to severed collagen and promote cell adhesion and subsequent functions. A syringe injection was also investigated for bone repairs. In vivo results showed that RNT composites were injected and solidified in the bone defects created in the tibia and femur of pigs. Moreover, RNT composites enhanced bone healing after 8 weeks from X-ray intensity measurements and histology stains as compared to negative (empty) and positive (autograft) controls. In addition, BMP-7 short peptides released from such composites further improved bone regeneration. Thus, the present thesis provides a novel nano-featured biomaterial (RNTs) that can be used in in situ injection techniques to improve bone and cartilage repair.