similar capabilities. Research in supramolecular engineering of functional biomaterials had sprouted from the need in (a) medicine for replacement materials and prosthetic devices with mechanical properties of soft and hard tissues such as skin, tendons, and bone, (b) agriculture and forestry for better crops and wood production, (c) food industries for improving production, quality, texture, processing, and manufacturing , and (d) the biomedical and human health area where there is an insatiable need for ultrasensitive detection methods, diagnostic tools, more effective therapies, and separation technologies.
During the last decade, many technologies based on nanomaterials and nanodevices have emerged [2-5]. The purpose of this chapter, however, is to focus specifically on the hierarchical architecture of bone tissue and how we can tailor the next generation of orthopedic implant materials using current knowledge in supramolecular engineering. First, we will begin by reviewing biological systems in the context of nanoscale materials. Second, for an appreciation of how nanoscale materials can be useful in the effective repair of the skeletal system, we will review the architectural schemes of bone as a supramolecular bionanomaterial. Third, we will examine the versatility of a new class of self-assembling organic nanotubes called helical rosette nanotubes (HRNs) and their potential in orthopedic implantology.
2.2 Bionanosciences: The Art of Replicating the Structure and Function of Biological Systems
We understand that a living cell contains a number of reacting chemicals orchestrated by a complex network of feedback loops and sensing mechanisms, within a finite space that allows various forms of energy to transit across its boundaries. We also understand that the cell is a dynamic structure, self-replicating, energy dissipating, and adaptive. Yet, we have little idea on how to connect these two sets of characteristics: How does life emerge from a system of chemical reactions? It is accepted today that the transition from the inanimate world of chemical reactions to that of living systems requires a new level of molecular and supramolecular organization. At the commencement of this process, biological systems build their structural components, such as microtubules, microfilaments, and chromatin in the range of 1-100 nm, a range that falls in between what can be manufactured through conventional microfabrication and what can be synthesized chemically. The associations maintaining these components and the associations of other cellular components seem relatively simple when examined at the atomic scale: shape complementarity, electroneutrality, hydrogen bonding, and hydrophobic interactions are at the heart of these processes. A key property of biological nanostructures, however, is molecular recognition, leading to self-assembly and to the templating of molecular and higher order architectures. For instance, complementary strands of DNA will pair to form a double helix (diameter = 2 nm). Then an octamer of histone proteins coils the DNA helix to generate the nucleosome (diameter = 11 nm). The latter forms a "bead-on-a-string" ensemble that folds into higher order fibers (diameter = 30 nm), which in few more self-assembly and templating steps lead to the familiar X-shaped chromosomes . This example illustrates three features of self-assembly: (a) the DNA strands recognize each other, (b) they form a predictable structure when they associate, and (c) they undergo a hierarchical and templated self-organization process leading to a functional chromosome. The process does not end here; the chromosomes are the repository of the genetic information and are thus in a constant and dynamic relationship with the cellular maintenance and replication machinery.
A comparison of synthetic self-assembling nanoscale materials and biological materials reveal some key differences. First, many biological materials possess well-defined hierarchical architectures organized into increasing size levels adapted to meet the functional requirements of the material. If we zoom in and out of these structural entities, we observe recognizable architectures ordered as substructures with scales spanning several orders of magnitude from whole organisms to subnanometer components. Such pervasive tendency for biological materials to undergo a hierarchical organization confers unique physical and chemical properties rarely paralleled in human-made materials. For example, bones are organized into finer structures made up of cells, collagen, and minerals. This arrangement confers strength to bone and a mechanism for active bone regeneration. Collagen itself self-assembles from procollagen molecules into triple-helical collagen fibrils and fibers that play important roles in the overall structure of various body tissues [7,8].
Second, self-assembly and order in biological systems are driven by function . For example, integral proteins aggregate to form focal points only when the cell begins to anchor on a surface. Filament structures responsible for cell repair appear only when a defect in the cell membrane exists, after which they disappear or cease to function. In contrast, synthetic materials require stepwise preparation, often irreversible, to generate the desired structure and to incorporate functionality .
