Diversification and enrichment of clinical biomaterials inspired by Darwinian evolution

Acta Biomaterialia xxx (2016) xxx–xxx

Contents lists available at ScienceDirect

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Review article

Diversification and enrichment of clinical biomaterials inspired by Darwinian evolution D.W. Green a,c, G.S. Watson b, J.A. Watson b, D.-J. Lee a, J.-M. Lee a, H.-S. Jung a,c,⇑ a Division in Anatomy and Developmental Biology, Department of Oral Biology, Oral Science Research Center, BK21 PLUS Project, Yonsei University College of Dentistry, Seoul, Republic of Korea b School of Science & Engineering, University of the Sunshine Coast, Sippy Downs, QLD 4556, Australia c Oral Biosciences, Faculty of Dentistry, The University of Hong Kong, 34, Hospital Road, Hong Kong SAR

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Article history: Received 2 January 2016 Received in revised form 11 June 2016 Accepted 21 June 2016 Available online xxxx Keywords: Biomaterials Directed evolution Protocells Synthetic biology Accelerated evolution Convergent evolution Biomimetics Darwinian evolution Artificial selection Computational modelling

a b s t r a c t Regenerative medicine and biomaterials design are driven by biomimicry. There is the essential requirement to emulate human cell, tissue, organ and physiological complexity to ensure long-lasting clinical success. Biomimicry projects for biomaterials innovation can be re-invigorated with evolutionary insights and perspectives, since Darwinian evolution is the original dynamic process for biological organisation and complexity. Many existing human inspired regenerative biomaterials (defined as a nature generated, nature derived and nature mimicking structure, produced within a biological system, which can deputise for, or replace human tissues for which it closely matches) are without important elements of biological complexity such as, hierarchy and autonomous actions. It is possible to engineer these essential elements into clinical biomaterials via bioinspired implementation of concepts, processes and mechanisms played out during Darwinian evolution; mechanisms such as, directed, computational, accelerated evolutions and artificial selection contrived in the laboratory. These dynamos for innovation can be used during biomaterials fabrication, but also to choose optimal designs in the regeneration process. Further evolutionary information can help at the design stage; gleaned from the historical evolution of material adaptations compared across phylogenies to changes in their environment and habitats. Taken together, harnessing evolutionary mechanisms and evolutionary pathways, leading to ideal adaptations, will eventually provide a new class of Darwinian and evolutionary biomaterials. This will provide bioengineers with a more diversified and more efficient innovation tool for biomaterial design, synthesis and function than currently achieved with synthetic materials chemistry programmes and rational based materials design approach, which require reasoned logic. It will also inject further creativity, diversity and richness into the biomedical technologies that we make. All of which are based on biological principles. Such evolution-inspired biomaterials have the potential to generate innovative solutions, which match with existing bioengineering problems, in vital areas of clinical materials translation that include tissue engineering, gene delivery, drug delivery, immunity modulation, and scar-less wound healing. Statement of Significance Evolution by natural selection is a powerful generator of innovations in molecular, materials and structures. Man has influenced evolution for thousands of years, to create new breeds of farm animals and crop plants, but now molecular and materials can be molded in the same way. Biological molecules and simple structures can be evolved, literally in the laboratory. Furthermore, they are re-designed via lessons learnt from evolutionary history. Through a 3-step process to (1) create variants in material building blocks, (2) screen the variants with beneficial traits/properties and (3) select and support their self-assembly into usable materials, improvements in design and performance can emerge. By introducing biological molecules and small organisms into this process, it is possible to make increasingly diversified, sophisticated and clinically relevant materials for multiple roles in biomedicine. Ó 2016 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.

⇑ Corresponding author at: Department of Oral Biology, Oral Science Research Center, BK21 PLUS Project, Yonsei University College of Dentistry, Seoul, Republic of Korea. E-mail address: [email protected] (H.-S. Jung). http://dx.doi.org/10.1016/j.actbio.2016.06.039 1742-7061/Ó 2016 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.

Please cite this article in press as: D.W. Green et al., Diversification and enrichment of clinical biomaterials inspired by Darwinian evolution, Acta Biomater. (2016), http://dx.doi.org/10.1016/j.actbio.2016.06.039

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Contents 1.

2. 3. 4.

5. 6.

Darwinian evolution as a driver for biomaterials design & diversification. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.1. The role of biomaterials in regenerative medicine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.2. The significance of biomimetic strategies in biomaterials diversification . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Neo-Darwinism and biomaterials diversification . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Evolutionary guided biomaterials fabrication. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . The evolutionary mechanisms for biomaterials fabrication. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.1. The directed evolution technique. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.2. Directed evolution of biomaterials related to regeneration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.3. Evolution on a chip . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Discussion and future prospects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conclusion and future prospects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Funding statement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1. Darwinian evolution as a driver for biomaterials design & diversification Darwinian evolution by natural selection has been the main force of creativity in biology [1]. It has generated integrated complexity of the highest high order and function. It is a process that has been copied and simulated in biotechnology mainly to redesign biological molecules for new purposes and more efficient roles. However, it has been difficult to capture, direct and control. Organic evolution is messy, opportunistic and contingent on what has occurred and developed before. Current developments highlight the increasing promise of experimental evolution to produce new biological products. Populations of small organisms have been cultivated, artificially mutated and selected within imposed environments to evolve new traits. Experimental evolution has been a tool to study evolutionary changes. In the science of biomaterials the explicit use of evolutionary processes and mechanisms to fabricate new natural biomaterials or biomaterials with living and adaptive qualities. The biomaterials we are discussing are those that can be evolvable. This is a substrate made within biological systems that can be processed and manipulated by a living cell, virus or small organism. Current biomaterials lack essential adaptation behaviour. Also current biomaterials need improvements to adapt and function in the laboratory, in the clinical environment, at implantation and in the wound environment. These are all prior to integration with natural healthy tissue they are typically designed to match. We review approaches and technical strategies to implement Darwinian evolution, in real time during biomaterials design, synthesis and fabrication. The literature in this regard is patchy. The purpose of this review is to consolidate the disparate areas of evolution related inputs to biomaterial development. We describe the potential of using Darwinian mechanisms in biomaterials development. In one of few examples, directed evolution has been used to diversify and preferentially select optimal functioning collagen mimicking materials derived from self-templating (the presence and activity of the first building blocks drive and build together the remaining building blocks entering the assembly) assemblages of virus capsids [2,3]. The harnessing of bacteriophage capsules (with wide range of shape and architecture), as a versatile and tunable material building block, for production of multiscale biomimetic collagen architectures ideal for cell and tissue engineering [4]. It is a way of diversification and making new unnatural biomaterials. In this review we cover and incorporate all other areas where Darwinian knowledge can be applied to the development of biomaterials. This includes, learning from the patterns of evolution during history, learning about the mechanisms and how they can be translated into the laboratory and learning how small

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organisms can be evolved and programmed to manufacture biomaterial building blocks. The learning is broad and encompasses evolutionary trends across history, comparative/convergent evolution analyses of biomaterials over time, harnessing synthetic biology, directed evolution artificial selection and the technologies to make evolution controlled, such as, microfluidics. It will include practical lessons on techniques to establish the controlled evolution habitats to enable our biomaterial assembly with evolution inputs. There exist protocols and techniques for carrying out experimental evolution [5]. The goal is to improve existing biomaterials in a number of useful ways. To help make synthesising biomaterials from small molecules more efficient in the laboratory-tailored to specific functions, tailor these biomaterial building blocks (e.g. so that they selforganise in specified ways), and to help in the design of new biomaterials with additional functions for the laboratory and the clinic. Darwinian evolution has produced countless bounty of materials design and innovation. This is possible with small organisms single cell (E. coli, bacteriophages and other viruses) or (lower invertebrates e.g. sponges), open to genetic manipulation and reprogramming, with rapid generation times and high tolerance to environmental stress. Such organisms are able to generate technologically viable yields of biomaterial substrates. These are the creations we are inspired to mimic and reproduce in nature’s image. In contrast the nuts and bolts of evolutionary mechanics is the tool for composing biomimetic inventions. This review will illustrate these two different elements, the products of evolution and the mechanisms used to make them. It is aimed at promoting the use of mechanisms for bioinspiration and biomimicry projects. The evolutionary based approaches to developing the new wave of dynamic, biologically enriched biomaterials will be exemplified by 4 strategies: (1) evolutionary screening of peptides from bacteriophage libraries that select biomaterial components with best functions, (2) repeat selection of bacteriophage or bacterial materials (viral nanoparticles, viral coat proteins and bacterial coat proteins) for designated properties conditioned and guided by living cells, (3) comparative and retrospective analysis of evolutionary biomaterial trends and innovations, (4) directed evolution of building block molecules for biomaterials. 1.1. The role of biomaterials in regenerative medicine Use of biomaterials as space-filling frameworks and templates is one of three major pillars, alongside living cells (adult stem cells) and biochemical (growth factors), supporting laboratory-grounded tissue self-assembly, self-organisation, developmental morphogenesis and regeneration strategies for tissues and organs [6–8].

