Optimally Porous and Biomechanically Compatible Scaffolds for Large-Area Bone Regeneration

Abstract

Large-area or critical-sized bone defects pose a serious challenge in orthopedic surgery, as all current treatment options present with shortcomings. Bone tissue engineering offers a more promising alternative treatment strategy. However, this approach requires mechanically stable scaffolds that support homogenous bone formation throughout the scaffold thickness. Despite advances in scaffold fabrication, current scaffold-based techniques are unable to support uniform, three-dimensional bone regeneration, and are limited to only the scaffold surface in vitro and in vivo. This is mainly because of inadequate scaffold pore sizes (<200 μm) and accessible pore volume, and the associated limited oxygen diffusion and vascular invasion. In this study, we have adopted a method combining microsphere-sintering and porogen-leaching techniques to fabricate scaffolds with an increased accessible pore volume. Of the scaffolds developed, moderately porous poly(85 lactide-co-15 glycolide) (PLGA) microsphere scaffolds were selected as most advantageous, since they retain mechanical strength in the range of human cancellous bone and display a significantly higher accessible pore volume, which is attributed to an increased percentage of larger pores (i.e., size range 200-600 μm). Unlike control scaffolds with a limited pore size and an accessible pore volume, moderately porous scaffolds displayed increased oxygen diffusion, pre-osteoblast cell infiltration, proliferation, and survival throughout the entire scaffold. Furthermore, moderately porous PLGA microsphere scaffolds displayed enhanced and homogenous mineralization in vitro. Since these newly designed moderately porous scaffolds are weight bearing, are fully osteoconductive, and have the ability to support vascularization, they may serve as effective scaffolds for large-area bone defect repair/regeneration. In addition, this study demonstrates the ability to modulate scaffold porosity and, in turn, to develop oxygen tension-controlled matrices that are effective for large-area bone regeneration.

Enhancing the bioactivity of Poly(lactic-co-glycolic acid) scaffold with a nano-hydroxyapatite coating for the treatment of segmental bone defect in a rabbit model

“…Owing to these features, porous PLGA scaffolds have been widely used in tissue engineering, including for the treatment of bone defects. 6,[27][28][29][30] While PLGA scaffolds have many advantages, their limited abilities regarding osteoconduction and osteoinduction hinder their application in bone tissue engineering. The surface characteristics of biomedical implants play an important role in implanting and eventual osteointegration.…”

The rational use of animal models in the evaluation of novel bone regenerative therapies

“…Advanced hydrogels, naturally derived collagen and gelatin gels as well as synthetic polyethylene glycol and poly-vinyl alcohol-based hydrogels, serve as matrices for other products and mimic the extracellular matrix topography [74][75][76]. Biomaterials with immunomodulatory strategies, such as artificial extracellular matrices (ECMs) (hydrogels, ECM coatings) and materials with surface property modulation, have the ability to modify the immune function and improve bone repair and regeneration [25,77].…”

Hybrid extracellular matrix design for cartilage‐mediated bone regeneration

“…Although it is a simple approach, the amount of the regenerated bone is limited in volume, such that the strategies cannot be applied for large bone defect repair. [1][2][3] This is mainly because the intramembranous ossification (IO) process lacks the vascularization step. Despite numerous vascularization strategies, vascularized bone regeneration is still a significant challenge.…”

“…Therefore, this work focused on establishing the best combination of the hyaluronan and fibrin hydrogels that would closely mimic the ECM microenvironment necessary for differentiation of progenitor stem cells into hypertrophic-cartilage template. 2 , and subsequently 20unit/mL of thrombin. In case of encapsulating cells, a predetermined cell suspension volume was resuspended in the hydrogels first before the addition of any crosslinker to ensure uniform distribution of cells.…”