Third, biological systems are dynamic. Channel proteins, for example, enter "on" and "off" states to allow select ions to pass through depending on the chemical environment and cellular needs. Finally, biological systems are responsive, adaptive, and restorative. Classical examples are the directed response in muscle tissues to loads and the many repair mechanisms in DNA [6,10]. As Jeronimidis elegantly pointed out, design is the expression of function, which very often includes achieving compromises between conflicting requirements while extracting maximum benefit from the materials used .
2.3 Supramolecular Engineering 2.3.1 Intermolecular Forces
Traditional organic chemists have for the past two centuries examined the reactions of molecules rather than their interactions [12-22]. Supramolecular chemists are interested in both because the synthesis of molecular assemblies requires designing and synthesizing building blocks capable of undergoing self-organization through intermolecular bonds akin to how nature holds itself. Driven by thermodynamics, self-assembling systems form spontaneously from their components. This also implies that they are in a dynamic equilibrium between associated and dissociated entities [12-43]. This feature confers a built-in capacity for error correction, a feature not available in fully covalent systems.
Noncovalent interactions include hydrogen bonding (H-bond) and p-p interactions. Dispersion, polarization, and charge-transfer interactions, combinations of which make up van der Waals forces, also play a significant role. The term H-bonds was used to describe the special structure of water. Consider molecules, A-H and B, where A in A-H and B are electronegative atoms (e.g., O, N, S, F, Cl). H-bonds occur when the hydrogen atom bonded to A (H-bond donor) is electronically attracted to B (H-bond acceptor). H-bonds can occur intra- or intermolecularly. Individual H-bonds tend to be weak. However, collectively, they can confer significant strength on a system. For neutral species, H-bond strengths are typically in the order of 5-60 kJ/mol. A distinct feature of H-bonds is their inherent directionality, which is well suited for achieving structural complementarity in supramolecular systems as will be seen in the rosette nanotubes (see Section 2.7). van der Waals interactions are long-range inductive or dispersive intermolecular forces. These interactions occur between nonpolar molecules at distances larger than the sum of their van der Waals radii. Although the magnitude of these forces varies as an inverse power of distance between the interacting species, and are thus weak, their effects are additive. The inductive forces include attractive permanent dipole-dipole and induced dipole-dipole interactions. The dispersion forces (also known as London dispersion forces), on the other hand, result from fluctuations of electronic density within molecules.
p-p interactions involve London dispersion forces and the hydrophobic effect. This form of stabilizing interaction is commonly found in DNA where the vertical base stacking contributes a significant stabilizing force to the double helix. In an aqueous environment, an unfavorable entropy effect occurs as a result of polar solvent molecules trying to order themselves around apolar (or hydrophobic) molecules. This unfavorable entropy provides a driving force for hydrophobic solute aggregation to reduce the total hydrophobic surface area accessible to polar solvent molecules. This form of binding can thus be described as the association of nonpolar regions of molecules in polar media, resulting from the tendency of polar solvent molecules to assume their thermodynamically favorable states.
The hydrophobic effect is a salient force in, for instance, micelle formation, protein-protein interactions, and protein folding.
The heart of supramolecular chemistry lies in the increasing complexity beyond the molecule through intermolecular interactions. It is the creation of large, discrete, and ordered structures from molecular synthons. Since Wohler's synthesis of the first organic molecule, urea, in 1828 , organic chemists have masterfully developed a cache of synthetic methods for constructing molecules by making and breaking covalentbonds between atoms in a controlled and precise fashion . However, nature's way of organizing and transforming matter from elementary particles into sophisticated functional structures has prompted chemists to think beyond the covalent bond and the molecule. Supramolecular chemists are thus concerned with forming increasingly complex molecules that are held together by noncovalent interactions. Lehn defined supramolecular chemistry as a sort of "molecular sociology,'' where the noncovalent interactions define the intercomponent bond, action, reaction, and behavior of an individual molecule and populations of molecules . Supermolecules are thus ensembles of molecules having their own organization, stability, dynamics, and reactivity.
Because the collective properties and function of materials depend both on the nature of its constituents and the interactions between them, it is anticipated that the art of building super-molecules will pave the way to designing artificial abiotic systems capable of displaying evolutive processes with high efficiency and selectivity, similar to natural systems. As we go further down in the scales, due to the difficulty in manipulating individual molecules and atoms, scientists and engineers developed self-assembly and supramolecular synthesis as new tools to overcome this challenge .