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The engineering of cells with materials is central to modern approaches in medical bioengineering. Such approaches are intrinsically biomimetic as the objective is to emulate functional clusters of human biology inclusive of the structure, design and function. It is also an objective to create deputizing replacements for missing tissues, organs and to carry-through key physiological processes in a naturally analogous coordinated process [9]. However, there is a paucity of clinically viable materials with a good range of biological functions needed to fully promote regeneration of permanent, self-supporting tissues. The problem relates to the insufficient replication of biocomplexity distributed between mechanical, structural and material hierarchies, biological recognition (between elements and factors), active molecule concentrations and spacings, cell distributions and multidimensional maps of protein conformations [10–13]. Furthermore, this has to be simulated across the space of the material and in time with remodelling and repair surrounding the material in situ. Wound healing is among the most intricate biological processes in the human body [14]. The biomaterial must adapt and process this environment to survive and function properly. To do this it must be able to express and emit information to drive biology. Some of this sophistication can arise through a dynamo of evolutionary selection of the most appropriate information imposed by the designer of function [15]. Biomaterials that are autonomously bioresponsive, selfadaptive and programmable are becoming highly desirable because they are more clinically acceptable, cueing the controls for natural biological processes and at increasing immune surveillance and responses and vaccine efficiency [16]. The reason is that biomaterials with these properties interact better and interplay with surrounding biology in a synergistic manner leading to higher function, proper integration and minimal disturbance to normal biology and systems. So, biomaterials carrying these attributes are perfect for important technical roles in tissue engineering and human therapies in particular. They also have important roles to play in drug delivery, for example heparin release and controlled blood coagulation [17], implant integration with surface tailoring [18], and nanodevice technologies, harnessing nanoparticles as autonomous robotic manipulators of the immune system [19,20]. Implementation of evolutionary principles and mechanisms into these bioengineering topics could lead to new material innovations (e.g. autonomy of action and reaction), templates for more sophisticated material designs, meta-biomaterials and material strategies

that mutually co-operate with natural host repair, regeneration and healing (Table 1). The products of this evolutionary throughput will be biomimetic and bioinspired materials selected for their optimal function. 1.2. The significance of biomimetic strategies in biomaterials diversification Concepts and techniques in biomimicry have been used to recapitulate materials synthesis, with development and formation into intricate structures, architectures and morphologies [71–73]. It comes in many approaches and strategies but generally does not require total biomimicry. This is an absolute copy of every major detail of the model object. The levels to which materials biomimicry has reached are still limited to gels with cross-linkages that can be broken with native remodelling enzymes [8,9,74,75], nano fibrous material architectures with nanoscale dimensions equivalent to native extracellular matrix (ECM) – made from peptides [10,76], proteins and lipids and biomaterials engineered with clusters of ligands and receptors in native densities and distributions [22,65]. There are numerous strategies aimed at generating higher and better performing analogues of natural biomaterials; striving for autonomous and bioresponsive material systems. This has been accomplished by constructing materials with short sequence peptides [77], and chiral peptides [78], enzymatically labile connectors (e.g. MMP sensitive) [79,80], bound growth factors [22], receptor binding sites, ligands [81], short peptide and glycan decorations [20,82–84]. Furthermore, the actions and influence need to be extended further in a timed sequence, in different parts of space and to influence repair processes that continue to hinder proper human incited regeneration. Biomaterials tissue engineers are faced with further problems related to successful material biomimicry, particularly at small nanoscales, programmed autonomy and orchestrating scarless wound healing, facilitated by TGF molecules; a major obstacle to the successful long term grafting of tissue engineered tissues [60,85]. Engineered biomaterials must also take account of the real-time sequence of biological wound healing and regeneration phenomena. However, the origins and pathways into pre-existing ‘‘organised” tissue and the re-emerging tissue (in the ‘‘regenerating tissue zone”) taken by progenitor cells involved in healing and repair processes are not clearly known. How immune cells

Table 1 A summary of significant trends in biomaterial functioning for regeneration that requires urgent improvements to provide increased clinical success. Accelerated integration and grafting, scarless healing and temporally co-ordinated delivery actions are specifically critical to future success in this field. Tissue regeneration biomaterials

Biomaterials for targeted delivery of biomolecules

Biomaterials for immunity stimulation & modulation

Integration biomaterials

Nanobiomaterials for regenerative medicine

Mimicry of ECM structure, organisation and architecture [21–24]

Growth factors and cytokines (BMP, TGF-beta, PDGF, FGF-2) to potentiate and promote tissue creation events [30,31] Nucleic acids (SiRNAs, miRNAs, DNA (genes)) [32–35]

Recruitment, alteration and dispersal of immune cells e.g. innate system [44]

Improvements to tissue bonding and annealing around implants [48–50]

Nanoparticles for delivery of factors towards immunity modulation [61]

Directing adaptive immunity; elicitation and tolerance (of Tand B-cells). [45,46] Modulating and tailoring activities of complement proteins (a component in regulation of regeneration) [47]

Mimicry of natural tissue fabric structures & architectures [16,51–53] Resorption in tempo and synchronised with tissue development, repair and regeneration processes [54,55] Mimicry of mechanical properties of tissues relating to elasticity, toughness and strength [20,56,57]

Nanofibres, nanocages, nanotubes for targeted delivery of biomolecules [62,63] Nanofibres, nanotubes, nanoparticles for construction of cell & tissue framework materials [64–66]

Mimicry of the hierarchical organisation of biological tissues [25] Mimicry of biomechanical properties of biological tissues [26,27]

Mimicry of intrinsic protein conformations in time and space according to external stressors [28] Performance through autonomy, selfadaptation [29]

Antibiotics, anti-microbials, antivirals (e.g. Ampicillin, Rifampicin) [36–38]

ECM proteins (e.g. CS, laminin, vitronectin, collagens, fibronectin) [39,40]

Steroids, anti-inflammatories & hormones [41–43]

Biomimetic nanostructures, nanobodies & molecular machines for generation of materials and biological systems [67–70]

Influence over normal tissue repair to prevent scar tissue and fibrosis [58–60]

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interplay during wound healing is a necessity to formulate rational therapeutic strategies [9]. Key questions remain such as, how does cell plasticity stretch into different phenotypic directions and what are the re-programming processes and pathways to embryonic analogues or specialized phenotypes. At a systems level of control; what are the master regulators? Transdifferentiation and dedifferentiation are significant events that transcend both development and regeneration. These represent a dramatic systems change in the natural history of most cells [86,87]. This uncertainty applies to the precise role of early developmental-similar processes of regeneration and wound healing, the innate inflammation procedures in wound repair and a neglected aspect of complement mediation of regenerative cells during tissue morphogenesis [88]. Complement, small blood proteins are one of the primary recruits in the inflammatory response. Better decisions can then be made on the optimal biomimetic strategy, or to decide what collection of elements need to be mimicked to produce the best functional outcome.

2. Neo-Darwinism and biomaterials diversification The Darwinian evolution process has induced the selection of thousands of varieties of natural-origin biomaterials with highly effective properties and characteristics. Human inventiveness is powerful. Although, these biomaterials are often superior in design and function to artificially engineered biomaterials (both from synthetic and biological products and raw materials), rivalling them in relation to their low energy usage, with a low number of selected constituents that tend to be environmentally abundant [89]. Particularly, it is their biological properties and responsiveness that cannot be easily emulated artificially. Evolution by natural selection is driven by stochastic changes in genetic make-up that provides phenotypic differences that confer differential fitness. These phenotype differences are a mixture of possible innovations, stagnation and dysfunction, which may or may not affect survival. In current biomaterial engineering, the level of biological sophistication and complexity is limited to a few functional elements, and consequently, they are below the standard of quality necessary for an accurate and functional biomimetic material design [72,73]. Biomimetic materials synthesis and cell-directed materials synthesis will be important methods for the artificial creation of

Fig. 1. How information from Darwinian evolution, mechanisms and comparative studies flow into successful design and fabrication of useful biomaterials for clinical tissue regeneration.

biological complexity [90]. To refine these methods and increase the diversity of functions, more information is needed regarding the molecular design and synthesis of materials in organisms and the evolutionary development of materials (Fig. 1). There are two main approaches in this respect. One approach is to use evolutionary mechanisms to create synthetic life forms with the ability to self-assemble material building blocks. The second approach is to compare and contrast biological phenomena between taxa and over evolutionary history, for instance, by mapping adaptive strategies in structural biomaterials.

3. Evolutionary guided biomaterials fabrication The historical record of adaptations, across evolutionary timescapes highlights the patterns of transformations in design and function. These transformations can be used as guides for the lab-based or computer based design, modelling and fabrication of biomaterials in general: synthetic and nature-origin. Most biomaterials, of synthetic and natural origins are manufactured according to the same strategy used in the manufacture of artificial materials. That is according to principles of rational (logical from start to finish with a safe prediction of the final product properties) design and planning towards a desired functional property. And it has been successfully applied to the design of an assortment of new and analogous biological molecules (proteins, nucleic acids and drugs) [91]. Rational design strategies only work properly when all the details are known about each component and how they assemble and organise into structures with complexity. Most often than not, purposeful design is created by empirical data and applying it to trial and error experimentation [92]. In contrast the evolution of biomaterials in organisms (biomaterials produced within a biological system), by natural selection, is a process that involves random experimentation of chance variants and the testing of function by competition for fitness. This runs autonomously and has no set goal as in rational design processes. Rational design of biological objects and systems is complicated by the paucity of knowledge regarding the detailed properties and the production goal [91,92]. Combinatorial approaches towards molecule selection have been common and include an element of the Darwinian principle. Use of combinatorial assortment techniques with materials is rare. Monte-Carlo computer simulations possess functions that equate to those in Darwinian selection. Computational evolution is employed in certain projects to design new composite materials for example on how wood and bone structures are optimised ideally to their adapted function through a self-minimisation process [93]. In one study evolutionary algorithms were programmed for generating functional morphologies in bone structures via finite element model analysis [94]. Evolutionary algorithms are computer-generated systems that optimise number sequences for a solution according to Darwinian natural selection. Number solutions are validated and selected as the optimal solution in each round. Repeated rounds of problem solving lead to ever increasing optimisation to the solution set as the ideal goal. This finite element model (FEM) created a quasi-realistic model of a bone tissue environment in a mechanical context. It also simulated random alterations in the mechanical behaviour that could be deliberately varied in the program simulation. The virtual bone was made of mineral material and vascular spaces. As the evolutionary algorithms (EA) ran its programmed course over many repeated alterations (simulated mutations) an adaptation took place in the distribution of vascular spaces and gave increases to mechanical resistance in the structure (Fig. 2) [95]. The FEM model was based on bone tissue. Such inquiries are not completely Darwinian as they are directed towards a predetermined goal. However, they

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Fig. 2. The use of analogues inspired by natural selection mechanisms for the rapid evolution of biomaterials and living biocomposites (Biomaterials with cells) in real time. Evolution as an optimising tool for tissue engineering (in silico evolution) using computational methods and Evolution carried out in microfluidics with simple tissues (Evolution-on-a-chip). (A) A computer generated evolutionary guided algorithm has been calculated to evolve new bone biomaterial functional morphology. In the simplest simulation stiffness was used as the single measure of fitness and was cycled 16,000 times (generations) [94]; (B) A microfluidic test chamber to control the environment among cells cultured on a micropatterned structure [97]; (C) A microfluidic device designed to regenerate blood vessels in their natural order. Such devices enable the environment to be precisely controlled and can be used to create the conditions for evolution of enclosed cells. Similarly, and when selecting for regeneration function, the natural selection analogy can be used in simple assays carried out inside microfluidic chip assemblies (B,C) [98].

