Biologically Inspired Biomaterials for Musculoskeletal Tissue Engineering

Abstract

Musculoskeletal system includes the bones of the skeleton and the cartilage, ligaments, tendons, and other connective tissue that stabilize or connect the bones which together provide the structural support and produce controlled body movements. The biological and mechanical properties of these closely associated tissues varies with the composition of extracellular matrix which also define their specific functions. There are various clinical issues associated with musculoskeletal tissues which affects the overall functioning of the system. Diseases such as osteoporosis, arthritis, muscular dystrophy, rotator cuff tear, anterior cruciate ligament injuries, and different other trauma conditions such as fractures and dislocations are common among human populations. Current surgical techniques for the musculoskeletal system damages can be often limited by the suitable availability and quality of materials, such as grafts and other implant. This has led to the exploration and development of novel therapeutic methods based on biomaterial based tissue engineering. Despite of the previous accomplishments in the musculoskeletal tissue engineering, translation of tissue engineering products in to clinics are still at infancy stage mainly due to the biochemical and structural complexities of these closely associated tissues. Due to this complexities, more smart biomaterial designs may needed for the future use of biomaterials in clinics. Herein, inspired from the natural complexities of musculoskeletal tissues, I developed biomaterials with spatially regulated biochemical and structural properties and examined their applicability in in vitro and in vivo musculosketal tissue regeneration. Electrospun poly(l-lactic acid) (PLLA) nanofibers with different morphology were fabricated to mimic the structural properties of the native tissues. Further, I used mussel inspired polydopamine (PD) chemistry for the surface modification on the PLLA nanofiber surfaces which alloweded efficient conjugation of different biomolecules on the nanofiber surfaces. More notably, the surface immobilized growth factor along with suitable nanofiber morphology induced the in vitro and in vivo bone regeneration and guided the collagen assembly and mechanical properties similar to the native bone. In order to engineer bone-soft tissue interface, I developed spatially regulated surface modified nanofiber to mimic the gradient properties of the interface tissues. By exploiting the close relation between oxygen availability and dopamine polymerization I developed a gradient in PD coating on the material surface. Notably, PD gradient on the material surface allowed controlled immobilization of different secondary molecules such as cells, growth factors, peptides, bio minerals etc. I then used PD gradient nanofibers to spatially restricted immobilization of platelet derived growth factor (PDGF), which allowed graded tenogenic differentiation of adipose derived stem cells (ADSCs) for development of in vitro mimicking bone-tendon insertion graft. Finally, I detailedly examine the role of different mineral concentration on osteogenic and chondrogenic differentiation of ADSCs and generated a mineral gradient on the nanofiber surface. Collectively, I fabricated biomaterial substrate with spatially restricted biochemical and structural properties inspired from native tissue features using electrospun nanofiber and mussel inspired chemistry and which was efficient in in vitro and in vivo engineering of bone and bone-interface tissues. Such designing concepts could be explored further of translation of musculoskeletal tissue engineering products in to clinics.