Self-assembly and self-organization processes are the thread that connects the reductionism of chemical reactions to the complexity and emergence of a dynamic living system. Understanding life will therefore require understanding these processes. Broadly defined, self-assembly [12,13,23-26,46-51] is the autonomous organization of matter into patterns or structures without human intervention. The principles of artificial self-assembly are derived from nature and its processes, and an understanding of these principles allows us to design nonbiological mimics with new types of function. Large molecules (e.g., histones), molecular aggregates (e.g., chromosomes), and complex forms of organized matter (e.g., cells) cannot be synthesized bond by bond. Rather, a new type of synthesis based on noncovalent forces is necessary to generate functional entities from the bottom up. This new field of chemistry, termed supramolecular synthesis [14-21], is the basis of nanoscale science and technology.
The organization of matter brought about by supramolecular synthesis makes feats of molecular engineering possible that are virtually unthinkable from a covalent perspective. The challenge lies both in the chemical design and synthesis: The conceptualization of an organized state of matter is intimately linked with the chemical information embedded in molecules in the form of charges, dipoles, and other functional elements necessary to translate chemical information into substances. Much of the research endeavor has been devoted to the use of noncovalent bonds as the alphabet for chemical information encoding, and the structures expressed have spanned the range of dimensions and shapes, from discrete [13-17,24,27-35] to infinite [12,20,21,23,25,36-42] networks. A step forward toward harnessing the noncovalent interaction is not only instructing the molecules to generate well-defined static assemblies but also designing them so that the ultimate entity displays a dynamic relationship with its environment, the ability to adapt, evolve, and self-replicate.
Despite the tremendous potential of supramolecular engineering in generating materials with tunable chemical, physical, and mechanical properties, this field has been absent in musculoskeletal tissue engineering. The goal of this chapter is to build the case for a novel approach for bone implant design based on supramolecular engineering.
In the United States alone, an estimated 11 million people have received at least one medical implant device. In 1992, of these implants, orthopedic fractures, fixation, and artificial joint devices accounted for 51.3% . If we examine the growth rate of joint replacements, surgery rates increased by 101% between 1988 and 1997 (Figure 2.1). The use of shoulder replacement increased by 126% and knee replacement rates increased by 120% . Since 1990, the total number of hip replacements, which is the replacement of both the femoral head and acetabular cup with synthetic materials, has been steadily increasing. In fact, the 152,000 total hip replacements in 2000 are a 33% increase from the number performed in 1990 and a little over half of the projected number of total hip replacements (272,000) by 2030. These numbers attest to the increasing demand in orthopedic replacement and fixation devices.
Due to surgery, hospital care, physical therapy costs, and recuperation time, implanting devices is not only very costly but also involves considerable patient discomfort . If postimplantation surgical revision becomes necessary, due to material failure under physiological loading condition, insufficient integration of implant to juxtaposed bone, or host tissue rejection, both cost and patient discomfort increase steeply. For instance, in 1997, 12.8% of the total hip arthroplasties were simply due to revision surgeries of previously implanted failed hip replacements . Furthermore, as revision surgeries require the removal of large amounts of healthy bone, most people can undergo only one such revision. This finite number of surgical revision calls for implants that can last for 20-60 years or more, especially for younger and more active patients with joint and bone complications. Bone nonunions, implant loosening owing to poor osseointegration of implant and osseodegradation of bone surrounding the implant are all difficult clinical problems. All these conditions lead to acute pain and poor mobility. These problems are reasons why careful design is necessary to improve the functional lifetime of implants and to promote new bone growth on the surface of an orthopedic implant material (osseointegration) in order to reduce costs associated with prostheses retrieval and re-implantation. These problems have driven engineers and scientists to reexamine and investigate improvements in the design and formulations of current orthopedic implant technology. In order to develop new strategies for fabricating materials useful in the repair of our skeletal system, we need to identify the hierarchical and supramolecular organizations of the bone responsible for its unique load-bearing properties.
Was this article helpful?