retain the elements of variation and selection of ‘‘Good” and ‘‘Bad” designs. Evolutionary genetic algorithms have also been employed to construct bone replacements with enhanced matching between conflicting properties (mechanical strength versus degradation rate) that both required to properly mimic bone [95]. Organisms, genes and biomaterials adapt and evolve to environmental changes. Biological materials, made by biology, are subject to influences from the environment and adapt at the supramolecular level in real time. Indeed one of the new avenues of research follow the ontogenetic history of biomaterials as they grow in situ, to extract information on how they are serially constructed and the principles behind it [96]. Incorporated into the adaptive functioning of biomaterials in evolution is a degree of latitude to modify its property and behaviour to current conditions. Evolutionary processes do not lead to perfect systems with maximum tolerance. Rather they lead to optimised fitness for their specific environment. It actually provides ideal solutions that balance and resolve all constraints and problems. The diversity of evolutionary biomaterials is reflected with varied design principles, blueprints and strategies. The variation in biomaterials mirrors the evolution in structure, form and morphology against a broad spectrum of environments and local conditions [99]. However, in both cases there is a high degree of convergence onto an individual function. Evolutionary trending towards convergence (on a functional design set) is a strong indicator among organisms for a good functional solution to a working problem. The evolutionary pathway can

Fig. 3. Use of remarkable evolutionary phenomena such as functional convergence (among assorted species phylogenies) and adaptive radiation can help promote mimicry strategies. It can also give rise to new biomaterials and analogues of native biomaterials that cater for healthcare applications. (A) Variations on a theme for surface attachment mechanisms among insects, arachnids and Lizards [101]; (B) A real-life technology whose design is inspired by the beetle footpad surface microstructures. In this example an adhesive bandage was made for the human skin surface [103]; (C) The study of billfish bone microarchitecture and biology has changed perceptions on how bone tissue is built and remodelled-without necessity for osteocytes. Its deep study offers new and significant information on strategies to re-engineer human bone tissues [108]; (D) Again comparing and contrasting design strategies in homologous tissues between species and taxa can spotlight new design principles that can have an influence on human biomedical materials engineering strategies. In this example, a new design for constructing a strong, resilient skeleton with soft gel encapsulating a ‘‘tessellated” pattern of mineralised panels (called tesserae), has been uncovered in Sharks, Rays and Stingrays (Urobatis halleri) [96].

show the design steps and assembly more clearly than by deconstructing the function in a single organism. Another approach for exploiting the technical richness of evolutionary adaptive strategies, in the full Darwinian tradition describing all evolutionary concepts, is to compare and contrast a shared function among different organisms. In this regard nature has tuned chemistry and physical structuring for specific and multifunctional tasks. In particular structuring can vary with size (height, width etc.), shape, spacing and mechanical properties. A good example is the common and differing features between

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organisms for adhesion and attachment on surfaces. Numerous attachment structures have evolved independently among insects, arachnids and gecko lizards (see Fig. 3A) [100,101]. Diversity is particularly large for attachment devices because of the survival and fitness significance of this function [101]. It is useful and helpful to provide classification schemes that map their evolution. This can help focus on the right strategies for biomimetic translation efforts, which need considerable information of composition at small scales as well as the prediction of emergent behaviour. Systematically arranged comparison in classification systems is a means to resolve the principles involved. Already there are many bioinspired adhesive patterned surfaces in the development of surgical gripping surfaces [100], tissue bandages-modelled on beetle feet structure [102], skin plasters modelled on Gecko foot pads (Fig. 3B) [104], pads for robotic walking and climbing machines and enhanced frictional properties for vehicle tyres [105–107]. These biomimetic translations are fixed on learning the outcomes of evolution rather than the process towards a functional adaptation. The study of tissue structures and their relation with mechanical performance, across taxonomic boundaries can yield principles for biomaterials design. Relations are frequently made between tissue structures and organisation between selected organisms for taxonomic classification systems. Cross-referencing between the structural organisation of tissue analogues from different organisms or between human tissues and other organisms generates new vital information about materials design [108]. And this can have clinical relevance related to the different patterns in bone structure and re-modelling following damage and trauma. Billfish bone tissue in contrast to mammalian bone do not possess osteocyte cells – the cells that initiate remodelling (Fig. 3C, D). Yet, these billfishes (Marlins and Swordfish) are shown to repair and remodel their bone tissue with an alternative mechanism-osteocyte free. It has put doubt on the role of osteocytes in this process in mammals. Sharks and Rays are supported by cartilage with no capacity for remodelling, which is a later evolutionary innovation. The design that evolved consisted of an ‘‘unmineralised” gel covered with ‘‘permanently mineralised tiles (tesserae)”. This design has inspired the development of facile biomimetic analogues for possible human applications. This is a skeletal system without cells for remodelling and without a complicated internal architecture. The structural design of tesserae panels in Sharks and Rays, show mechanical development for combatting fatigue and tearing. This is achieved by reducing minerlisation content and stiffness to a degree in contrast to mammalian bone construction. Some of these advantages can be exploited in biomimetic analogues for human bone replacement. These non-human parallel biomaterials that serve the same function as the human skeletal model but provide different solutions opens up new structures, properties and functions with a common biomaterial for a specific purpose. Countless animals and plants have evolved physical devices for attachment to every possible surface in every kind of environment. The example of attachment devices is a fine example for analysing evolutionary development of biomaterials and their unique set of functions. This relates to the design of biomaterials and structures with biomaterial substrates. Typically, among evolutionary development there are a large number of functional solutions. There are 4 identified principles involved, wet adhesion, hooks, locking mechanisms and suction cups which harness physics and chemical physics of electrostatics, capillary forces, viscous forces, friction etc. The first step in the analysis of evolution of functional design solutions is to classify them in such a way as to highlight the patterns, relationships and interconnections. Stanislav Gorb published a paper showing how this analysis is carried out with the goal of providing the relevant information for biomimetic translation [101]. This type of inventive information, nature’s patents,

provides information for the design of biomaterial-based adhesives, dispense systems, fasteners, manual and robotic manipulators, grippers and fasteners and anti-slip devices. Such investigations involve intensive observational study of the organism in their natural habitat or in lab chambers at least for small insects. Genotyping and phenotyping is used to create the interrelationships. Other forms of analysis involve describing and measuring the features and characteristics of structures or materials under examination. Regarding the analysis of materials, measurements are taken of mechanical, chemical and physical properties, as well as 3d imaging down to small scales. Structures are observed and characterised at microscopic and ultrastructural levels. These measurements are used to construct clade diagrams and phylogenetic trees. The clade analysis determines the close relationships between organisms based on shared characteristics that together home towards a common ancestor. Software is used to associate and relate the characters put into the calculation engine. The evolution of the character set (say the foot pads of lizards) is mapped and displayed as a diagram. A collection of co-related phenotypic characters are used to capture functional, structural change events [109]. The tree-like relationships from phylogenetic analysis capture changes more broadly with a greater number of organisms. Algorithms have been calculated to sort and categorise characters, properties and functions into meaningful patterns. There is also the aspect of mapping and analysing phylogenetics of key genes encoding very useful biomaterials, i.e. those with properties better than synthetic materials. The technological advantages of investigating the phylogenetics of the genes for Squid sucker ring teeth proteins was highlighted by Guerette et al. [110]. The unique protein has extraordinary properties with high biomimetic utility. They looked at suckerin genes encoding a biomaterial product made of protein beta sheets wrapped into a tight nanonetwork, which has superior ‘‘mechanically reinforced” properties suited as a possible analogue material for human ligaments and bone. Some of these technical functions can be used in biomaterials for regeneration but many others could translate into devices for biomedical surgery. There is a strong need for adhesives that work within tissues and physical attachment devices as tapes and bandages in wound healing and surgical procedures for connecting and separation tissue structures. Problems continue in replicating the intricate geometries at many different scales and to integrate them. As more is studied in depth, with sophisticated imaging techniques, of the structures and their composition then translation will be more accurate and the end product will have stronger and better functions. Similarly, further studies comparing the systems between and within organisms over evolutionary time will uncover more design principles and more functions that can be exploited for biomedical technology. All these approaches apply knowledge of evolution retrospectively over the course of history. This has in some instances led to more biologically informed design of biomimetic and bioinspired analogues.

4. The evolutionary mechanisms for biomaterials fabrication Evolutionary mechanisms of natural selection can be translated into practice in the laboratory. Presently, viruses and bacteria have been manipulated to generate biomaterial building blocks that organise themselves, automatically, into biomimetic structures with enhanced properties and functions. This strategy is strengthening in the production of mimics of human tissue ECMs, and nature-based functional analogues of native human tissues with added properties. An emerging research direction is the synthesis and fabrication of medical biomaterials using the process of

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Fig. 4. Mechanisms distilled from Darwinian evolution can be appropriated for the synthesis of new biomaterials. (A, B) Artificial induced selection of material structure and architecture leading to adaptive colour change in the Butterfly wing [118]; (C) Directed evolution of E. coli to enhance enzyme catalysis [125], and (D), a schematic of viral-based directed evolution of the creation of new biomaterials for tissue replacement and regeneration [4].

