Inspiration and application in the evolution of biomaterials

Abstract

Biomaterials, traditionally defined as materials used in medical devices, have been used since antiquity, but recently their degree of sophistication has increased significantly. Biomaterials made today are routinely information rich and incorporate biologically active components derived from nature. In the future, biomaterials will assume an even greater role in medicine and will find use in a wide variety of non-medical applications through biologically inspired design and incorporation of dynamic behaviour.

Figure 1. History and growth of biomaterials as a field and industry

a, Prosthetics fashioned from natural materials: wooden toe, circa 1065–740 bc, used as a prosthetic to replace an amputated toe and identified in an anthropological excavation of the Thebes West tombs, Egypt. (Image courtesy of J. Finch, KNH Centre for Biomedical Egyptology, University of Manchester, UK, and The Egyptian Museum, Cairo.) b, The SYNERGY hip implant is an example of a state-of-the art prosthetic device that uses synthetic materials fabricated and engineered to meet performance demands. (Image courtesy of Smith & Nephew, London.) c, d, Commercially available combination products with both synthetic components and biological activity. c, The TAXUS Express Atom Stent, a metal stent from which paclitaxel is eluted into small coronary vessels to prevent restenosis (cell-mediated narrowing of the vessels). (Image courtesy of Boston Scientific Corporation, Massachusetts.) d, The INFUSE Bone Graft device, a combination product that uses both traditional prosthetic components (a steel cage) and a tissue-engineering approach (a bovine type I collagen sponge from which recombinant human bone morphogenetic protein 2 is eluted) to provide stability while spinal tissues are being regenerated. (Image courtesy of G. K. Michelson and Medtronic, Burlington, Massachusetts.)

Figure 2. Information-rich biomimetic materials

a, Schematic of the natural ECM across different spatial scales. The ECM contains a variety of peptide epitopes (coloured rectangles, labelled with amino-acid sequences of the epitopes) that facilitate integrin-mediated adhesion and other receptor-linked functions. These epitopes are organized in a specific pattern on the nanometre scale within each protein molecule (left) and on the micrometre scale in fibrillar and other structures (centre). The ECM may also regulate the diffusion of soluble proteins, mediating gradients of morphogens between cells on larger length scales (millimetres) (right); the blue colour scale represents one such gradient, with the concentration (from high to low) of morphogen (for example vascular endothelial growth factor (VEGF)) proportional to intensity. b–e, Synthetic mimics of the information-rich natural ECM. b, c, Schematic (b) and scanning electron micrograph (c) analysis of modularly designed peptide amphiphiles that self-assemble into nanofibres presenting a high density of neural-progenitor-binding epitopes (labelled with the amino acids K, V, I and A). Scale bar, 300 nm. (Image reproduced, with permission, from ref. 9). d, Scanning electron micrograph analysis of a surface containing micropatterned islands presenting RGD (adhesive) ligands (white dots) with precisely controlled nanometre-scale spacing. Scale bars, 1 μm (right) and 200 nm (inset, left). (Image reproduced, with permission, from ref. .) e, A micrograph of a biomaterial modified to present gradients or other complex spatial patterns of morphogens. The fluorescent dyes Alexa Fluor 488 maleimide (green squares) and Alexa Fluor 546 maleimide (red circles) are placed to demonstrate the spatial precision with which bioactive moieties (for example morphogens) could be patterned. Scale bar, 60 μm. (Image reproduced, with permission, from ref. .)

Figure 3. Regulating biology at a distance: designing materials to target or mimic the niches of specific cell populations

a, Schematic of microparticles or nanoparticles (grey) whose assembly enables them to target specific anatomical or cellular regions of the body. This targeting occurs on the basis of the particles’ size, shape and presentation of molecules (targeting molecules, purple) that are complementary to specific features of target cell populations. The particles subsequently manipulate cell fate locally through programming factors (pink). b, Schematic of an implantable biomaterial that mimics certain aspects of stem-cell niches in that it activates transplanted progenitor cells to proliferate and programs them to differentiate into cells that migrate into damaged tissues to participate in regeneration. c, Schematic of an implantable biomaterial system that mimics the microenvironment of an infection, allowing the recruitment, programming and subsequent targeting of activated antigen-presenting dendritic cells to the lymph nodes to participate in a potent antitumour response.

Figure 4. Using components of biological organisms and materials in novel applications

a, The chemical and physical properties of materials used by organisms to facilitate surface adhesion can be mimicked, allowing the generation of synthetic coatings that modify surface chemistry or prevent biofouling. For example, 3,4(OH)₂ phenylalanine (DOPA), a naturally occurring chemical adhesive used to facilitate the adhesion of mussels to surfaces in wet environments, has been combined with the physically patterned nanopillar topography found in the toes of geckos, which facilitates strong adhesion in dry environments, to produce novel adhesives that work in both wet and dry environments. b, The molecular templating of whole viruses allows high-precision, multiscale patterning of electronic devices. Genetic modification of the organism (left) is used to engender bimolecular organic–inorganic interactions that lead to the coating of viruses with desired inorganic materials and their macromolecular assembly (centre). Low-cost, high-precision energy-storage systems (right) are one potential application of this concept.

Figure 5. The future: rethinking how inspiration is drawn from biology, and applying biological design principles to new areas

a, Microtubules are an example of a multifunctional natural material with a dynamic structure, responsiveness to multiple environmental cues (for example chemical stimuli and mechanical forces) and the ability to regulate a variety of events at the molecular and cellular levels. The dynamic nature of microtubules allows these polymers, which are assembled from relatively simple monomeric components (tubulins) at microtubule-organizing centres (MTOCs), to operate with a high degree of functional complexity in cells. Their dynamic assembly and disassembly in response to both chemical and mechanical stimuli from the environment is shown (left). Alterations in microtubule assembly can regulate a variety of cellular events (right), ranging from protein-mediated signalling (for example by regulating the localization of a protein kinase), which occurs on the nanometre scale, to mechanical control over cellular structure and organization during mitosis, which occurs on the micrometre scale. b, Potential biomedical devices inspired by microtubules. Structurally simple synthetic polymers can be designed to self-assemble in response to triggering molecules (for example ECM proteins or ions) and further assemble or disassemble in response to other environmental cues (for example pH, matrix metalloproteinases and physical forces) (left). Assembled polymers can subsequently regulate signalling between and within target cell populations to bring about biologically complex changes in their local environment. For example, they may bind to ECM proteins, initiating assembly or restructuring of the ECM and thereby manipulating cells locally (right). At the same time, they may sequester morphogens, generating gradients that alter cell behaviour over longer distances. As is the case for the natural materials that inspired their design, these synthetics undergo reorganization in response to changes in the local environment, subsequently altering the ways in which they interact with cells. This allows relatively simple materials to carry out the complex functions of both integrating multiple inputs from the environment and providing multiple outputs (cell-interactive stimuli) to regulate local biological events.

Figure 6. The future: drawing inspiration from nature to rethink how materials and pharmaceuticals are manufactured

Schematic of a typical factory used for materials manufacturing, with associated inputs of raw materials and energy, and output waste streams (a). Schematic of a rice terrace, with its associated inputs and outputs (b). The relative sizes of manufactured products and the associated wastes shown represent the scale of waste streams and input materials in the respective schemes. The ability of natural systems to use renewable energy sources (for example solar energy) effectively and to recycle waste streams when generating products is inspiring novel approaches to manufacturing.