The potential of biomimesis in bone tissue engineering: lessons from the design and synthesis of invertebrate skeletons

Abstract

Synthetic bone replacement materials are now widely used in orthopedics. However, to date, replication of trabecular bone structure and mechanical competence has proved elusive. Maximization of bone tissue attachment to replacement materials requires a highly organized porous structure for tissue integration and a template for assembly, combined with structural properties analogous to living bone. Natural structural biomaterials provide an abundant source of novel bone replacements. Animal skeletons have been designed through optimization by natural selection to physically support and physiologically maintain diverse tissue types encompassing a variety of functions. These skeletons possess structural properties that provide support for the complete reconstruction and regeneration of ectodermal, mesodermal, and bone tissues derived from animal and human and are thus suited to a diversity of tissue engineering applications. Increased understanding of biomineralization has initiated developments in biomimetic synthesis with the generation of synthetic biomimetic materials fabricated according to biological principles and processes of self-assembly and self-organization. The synthesis of complex inorganic forms, which mimic natural structures, offers exciting avenues for the chemical construction of macrostructures and a new generation of biologically and structurally related bone analogs for tissue engineering.

Introduction

Bone as an organ is a complex, highly organized, mineralized tissue that consists of a structural hierarchy of collagen-based microstructures in association with cartilage, hemopoietic, and connective tissues. Throughout life, the skeleton is constantly being formed and resorbed, events that are necessary for normal skeletal tissue integrity and maintenance of mineral homeostasis. With increasing age, an imbalance between bone resorption and formation can lead to reduced skeletal bone mass, and the requirement to replace or restore the function of traumatized or degenerated bone, or lost mineralized tissue. With an increasing aging population, techniques to regenerate bone have now become a major clinical need in the developed world. In the USA alone, 280,000 hip fractures, 700,000 vertebral, and 250,000 Colles fractures occur each year at a cost of $10 billion.28 Each year in the UK there are over 50,000 primary hip replacement operations at a cost of £250 million. This is expected to rise to 65,000 operations by 2026. Furthermore, 30%–50% of these hip operations will require subsequent revision surgery and, in a large proportion, bone augmentation will be necessary to facilitate this surgery.

The paucity of techniques in reconstructive surgery and trauma emphasize the need for alternative bone formation strategies. Current approaches include the use of biomaterials, autologous and allogeneic bone to restore the function of traumatized or degenerated connective tissue, or for the replacement of lost mineralized tissue. However, the failure of complete resorption of autogenous bone, difficulties in shaping the bone graft to fill the defect, and often a lack of sufficient material precludes the universal use of autogenous bone for orthopedic application. In addition, the use of allogeneic bone for transplantation, despite being more readily available, carries potential risks of cell-mediated immune responses to alloantigens and transmission of pathogens such as human immunodeficiency virus (HIV) from viral contamination as well as the need for immunosuppression.

Although regimes for stimulating bone formation hold the promise of significantly large increases in bone density, they have yet to become available. The development and application of bone tissue engineering offers alternative solutions with important potential for reconstruction and augmentation. The formative approach involves the combination of mesenchymal stem cells or progenitor bone cells from the patient with a scaffold to support and guide regeneration together with judicious selection of appropriate growth factors to induce bone formation.39 At present, protocols exist to extract committed mesenchymal stem cells from the marrow cavity, which can be expanded to provide cells with osteogenic capacity.7 Moreover, the progenitor cells can be enriched using the STRO-1 antigen from a CD34⁺ fraction.23, 52, 55 A key requirement in the differentiation and subsequent mineralization of these precursor cells is the design of the scaffold upon which the cells are seeded. This should effectively deliver and support these precursor populations and stimulate them to function to type. The synthetic bone scaffold should conduct bone deep inside the structure and fuse on the periphery with surrounding tissues if new functioning bone is to be generated.

Biomimetic materials chemistry has sought to reproduce in synthetic systems aspects of the complex skeletal structures that occur in nature and thus generate accurate and specifiable biomaterials. It is now possible to extend beyond methods that employ preformed natural scaffolds and use synthetic analogs of the biological frameworks. This review describes the current use of natural inorganic skeletons as bone regeneration scaffolds and then examines some recent developments in the synthesis of biomimetic inorganic frameworks. The current advances in biomimesis suggest that it is timely to consider biomineral-inspired approaches as a springboard for the next generation of biologically and structurally realistic bone analogs for orthopedic application.