Evolution by natural selection, which is such an exemplary problem-solving mechanism (Fig. 4). Approaches to biomaterials design have previously focused on combinatorial and computational methods grounded on the rationality of complete knowledge about the materials system to be upgraded [111]. Further attention on functionally rich libraries of components may reduce the need for such large amount of information. This potential overload of information is time consuming to collate and interpret [112]. The so termed semi-rational approaches address the limitations of directed and rational strategies [113]. Although natural selection is a potent generator of innovation in practice, it is constrained

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because the large variation needed for selection is challenging to recreate in the laboratory. Evolutionary routes in materials synthesis and engineering have specific advantages over rational design strategies, which is the primary best practice for manufacturing materials constituent by constituent because it is efficient, cost effective and is less time consuming to implement. The main advantage of evolution based strategies, however relates to the genetic driving force and control of building block features (e.g. folding and conformation) that are mostly not known or cannot be properly implemented in a rational based approach. ‘‘Evolution in real time” experiments have been possible with prokaryotes, which undergo 16–168 generations per week limited by raw materials and competition for space [114]. The problem with laboratory evolution is in the creation of sufficient levels of diversity via mutagenesis for the emergence and selection of improvements. Another issue is the insufficient time for evolutionary mechanisms to produce results since only between 4 and 20 mutations may occur in 1000 generations [114,115]. Genome engineering overcomes limited variation by modulating the genome at numerous areas of the chromosome leading to larger number of mutations and more direction of modifications than naturally occurring spontaneous changes. Genome engineering is facilitated by methods for editing, reduction, de novo synthesis, merging and shuffling procedures [114]. Additionally, evolutionary adaptations can take thousands of years and generations to appear. Thus, using natural selection to generate biological materials in the laboratory is only possible when using biological entities that self-replicate rapidly or can be selected in the favoured direction. Current synthetic life generating techniques are sufficiently sophisticated to create self-replicating protocells [116] (cells with basic elements and features) that can be programmed to synthesize base materials or even simple structures from the information transcribed by inserted genetic machinery. The base materials can be programmed for self-assembly, with further construction of hierarchical designs feasible via application of appropriate force fields. This process may most appropriately be considered to be artificial selection, in which direction is given regarding the features that are and are not required. For single traits, directed materials evolution has already been practiced on various microorganisms and some insect species [117]. It was possible for these traits to undergo rapid adaptation in only a few generations in the laboratory because, in certain species, there exists latent genetic variation to act upon. To illustrate this point, butterfly (Bicyclus anynana) wing coloration evolved by deliberately and artificially placing this trait under selective pressures in the laboratory [118]. By applying selection pressure to the coloration of wing scales, wing colour evolved from its wild type brown hue to violet blue (Fig. 4A, B). Although, the objective of this study was to investigate structural colour evolution, it also promotes the possibility that preplanned design and fabrication of biomaterials may be possible by hijacking the heredity of material traits. The forced alteration of material traits is already possible in a single generation of unicellular organisms such as, diatoms, which have an exploitable glass skeleton for particular tissue engineering and drug delivery applications. The high surface area of the shells and the pore and channel architecture are of high biotechnological value. Also the skeletal forming chemistry is responsive to environmental conditions. This alteration is accomplished by growing diatoms in an abnormal environment where the conditions force changes in skeletal architecture [119]. Nickel sulfate dosaging of Diatoms induces a stress response in the skeletal formation compartment, leading to rapid changes in skeletal architecture. Within stressful environments or fluctuating conditions Diatoms readily respond with real time adaptations (phenotype plasticity) that can also be inherited in the population. However, care must be taken to

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account for forced selection pressures that are detrimental to the organism itself. There needs to be a compromise between the technological features and properties imposed by directed selection and the survivability and fitness of the experimental organism. As with small microbes, which develop large populations and express rapid, environmentally responsive rates of cell division, Diatoms can be evolved in weeks and months. A recent study has shown how it was possible to undertake in situ (in a mesocosm unit) experimental evolution related to carbon dioxide ‘‘enrichment” and also temperature changes [119]. To create adaptations in single celled organisms, artificial selection can delve deeper into the evolutionary design space by altering proteins and nucleic acids in the laboratory [120–122]. Rapid generational replicating Bacteria and virus particles are prime subjects for directed or artificial selection for multiple applications in gene delivery to pluripotent cells, entirely new ‘‘genetic circuits”, more powerful regulation of transcription and novel metabolic production systems in engineered bacteria [123,124] (Fig. 4C, D). To make this work, methods of generating variation must exist, and variants with appropriate traits must be artificially selected, which will result in organisms with traits that have the desired function. Selection is, however a cumbersome, work intensive process. Semi-automated systems have been devised to facilitate more efficient screening and selection of the most appropriate variants. In one instance this has been achieved using microfluidic technology, which is fast and highly controllable (Fig. 4C) [125]. An enzyme was enclosed inside hydrogel beads, which provide a suitable enclosed environment for activity of the phosphotriesterase enzymatic catalyst (for bioremediation) and its encoded DNA with fluorescence products. Such beads with fluorescence were sorted in fast flow microfluidic devices and flow cytometry to pull-out the successful fluorescence producing enzyme containing beads. Employing evolution to generate new functional materials is still open to substantial exploration, especially in the field of biomaterials. Rational design strategies tend to be laborious and require detailed information about the biological objects being used for the engineering goal. Significant progress is being made to artificially induce evolution of key functional biological molecules, enzymes (functional protein scaffolds with newly evolved active sites or ‘‘folds”) [123,126], nucleic acid and drug molecules [127], and entire genomes. Directed evolution has also been applied to streamlining the performances of targeting peptides, antibodies and viral vectors [128]. Theoretically the evolution of differential molecular selection in engineered microorganisms (principally bacteria and viruses) can lead to outputs of biomaterial molecular building blocks at one level and self-organising supramolecular materials at a higher order (Fig. 4D) [4]. Techniques for designing bacterial genetic and signalling circuits that can be induced at will provide a mechanism for Multi-level ‘‘curli” amyloid biofilm based materials that can be chemically specified have been engineered inside E. coli cells [90]. The fine-tuning of the E. coli gene network leads to downstream regulation of curli fibre secretions, depositions and the final self-assembly of ordered protein structures. The objective of this study is removed from an immediate biomedical application and was directed to the coherence of metallic inorganic nanoparticles (gold), quantum dots, (cadmium (Cd) and zinc (Zns)) and soft matter properties [90,129]. Evolution has been applied in the laboratory to small organisms with their rapid reproduction cycles spanning manageable time scales of weeks and months. It has been forcibly accelerated, directed and targeted to one or more segments of the genome and recreated within artificial cells and basic artificial life forms. Some of these forced manipulations for evolution can also occur spontaneously, during evolutionary transformations, many others do not arise naturally. Such manipulations are used to promote

evolution in the laboratory. Such techniques can be applied into fabrication of novel biomaterials or formative substrates for new biomaterials and biomimetic analogues using the mechanics of evolution by natural selection. Bacteria can serve as factories for biomaterial proteins. The strategies for implementing evolution in the laboratory have varied with a number of promising approaches tied in with the principle of variation and selection. We now briefly highlight the technical coverage of general approaches, which will drive the synthetic fabrication of novel biomaterial analogues, in whole or the component parts of biomaterials, using the mechanics of evolution by natural selection. Two techniques for harnessing, will be prominent, accelerated evolution by MAGE, CAGE, CRSPR-Cas9 editing and directed evolution. The cycle of igniting variation, sifting and capturing best performing variants and then replicating them to generate populations with the desirable traits, features and functions is often too slow as mutations are rare, but also their selection is much rarer. In the laboratory there are new techniques for deliberately increasing yield of mutations in a single genome, called Multiplex Genome Engineering, MAGE (multiplex automated genome engineering) and CAGE (conjugative assembly genome) [130,131]. These techniques will ensure that it is done efficiently within short timeframes and with fewer complicated steps and procedures. One of the first main requirements in experimental evolution is genetic manipulation to increase variation and to accelerate the process. Directed evolution is the overall technique employing some of these techniques and guiding the real time evolution towards the designated goal. In the next sections we describe the prominent and most important technical procedure to enable evolution to operate on our chosen living systems-viruses and microorganisms (and speculatively living eukaryote cells). 4.1. The directed evolution technique In the lab there is no convention for allowing evolution to take its course through multiple rounds of variation and selection. There is always a deliberate aim for a useful function. This is a process much like artificial selection but is more invasive than ‘‘farming” living organisms for new and useful traits and properties. This has been applied widely to enzymes, nucleic acids and proteins for 45 years [132]. One of the first directed evolution technologies is (bacterio)phage display and has been useful in materials development [129]. Phage display was used to pick-out peptides with binding strengths for specific surfaces molecular signatures and for peptides with specific binding affinities for inorganic elements. Living systems are evolvable, self-organising, environmentally responsive. These are characteristics desired for synthetic and artificial materials and objects as new and useful with exceptional, ideal functions of evolvability, self-healing, self-adaptation. The synthesis is molecular based, autonomous and environmentally benign. The generation of genetic libraries, representing variation, preferential selection and replication of favoured variants is all tightly controlled and regulated in the laboratory [4,133]. Directed evolution alongside accelerated evolution mechanisms are helping to hasten the capabilities to generate many structural and sequenced variants of DNA, RNA, proteins etc. Improved biomolecule functions arise from implementing directed evolution, gradually selecting ideal changes [134]. The range and diversity of biomolecules has been limited by the large efforts needed to create variation, screen every candidate and gradually focus on the most ideal candidates. There have been attempts to streamline this process with small-scale engineering devices such as, micro capillary networks. Engineered devices establish fast, automated screening of best candidates for instance by sorting inside a microfluidic network [125]. It is claimed that protein with DNA interactions, catalytic efficiencies and inhibitor resilience is increased 1000 s of

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times. The manufacture of genetic and molecular diversity is the driving force for evolutionary change by selection. There are numerous methods of doing this. DNA shuffling is a powerful artificial instigator of diversity among biomolecules. 4.2. Directed evolution of biomaterials related to regeneration This describes a protocol for evolving the manufacture of better performing and useful biomaterial substances using evolvable micro-organisms and viruses. The protocol can also apply to artificial cells and protocells, made from lipids or inorganics. The application of directed evolution can be speculatively extended from molecules, supramolecules to the whole biomaterial. This is the most ambitious, yet the most incomplete project for evolution of biomaterials. The question is how to select and at what level selection can act (genetic or cellular) – gradually and without disrupting other functions – the biomaterial variants, with the desired regeneration boosting traits and functions – increased migration [135,136] and proliferation. It is only feasible to carry out positive and negative selection (of winners and losers) using basic assays that represent very simple parts of the regeneration process such as, chemotaxis in modified Boyden chambers (i.e. polymorphonuclear leukocytes PMLs and macrophage movement to injury sites) [137], collective migration with a scratch, physical barrier and chemical assay [138] and ECM matrix expansion and organisation with the aid of microfluidics. Unlike the directed evolution of enzymes and proteins there is no activity that allows for automated recycling of successful variants into the next round of variation. Unless the biomaterials used in the directed evolution system is itself a living biocomposite material. One possibility is to harness small prokaryotic organisms capable of self-secreting native materials and structures that can be directly used in a tissue regenerative capacity. That is, a material integrated within wellorganised living autonomous cells and tissues. Relatively simple Diatom shells can be employed as diffuse scaffolding to mineralised tissue regeneration. Diatoms are open to rounds of mutations and selection for structures with ideal tissue support, repair and regeneration capacities [119]. Viruses and bacteria are readily available for directed evolutionary based selection of genetically encoded secreted structures (skeletons and frameworks) that can yield organised and ordered materials with biological identities (bacteria surface-layer proteins (S-layer) that self-assemble into nanopore (2–8 nm) networks) [139], or single and hierarchical structures too sophisticated to make synthetically using virus particle building blocks with additional richness in shape size, periodic nanostructure and self-assembled microstructures. They can also be designed to display desired peptides and surface charges to aid their biological application [4,65]. 4.3. Evolution on a chip We have reviewed the different living entities used that undergo real time evolution, then the protocols, procedures to carry out and pressume the controlled evolution of the living entities. Now we describe some of the new technologies that can facilitate and improve the effectiveness and speed of evolution. One very useful technology is microfluidic chambers and conduits or microarrays. It will be increasingly important to have technology systems, preferably minituarised that can automate experimental evolution uniformly, repeatedly with tunability function. Intricate bioreactors can be designed to control the components of the evolution environment. Microfluidic based chips already have the capability to monitor and test for the function of the products of artificial evolution from cells (protocells, viruses, bacteria) incorporated into the chambers. The microfluidic system enables automation and scaling up into technologically viable yields.

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Evolutionary events have been recreated on small chips to recapitulate biological reorganisation into new winning solutions [140]. Microfluidic and microarray platforms could be used to widely distribute environmental variations over cells and microtissues captured inside wells and capillaries. In applying evolution to multicomponent systems beyond individual organisms with a generational cycle, some type of human intervention is necessary. Computer controlled direction for evolution of RNA enzymes (but not organisms or larger biological systems) within microfluidic channels has shown in one instance to drive the process automatically [140]. The population of RNA enzymes grew over time to achieve significantly larger growth rates (compared to starting growths). In an un-automated manual approach there are problems with selecting the winners and losers especially with such a complex process as regeneration, which has so many levels of action. Analysis of cell and tissue responses for regenerative peak events is needed at the selection phase. It is difficult to define what makes a particular biomaterial a success only in the position of a living tissue. Microfluidic chips may herald the way to create a quasi living system that simulates a regeneration environment – specifically in vivo-like microenvironments – perhaps leading to regeneration on a chip as a model system [141]. Microfluidic systems engender good possibilities for recreating the physics of cell microenvironment and cellular assemblies, soluble gradients of chemical signals and mechanical gradients, solid-state chemical signals and create available space for single cells, cell sheets and small organoid assemblies. The control they give to spatial organisation, fluid properties, physical, chemical and mechanical cues, biological systems for vascular channels and neuronal regeneration have been fabricated within microfluidic devices [97,142,143].

5. Discussion and future prospects Use of evolutionary concepts and mechanisms in medicine has significantly expanded our understanding of the underlying mechanics of various infectious diseases including cancer. So far, evolutionary explanations of diverse regeneration biologies and the comparative contrasts between different regeneration mechanisms and processes in other organisms have not provided sufficient leads for human therapeutic strategies. Although a variety of molecular and cellular mechanisms are understood, it has been difficult to translate and deliver them into the human system, which lacks plasticity to perform rapid changes in phenotype and collective re-arrangements (triumph of embryological development) and re-ordering. Events such as the formation of a blastema have no foundation in the adult human body. Central to current progress has been the examination and understanding of molecular mechanisms in networks and microscopic environments controlling cell behaviour, interactions and activities. There is a new wave of interest in building biological and biomaterial systems that independently evolve to any circumstance. Still much of the information about how natural selection events have given rise to diversity is absent. Uncovering the important detail relating to differences between varieties of biomaterials and functional structures in organisms, specifically in molecular detail, will open up ‘‘vast solutions” for use in manufacturing new and mimetic materials. The molecular underpinning to diversity can be interpreted through bioinformatic datasets. This will open the way for exploring all the possible solutions that work for any given criteria. Using Evolutionary based methods will allow us to explore more of these solutions. However we must realise that computational and fast-processing experiments, with bioinformatics ‘‘big data” will be needed in tandem to search and capture ideal solutions [NSF Biomaterials Workshop, Biomaterials: important areas for future investment].

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We have considered the possibility of using specific kinds of evolutionary knowledge such as comparative regeneration and biomaterial phylogenies, and applying it to how we design and manufacture materials for tissue engineering. The use of evolutionary knowledge (information or as a device for innovation) to generate biomaterials with a set of pre-defined qualities, characters and behaviours is relatively unexplored and unexploited in regenerative medicine. At a mechanistic or process level the integration into materials synthesis and fabrication is more facile. Deconstruction of evolutionary trends across the biological history of regeneration in different organisms allows us to rediscover strategies that are lost in humans but may still retain the framework for future use. Such studies will highlight the missing parts to exceptional regeneration and indicate the most effective strategic routes to imitate. This information underpins the development of new potential fixes for the human biosystem. Tissue engineers have yet to achieve perfected functional mimicry of artificial organs and tissues, which have suppressed the range and diversity of clinically acceptable tissue-engineered products to corneal surfaces [144], skin explants, trachea implants [145] and patch implants for bladder [146], cartilage [147] and bone [148]. A more fundamental problem hindering progress is the incapacity to regenerate tissues, of any kind, in quantities that meet the needs of everyday surgery. Generating adequate numbers of cells with a mixture of tissue specific phenotypes and genotypes will be vital in this regard. Biomaterials too, are a core component in both tissue engineering and cell therapy, and they will continue to be a prime contributor to the clinical translation of artificially contrived tissue analogues with all their available biological richness and diversity. Knowledge of evolution and the development of biological complexity can play a larger role in this regard. So far, we have seen a paucity of biomaterial manufacturing developments incorporating knowledge gleaned from evolutionary history and comparative studies among taxa and full use of evolutionary mechanisms to recreate analogues and materials without natural counterparts or comparisons. Thus, in this perspective, we have argued for a greater appreciation of evolutionary information, often beyond human biology and throughout evolutionary history as a good source of potential for innovation in biomaterial science and regeneration therapy. Evolutionary knowledge can strongly contribute towards the goal of stronger mimicry and biological realism in biomaterials. We have specifically highlighted the main evolutionary-based themes that can yield clinically acceptable enhancements to current and future biomaterial design and fabrication. In addition, we have described the rationale of using tools from evolutionary history, lineage progression and development. These tools provide us with a fresh biological understanding of the origin and diversification of mechanisms and processes leading to functional adaptations. An evolutionary perspective asks questions about why development progresses in the way it does, and it can offer a more complete understanding of evolutionary constraints, enacted trade-offs and refinements that shaped the entire process of tissue and organ design and construction. Another role for an evolutionary perspective is to use natural selection to develop the most optimised solution available. These approaches are rooted in traditional themes of Darwinian evolution. There are mechanistic and technical driven approaches that harness the mechanism of natural selection to generate ideal adaptations and optimisations among biomolecules and natural and artificial cells. There is also the strong possibility of harnessing, recent emerging technological innovations: synthetic biology incorporating protocells and artificial life forms, design via computer driven evolutionary algorithms and the use of microdevices to automate natural selection of RNA. As yet there is no example related to supramolecules or materials.

In contrast to harnessing the lessons of design and productions from evolutionary along a biomimetic and bioinspired pathway we can learn how to capture the natural selection mechanism at play in Darwinian evolution to generate nature based unnatural clinical biomaterials. Implementation of evolutionary mechanisms, such as selection based on survival capacity, to generate tissues de novo as well as to fabricate materials, structures and devices for regenerative purposes have not progressed and properly developed. In this review we have attempted to highlight where knowledge of evolution can be successfully harnessed in regenerative medicine including the strong innovative possibilities of using laboratory evolution techniques to shape the design and function of biomaterials. And this has advantages over rational design approaches, where there is no need to have an understanding of the connections and interplay between molecular structures, compositions and their functions. It has been far simpler to synthetically evolve biological molecules. This has been standard practice for many years to generate tailored variants and diversity among proteins (in their structure and function). Laboratory induced evolution has been a common practice in re-programming microorganisms such as E. coli. The process of change and adaptation and the regulatory networks involved in generating diversity to confront external survival and fitness challenges is leading to solutions via mathematical modelling, large, in-depth computations using bioinformatics data, frequently by comparisons. The focus on the genetic mechanisms that drive adaptation and innovation is important for the development of an evolutionary model designed to generate practical levels of biomaterial diversity and richness. Faithfully carried out, Darwinian evolution of complete materials and structures in complex forms is not feasible, as natural selection requires a large spread of variation to act upon and allow for selection of viable alternatives. Directed evolution is the primary Darwinian evolution analogue for in-lab experimentation. Darwinian evolution and its directed analogue require large libraries of generated variants to start with (Darwinian randomly and directed deliberately). Selection via directed evolution is deliberately focused and not guided to deliver the best survival benefits. It also requires long periods of time (tens of thousands of generations) to create optimised adaptations that strongly maximize fitness. These winning solutions are therefore hard to collect. Use of bacteria vectors to express molecules and supra molecules for further self-assembly though is a feasible strategy with rapid ‘‘real-time” evolution in weeks and months. It is also feasible to produce viable yields of biomaterials and biomaterial substrates for self-organised assembly. Synthetic cells could be designed to manufacture materials autonomously via a genetic and metabolic program. We have highlighted, from preliminary and speculative groundwork, the implementation strategies that are available when using evolutionary comparisons and natural selection to improve the design and fabrication of biomaterials for tissue engineering. There may be many more possibilities and opportunities to harness these strategies for developing innovative biomaterials in medicine with special adaptations and for a range of other therapeutic purposes such as, drug and ‘‘non-viral” gene delivery, immune modulation and as complement carriers for supporting tissue growth, maintenance and regeneration. 6. Conclusion and future prospects We have championed strategies to integrate the drivers of Darwinian evolution as a tool for better biomimetic design and fabrication of ideal clinical biomaterials, (nature-based, products of biology systems, human and non human) biomaterials with the principal innovative products that tend to arise from Darwinian evolution: evolvability, self organising, environmentally

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responsive (Fig. 1). We have delineated two learning courses from Darwinian evolution. One is the products of evolution we aspire to ‘‘capture” and mimic and the second being harnessing and direct use of the evolutionary mechanisms themselves. It must be noted that self-organisation is sometimes harnessed as an alternative for generating complexity in biological systems. As defined the evolvable biomaterials are nature-based and products of living systems. Principally Darwinian selection is applied to the molecules and to genetically modulated single cell organisms and viruses. These are fast and effective model biological systems of experimental and directed evolution. Microfluidic based evolution-on-a-chip apparatus will be highly important in making experimental evolution more widely available and easier to implement. Artificial and directed evolutions have been successfully applied to small molecules and small single-celled prokaryotes. Evolution may be applied to living eukaryote cells to design and shape materials synthesis and tissue generation. Bacteria can be used as factories for manufacturing tailored biomaterial supramolecules. Darwinian selection can be applied to fabricate, shape and synthesize biomaterials de novo. There is also some potential to use Darwinian selection (not in a true sense since the competitive selection is imposed externally by the experimenter) to delineate nature derived and living cell/viral based biomaterials with the ideal properties for regeneration (directed differentiation with proliferation, good anatomical replication). Biomaterials can be placed into a series of rounds of making variation and winner selection with simple regeneration assays (chemotaxis, lineage determination). So far, judged from the published literature, viral based biomaterials with strong biomimicry to a variety of human tissues (mimicking the structure of collagen at many scales) have shown the greatest development to become clinically useful. Finally, well honed pattern recognition tools, for analysing and determining phylogenetic, cladistic and evolutionary interrelationships between organisms can be harnessed to chart functional adaptations in the development of biomaterial designs throughout evolutionary history. The information extracted from the evolutionary history of design can be implemented usefully in the production of nature-based and synthetic biomaterials. Funding statement This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIP) (No. 2014R1A2A1A11050764). This research was supported by the Bio & Medical Technology Development Program of the National Research Foundation (NRF) funded by the Korean government (MSIP) (No. 2012M3A9B4028738). References [1] C. Zimmer, The surprising origins of life’s complexity, Sci. Am. 309 (2013) 84– 89. [2] H.E. Jin, J. Jang, J. Chung, H.J. Lee, E. Wang, S.W. Lee, W.J. Chung, Biomimetic self-templated hierarchical structures of collagen-like peptide amphiphiles, Nano Lett. 15 (2015) 7138–7145. [3] W.J. Chung, J.W. Oh, K. Kwak, B.Y. Lee, J. Meyer, E. Wang, A. Hexemer, S.W. Lee, Biomimetic self-templating supramolecular structures, Nature 478 (2011) 364–368. [4] A.V. Bryskin, A.C. Brown, M.M. Baksh, M.G. Finn, T.H. Barker, Acta Biomater. 10 (2014) 1761. [5] T.J. Kawecki, R.E. Lenski, D. Ebert, B. Hollis, I. Olivieri, M.C. Whitlock, Experimental evolution, Trends Ecol. Evol. 27 (2012) 547–560. [6] A. Atala, F.K. Kasper, A.G. Mikos, Engineering complex tissues, Sci. Transl. Med. 4 (2012). 160rv12. [7] K.A. Athanasiou, R. Eswaramoorthy, P. Hadidi, J.C. Hu, Self-organization and the self-assembling process in tissue engineering, Annu. Rev. Biomed. Eng. 15 (2013) 115–136. [8] K.C. Rustad, M. Sorkin, B. Levi, M.T. Longaker, G.C. Gurtner, Strategies for organ level tissue engineering, Organogenesis 6 (2010) 151–157.

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[9] M. Mehta, K. Schmidt-Bleek, G.N. Duda, D.J. Mooney, Biomaterial delivery of morphogens to mimic the natural healing cascade in bone, Adv. Drug Deliv. Rev. 64 (2012) 1257–1276. [10] M.M. Stevens, J.H. George, Exploring and engineering the cell surface interface, Science 310 (2005) 1135–1138. [11] E.S. Place, N.D. Evans, M.M. Stevens, Complexity in biomaterials for tissue engineering, Nat. Mater. 8 (2009) 457–470. [12] N.P. Murphy, K.J. Lampe, Mimicking biological phenomena in hydrogel-based biomaterials to promote dynamic cellular responses, J. Mater. Chem. B 3 (2015) 7867–7880. [13] R.J. Wade, J.A. Burdick, Engineering ECM signals into biomaterials, Mater. Today 15 (2012) 454–459. [14] G.C. Gurtner, S. Werner, Y. Barrandon, M.T. Longaker, Wound repair and regeneration, Nature 453 (2008) 314–321. [15] N. Huebsch, D.J. Mooney, Inspiration and application in the evolution of biomaterials, Nature 462 (2009) 426–432. [16] J. Kim, W.A. Li, Y. Choi, S.A. Lewin, C.S. Verbeke, G. Dranoff, D.J. Mooney, Injectable, spontaneously assembling, inorganic scaffolds modulate immune cells in vivo and increase vaccine efficacy, Nat. Biotechnol. 33 (2015) 64–72. [17] M.F. Maitz, U. Freudenberg, M.V. Tsurkan, M. Fischer, T. Beyrich, C. Werner, Bio-responsive polymer hydrogels homeostatically regulate blood coagulation, Nat. Commun. 4 (2013) 2168. [18] S. Pacelli, V. Manoharan, A. Desalvo, N. Lomis, K.S. Jodha, S. Prakash, A. Paul, Tailoring biomaterial surface properties to modulate host-implant interactions: implication in cardiovascular and bone therapy, J. Mater. Chem. B 4 (2015) 1586–1599. [19] M. Colill, B. Gonzálezab, M. Vallet-Regíand, Mesoporous silica nanoparticles for the design of smart delivery nano devices, Biomater. Sci. 1 (2013) 114– 134. [20] R.M. Boehler, J.G. Graham, L.D. Shea, Tissue engineering tools for modulation of the immune response, Biotechniques 51 (2011) 239–240. [21] H. Geckil, F. Xu, X. Zhang, S. Moon, U. Demirci, Engineering hydrogels as extracellular matrix mimics, Nanomedicine (London) 5 (2010) 469–484. [22] X. Wang, B. Ding, C. Li, Biomimetic electrospun nanofibrous structures for tissue engineering, Mater. Today (Kidlington) 1 (2013) 229–241. [23] L. Cai, S.C. Heilshorn, Designing ECM-mimetic materials using protein engineering, Acta Biomater. 10 (2014) 1751–1760. [24] A. Shekaran, A.J. Garcia, Nanoscale engineering of extracellular matrixmimetic bioadhesive surfaces and implants for tissue engineering, Biochim. Biophys. Acta 2011 (1810) 350–360. [25] V. Marx, Tissue engineering: organs from the lab, Nature 522 (2015) 373– 377. [26] S. Lv, D.M. Dudek, Y. Cao, M.M. Balamurali, J. Gosline, H. Li, Designed biomaterials to mimic the mechanical properties of muscles, Nature 465 (2010) 69–73. [27] H. Li, Y. Cao, Protein mechanics: from single molecules to functional biomaterials, Acc. Chem. Res. 43 (2010) 1331–1341. [28] M.P. Lutolf, J.A. Hubbell, Synthetic biomaterials as instructive extracellular microenvironments for morphogenesis in tissue engineering, Nat. Biotechnol. 23 (2005) 47–55. [29] J. Patterson, M.M. Martinoa, J.A. Hubbell, Biomimetic materials in tissue engineering, Mater. Today 13 (2010) 14–22. [30] T.N. Vo, F.K. Kasper, A.G. Mikos, Strategies for controlled delivery of growth factors and cells for bone regeneration, Adv. Drug Deliv. Rev. 64 (2012) 1292– 1309. [31] K. Lee, E.A. Silva, D.J. Mooney, Growth factor delivery-based tissue engineering: general approaches and a review of recent developments, J. R. Soc. Interface 8 (2011) 153–170. [32] C. Chiappini, E. De Rosa, J.O. Martinez, X. Liu, J. Steele, M.M. Stevens, E. Tasciotti, Biodegradable silicon nanoneedles delivering nucleic acids intracellularly induce localised in vivo neovascularisation, Nat. Mater. 14 (2015) 532–539. [33] X. Guo, L. Huang, Recent advances in nonviral vectors for gene delivery, Acc. Chem. Res. 45 (2012) 971–979. [34] J. Wang, Z. Lu, M.G. Wientjes, J.L. Au, Delivery of siRNA therapeutics: barriers and carriers, AAPS J. 12 (2010) 492–503. [35] J.K. Lam, M.Y. Chow, Y. Zhang, S.W. Leung, SiRNA versus miRNA as therapeutics for gene silencing, Mol. Ther. Nucleic Acids 4 (2015) e252. [36] Y. Barkov-Zrihen, K.D. Green, K.J. Labby, M. Feldman, S. Garneau-Tsodikova, M. Fridman, Synthesis and evaluation of hetero- and homodimers of ribosome-targeting antibiotics: antimicrobial activity, in vitro inhibition of translation, and drug resistance, J. Med. Chem. 56 (2013) 5613–5625. [37] D.N. Wilson, Ribosome-targeting antibiotics and mechanisms of bacterial resistance, Nat. Rev. Microbiol. 12 (2014) 35–48. [38] H. Pinto-Alphandary, A. Andremont, P. Couvreur, Targeted delivery of antibiotics using liposomes and nanoparticles: research and applications, Int. J. Antimicrob. Agents 13 (2000) 155–168. [39] K. Chen, X. Chen, Integrin targeted delivery of chemotherapeutics, Theranostics 17 (2011) 189–200. [40] D. Nikitovic, K. Kouvidi, R.M. Kavasi, A. Berdiaki, G.N. Tzanakakis, Hyaluronan/ Hyaladherins – a promising axis for targeted drug delivery in cancer, Curr. Drug Deliv. 13 (2016) 500–511. [41] S. Mitragotri, P.A. Burke, R. Langer, Overcoming the challenges in administering biopharmaceuticals: formulation and delivery strategies, Nat. Rev. Drug Discovery 13 (2014) 655–672.

Please cite this article in press as: D.W. Green et al., Diversification and enrichment of clinical biomaterials inspired by Darwinian evolution, Acta Biomater. (2016), http://dx.doi.org/10.1016/j.actbio.2016.06.039

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D.W. Green et al. / Acta Biomaterialia xxx (2016) xxx–xxx

[42] T.H. Tran, M.M. Amiji, Targeted delivery systems for biological therapies of inflammatory diseases, Expert Opin. Drug Deliv. 12 (2015) 393–414. [43] P.K. Mishra, A. Gulbake, A. Jain, S.P. Vyas, S.K. Jain, Targeted delivery of an anti-cancer agent via steroid coupled liposomes, Drug Deliv. 16 (2009) 437– 447. [44] B. Finan, B. Yang, N. Ottaway, K. Stemmer, T.D. Müller, C.X. Yi, K. Habegger, S. C. Schriever, C. García-Cáceres, D.G. Kabra, J. Hembree, J. Holland, C. Raver, R.J. Seeley, W. Hans, M. Irmler, J. Beckers, M.H. de Angelis, J.P. Tiano, F. MauvaisJarvis, D. Perez-Tilve, P. Pfluger, L. Zhang, V. Gelfanov, R.D. DiMarchi, M.H. Tschöp, Targeted estrogen delivery reverses the metabolic syndrome, Nat. Med. 18 (2012) 1847–1856. [45] N.A. Hotaling, L. Tang, D.J. Irvine, J.E. Babensee, Biomaterial strategies for immunomodulation, Annu. Rev. Biomed. Eng. 17 (2015) 317–349. [46] S. Franz, S. Rammelt, D. Scharnweber, J.C. Simon, Immune responses to implants – a review of the implications for the design of immunomoldulatory biomaterials, Biomaterials 32 (2011) 6692–6709. [47] C. Mora-Solano, J.H. Collier, Engaging adaptive immunity with biomaterials, J. Mater. Chem. B: Mater. Biol. Med. 2 (2014) 2409–2421. [48] A. Purwada, K. Roy, A. Singh, Engineering vaccines and niches for immune modulation, Acta Biomater. 10 (2014) 1728–1740. [49] T.A. Petrie, J.E. Raynor, D.W. Dumbauld, T.T. Lee, S. Jagtap, K.L. Tampleman, D. M. Collard, A.J. Garcia, Multivalent integrin-specific ligands enhance tissue healing and biomaterial integration, Sci. Transl. Med. 2 (2010) 45–60. [50] T.A. Petrie, J.E. Raynor, C.D. Reyes, K.L. Burns, D.M. Collard, A.J. García, The effect of integrin-specific bioactive coatings on tissue healing and implant osseointegration, Biomaterials 29 (2008) 2849–2857. [51] A.E. Porter, L.W. Hobbs, V.B. Rosen, M. Spector, The ultrastructure of the plasma-sprayed hydroxyapatite-bone interface predisposing to bone bonding, Biomaterials 23 (2002) 725–733. [52] S.F. Badylak, D.O. Freytes, T.W. Gilbert, Extracellular matrix as a biological scaffold material: structure and function, Acta Biomater. 5 (2009) 1–13. [53] C.M. Nelson, J. Tien, Microstructures extracellular matrices in tissue engineering and development, Curr. Opin. Biotechnol. 17 (2006) 518–523. [54] J.A. Hubbell, Materials as morphogenetic guides in tissue engineering, Curr. Opin. Biotechnol. 14 (2003) 551–558. [55] K. Shapira-Schweitzer, D. Seliktar, Matrix stiffness affects spontaneous contraction of cardiomyocytes cultured within a PEGylated fibrinogen biomaterial, Acta Biomater. 3 (2007) 33–41. [56] S.F. Badylak, Regenerative medicine and developmental biology: the role of the extracellular matrix, Anat. Rec. B: New Anat. 287 (2005) 36–41. [57] M.A. Fernandez-Yague, S.A. Abbah, L. McNamara, D.I. Zeugolis, A. Pandit, M.J. Biggs, Biomimetic approaches in bone tissue engineering: integrating biological and physicomechanical strategies, Adv. Drug Deliv. Rev. 84 (2015) 1–29. [58] G. Zhang, Biomimicry in biomedical research, Organogenesis 8 (2012) 101– 102. [59] A.D. Metcalfe, M.W. Ferguson, Tissue engineering of replacement skin: the crossroads of biomaterials, wound healing, embryonic development, stem cells and regeneration, J. R. Soc. Interface 4 (2007) 413–437. [60] S. Ud-Din, S.W. Volk, A. Bayat, Regenerative healing, scar-free healing and scar formation across the species: current concepts and future perspectives, Exp. Dermatol. 23 (2014) 615–619. [61] M.S. Hu, Z.N. Maan, J.C. Wu, R.C. Rennert, W.X. Hong, T.S. Lai, A.T. Cheung, G.G. Walmsley, M.T. Chung, A. McArdle, M.T. Longaker, H.P. Lorenz, Tissue engineering and regenerative repair in wound healing, Ann. Biomed. Eng. 42 (2014) 1494–1507. [62] R.A. Meyer, J.C. Sunshine, J.J. Green, Biomimetic particles as therapeutics, Trends Biotechnol. 33 (2015) 514–524. [63] Y. Xia, W. Li, C.M. Cobley, J. Chen, X. Xia, Q. Zhang, M. Yang, E.C. Cho, P.K. Brown, Gold nanocages: from synthesis to theranostic applications, Acc. Chem. Res. 44 (2011) 914–924. [64] T. Garg, G. Rath, A.K. Goyal, Biomaterials-based nanofiber scaffold: targeted and controlled carrier for cell and drug delivery, J. Drug Target. 23 (2015) 202–221. [65] A. Merzlyak, S. Indrakanti, S.W. Lee, Genetically engineered nanofiber-like viruses for tissue regenerating materials, Nano Lett. 9 (2009) 846–852. [66] S. Zhang, Fabrication of novel biomaterials through molecular self-assembly, Nat. Biotechnol. 21 (2003) 1171–1178. [67] A. Prokop, Bioartificial organs in the twenty-first century: nanobiological devices, Ann. N.Y. Acad. Sci. 944 (2001) 472–490. [68] N.C. Rivron, J. Rouwkema, R. Truckenmüller, M. Karperien, J. De Boer, C.A. Van Blitterswijk, Tissue assembly and organization: developmental mechanisms in microfabricated tissues, Biomaterials 30 (2009) 4851–4858. [69] T.J. Huang, B.K. Juluri, Biological and biomimetic molecular machines, Nanomedicine (London) 3 (2008) 107–124. [70] C.R. Lowe, Nanobiotechnology: the fabrication and applications of chemical and biological nanostructures, Curr. Opin. Struct. Biol. 10 (2000) 428–434. [71] P.X. Ma, Biomimetic materials for tissue engineering, Adv. Drug Deliv. Rev. 60 (2008) 184–198. [72] F. Barthelat, Biomaterials for next generation materials, Philos. Trans. A: Math. Phys. Eng. Sci. 365 (2007) 29072919. [73] C. Sanchez, H. Arribart, M.M. Guille, Biomimetism and bioinspiration as tools for the design of innovative materials and systems, Nat. Mater. 4 (2005) 277– 288. [74] Y. Chau, Y. Luo, A.C. Cheung, Y. Nagai, S. Zhang, J.B. Kobler, S.M. Zeitels, R. Langer, Incorporation of a matrix metalloproteinase-sensitive substrate into

[75] [76]

[77] [78]

[79]

[80]

[81]

[82]

[83]

[84] [85]

[86] [87]

[88]

[89] [90]

[91]

[92] [93] [94]

[95]

[96]

[97]

[98]

[99] [100]

[101]

[102]

[103]

[104]

self-assembling peptides – a model for biofunctional scaffolds, Biomaterials 29 (2008) 1713–1719. J.L. West, J.A. Hubbell, Polymeric biomaterials with degradation sites for proteases involved in cell migration, Macromolecules 32 (1999) 241–244. A. Mata, Y. Geng, K. Henrikson, C. Aparicio, S. Stock, R.L. Satcher, S.I. Stupp, Bone regeneration mediated by biomimetic mineralization of a nanofiber matrix, Biomaterials 31 (2010) 6004–6012. J.H. Collier, T. Segura, Evolving the use of peptides as components of biomaterials, Biomaterials 32 (2011) 4198–4204. Z. Luo, Y. Yue, Y. Zhang, X. Yuan, J. Gong, L. Wang, B. He, Z. Liu, Y. Sun, J. Liu, M. Hu, J. Zheng, Designer D-form self-assembling peptide nanofiber scaffolds for 3-dimensional cell cultures, Biomaterials 34 (2013) 4902–4913. K.B. Fonseca, D.B. Gomes, K. Lee, S.G. Santos, A. Sousa, E.A. Silva, D.J. Mooney, P.L. Granja, C.C. Barrias, Injectable MMP-sensitive alginate hydrogels as hMSC delivery systems, Biomacromolecules 15 (2014) 380–390. J. Patterson, J.A. Hubbell, Enhanced proteolytic degradation of molecularly engineered PEG hydrogels in response to MMP-1 and MMP-2, Biomaterials 31 (2010) 7836–7845. C.A. Custódio, R.L. Reis, J.F. Mano, Engineering biomolecular microenvironments for cell instructive biomaterials, Adv. Health Mater. 3 (2014) 797–810. D.Y. Fozdar, P. Soman, J.W. Lee, L.-H. Han, S. Chen, Three-dimensional polymer constructs exhibiting a tunable negative Poisson’s ratio, Adv. Funct. Mater. 21 (2011) 2712–2720. B.M. Holzapfel, J.C. Reichert, J.T. Schantz, U. Gbureck, L. Rackwitz, U. Nöth, F. Jakob, M. Rudert, J. Groll, D.W. Hutmacher, How smart do biomaterials need to be? A translational science and clinical point of view, Adv. Drug Deliv. Rev. 65 (2013) 581–603. M.P. Lutolf, Integration column: artificial ECM: expanding the cell biology toolbox in 3D, Integr. Biol. (Camb.) 1 (2009) 235–241. M.W. Ferguson, S. O’Kane, Scar-free healing: from embryonic mechanisms to adult therapeutic intervention, Philos. Trans. R. Soc. Lond. B: Biol. Sci. 359 (2004) 839–850. S. Sisakhtnezhad, M.M. Matin, Transdifferentiation: a cell and molecular reprogramming process, Cell Tissue Res. 348 (2012) 379–396. C. Eguizabal, N. Montserrat, A. Veiga, J.C. Izpisua Belmonte, Dedifferentiation, transdifferentiation, and reprogramming: future directions in regenerative medicine, in: Semin. Reprod. Med. 31 (2013) 82–94. D.C. Mastellos, R.A. DeAngelis, J.D. Lambris, Complement-triggered pathways orchestrate regenerative responses throughout phylogenesis, Semin. Immunol. 25 (2013) 29–38. J.F.V. Vincent, Survival of the cheapest, Mater. Today 5 (2002) 28–41. A.Y. Chen, Z. Deng, A.N. Billings, U.O. Seker, M.Y. Lu, R.J. Citorik, B. Zakeri, T.K. Lu, Synthesis and patterning of tunable multiscale materials with engineered cells, Nat. Mater. 13 (2014) 515–523. J. Chen, Y. Wang, D. Guo, B. Shen, A systems biology perspective on rational design of peptide vaccine against virus infections, Curr. Top. Med. Chem. 12 (2012) 1310–1319. M.H. Van Regenmortel, The rational design of biological complexity: a deceptive metaphor, Proteomics 7 (2007) 965–975. M.J. Platts, in: M.W. Collins et al. (Eds.), Nature and Design, WIT Press, Southampton, 2005, pp. 157–167. E. de Margerie, P. Tafforeua, L. Rakotomanana, In silico evolution of functional morphology: a test on bone tissue biomechanics, J. R. Soc. Interface 3 (2006) 679–687. M.K. Heljak, W. S´wieszkowski, C.X.F. Lam, D. Hutmacher, K.J. Kurzydlowski, Evolutionary design of bone scaffolds with reference to material selection, Int. J. Numer. Methods Biomed. Eng. 28 (2012) 789–800. J.-H. Lee, Y. Gu, H. Wang, W.Y. Lee, Microfluidic 3D bone tissue model for high-throughput evaluation of wound-healing and infection-preventing biomaterials, Biomaterials 33 (2012) 999–1006. Y. Zheng, J. Chen, M. Craven, N.W. Choi, S. Totorica, A. Diaz-Santana, P. Kermani, B. Hempstead, C. Fischbach-Teschl, J.A. López, A.D. Stroock, In vitro microvessels for the study of angiogenesis and thrombosis, Proc. Natl. Acad. Sci. U.S.A. 109 (2012) 9342–9347. M.N. Dean, C.G. Mull, S.N. Gorb, A.P. Summers, Ontogeny of the tessellated skeleton: insight from the skeletal growth of the round stingray Urobatis halleri, J. Anat. 215 (2009) 227–239. J.H. Waite, C.C. Broomell, Changing environments and structure-property relationships in marine biomaterials, J. Exp. Biol. 215 (2012) 873–883. P.J. Perez-Goodwyn, S.N. Gorb, Frictional properties of contacting surfaces in the hemelytra-hindwing locking mechanism in the bug Coreus marginatus (Heteroptera, Coreidae), J. Comp. Physiol. A. 190 (2004) 575–580. S.N. Gorb, Biological attachment devices: exploring nature’s diversity for biomimetics, Philos. Trans. A: Math. Phys. Eng. Sci. 366 (2008) 1557– 1574. S.N. Gorb, M. Sinha, A. Peressadko, K.A. Daltorio, R.D. Quinn, Insects did it first: a micropatterned adhesive tape for robotic applications, Bioinspiraion Biomimetics 2 (2007) S117–S125. M.K. Kwak, H.E. Jeong, K.Y. Suh, Rational design and enhanced biocompatibility of a dry adhesive medical skin patch, Adv. Mater. 23 (2011) 3949–3953. A. Mahdavi, L. Ferreira, C. Sundback, J.W. Nichol, E.P. Chan, D.J.D. Carter, C.J. Bettinger, S. Patanavanich, L. Chignozha, E. Ben-Joseph, A. Galakatos, H. Pryor, I. Pomerantseva, P.T. Masiakos, W. Faquin, A. Zumbuehl, S. Hong, J. Borenstein, J. Vacanti, R. Langer, J.M. Karp, A biodegradable and

Please cite this article in press as: D.W. Green et al., Diversification and enrichment of clinical biomaterials inspired by Darwinian evolution, Acta Biomater. (2016), http://dx.doi.org/10.1016/j.actbio.2016.06.039

D.W. Green et al. / Acta Biomaterialia xxx (2016) xxx–xxx

[105]

[106] [107]

[108]

[109] [110]

[111] [112] [113] [114] [115]

[116]

[117] [118]

[119] [120] [121] [122] [123] [124]

[125]

[126]

biocompatible gecko-inspired tissue adhesive, Proc. Natl. Acad. Sci. U.S.A. 105 (2008) 2307–2312. D.-M. Drotlef, L. Stepien, M. Kappl, W.J.P. Barnes, H.-J. Butt, A. del Campo, Biomimetics: insights into the adhesive mechanisms of tree frogs using artificial mimics, Adv. Funct. Mater. 23 (2013) 1137–1146. A.D. Roberts, Squeeze films between rubber and glass, J. Phys. D: Appl. Phys. 4 (1971) 423–432. W. Federle, W.J.P. Barnes, W. Baumgartner, P. Drechsler, J.M. Smith, Wet but not slippery: boundary friction in tree frog adhesive toe pads, J. R. Soc. Interface 3 (2006) 689–697. A. Atkins, M.N. Dean, M.L. Habegger, P.J. Motta, L. Ofer, F. Repp, A. Shipov, S. Weiner, J.D. Currey, R. Shahar, Remodeling in bone without osteocytes: billfish challenge bone structure-function paradigms, Proc. Natl. Acad. Sci. U. S.A. 111 (2014) 16047–16052. S.N. Gorb, R.G. Beutel, Evolution of locomotory attachment pads of hexapods, Naturwissenschaften 88 (2001) 530–534. P.A. Guerette, S. Hoon, D. Ding, S. Amini, A. Masic, V. Ravi, B. Venkatesh, J.C. Weaver, A. Miserez, Nanoconfined b-sheets mechanically reinforce the suprabiomolecular network of robust squid sucker ring teeth, ACS Nano 8 (2014) 7170–7179. J. Kohn, New approaches to biomaterials design, Nat. Mater. 3 (2004) 745– 747. S. Lutz, Beyond directed evolution-semi-rational protein engineering and design, Curr. Opin. Biotechnol. 21 (2010) 734–743. U.T. Bornscheuer, M. Pohl, Improved biocatalysts by directed evolution and rational protein design, Curr. Opin. Chem. Biol. 5 (2001) 137–143. C. Pál, B. Papp, G. Pósfai, The dawn of evolutionary genome engineering, Nat. Rev. Genet. 15 (2014) 504–512. J.R. Dettman, N. Rodrigue, A.H. Melnyk, A. Wong, S.F. Bailey, R. Kassen, Evolutionary insight from whole-genome sequencing of experimentally evolved microbes, Mol. Ecol. 21 (2012) 2058–2077. M. Li, R.L. Harbron, J.V. Weaver, B.P. Binks, S. Mann, Electrostatically gated membrane permeability in inorganic protocells, Nat. Chem. 5 (2013) 529– 536. F.H. Arnold, Design by directed evolution, Acc. Chem. Res. 31 (1998) 125– 131. B.R. Wasik, S.F. Lieu, D.A. Lilien, A.J. Dinwiddie, H. Noh, H. Cao, A. Monteiro, Artificial selection for structural color on butterfly wings and comparison with natural evolution, Proc. Natl. Acad. Sci. USA 111 (2014) 12109–12114. N. Kröger, Prescribing diatom morphology: toward genetic engineering of biological nanomaterials, Curr. Opin. Chem. Biol. 11 (2007) 662–669. G.F. Joyce, Directed evolution of nucleic acid enzymes, Annu. Rev. Biochem. 73 (2004) 791–836. S. Kosuri, G.M. Church, Large-scale de novo DNA synthesis: technologies and applications, Nat. Methods 11 (2014) 499–507. G.M. Church, M.B. Elowitz, C.D. Smolke, C.A. Voigt, R. Weiss, Realizing the potential of synthetic biology, Nat. Rev. Mol. Cell Biol. 4 (2014) 289–294. M.J. Dougherty, F.H. Arnold, Directed evolution: new parts and optimized function, Curr. Opin. Biotechnol. 20 (2009) 486–491. P. Asuri, M.A. Bartel, T. Vazin, J.H. Jang, T.B. Wong, D.V. Schaffer, Directed evolution of adeno-associated virus for enhanced gene delivery and gene targeting in human pluripotent stem cells, Mol. Ther. 20 (2012) 329–338. M. Fischlechner, Y. Schaerli, M.F. Mohamed, S. Patil, C. Abell, F. Hollfelder, Evolution of enzyme catalysts caged in biomimetic gel-shell beads, Nat. Chem. 6 (2014) 791–796. F.A. Chao, A. Morelli, J.C. Haugner, L. Churchfield, L.N. Hagmann, L. Shi, L.R. Masterson, R. Sarangi, G. Veglia, B. Seelig, Structure and dynamics of a

[127] [128] [129] [130]

[131] [132] [133]

[134]

[135] [136] [137]

[138] [139]

[140] [141]

[142]

[143] [144]

[145]

[146] [147]

[148]

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primordial catalytic fold generated by in vitro evolution, Nat. Chem. Biol. 9 (2013) 81–83. M.D. Lane, B. Seelig, Advances in the directed evolution of proteins, Curr. Opin. Chem. Biol. 22 (2014) 129–136. K. Hida, J. Hanes, M. Ostermeier, Directed evolution for drug and nucleic acid delivery, Adv. Drug Deliv. Rev. 59 (2007) 1562–1578. A.Y. Chen, C. Zhong, T.K. Lu, Engineering living functional materials, ACS Synth. Biol. 4 (2015) 8–11. H.H. Wang, F.J. Isaacs, P.A. Carr, Z.Z. Sun, G. Xu, C.R. Forest, G.M. Church, Programming cells by multiplex genome engineering and accelerated evolution, Nature 460 (2009) 894–898. J. Jeong, N. Cho, D. Jung, D. Bang, Genome-scale genetic engineering in Escherichia coli, Biotechnol. Adv. 31 (2013) 804–810. L. Yuan, I. Kurek, J. English, R. Keenan, Laboratory-directed protein evolution, Microbiol. Mol. Biol. Rev. 69 (2005) 373–392. Z. Kang, J. Zhang, P. Jin, S. Yang, Directed evolution combined with synthetic biology strategies expedite semi-rational engineering of genes and genomes, Bioengineered 6 (2015) 136–140. J.R. Werkman, S. Pattanaik, L. Yuan, Directed evolution through DNA shuffling for the improvement and understanding of genes and promoters, Methods Mol. Biol. 754 (2011) 325–342. P. Friedl, D. Gilmour, Collective cell migration in morphogenesis, regeneration and cancer, Nat. Rev. Mol. Cell Biol. 10 (2009) 445–457. C.N. Shen, Z.D. Burke, D. Tosh, Transdifferentiation, metaplasia and tissue regeneration, Organogenesis 1 (2004) 36–44. T.A. Robertson, M.A. Maley, M.D. Grounds, J.M. Papadimitriou, The role of macrophages in skeletal muscle regeneration with particular reference to chemotaxis, Exp. Cell Res. 207 (1993) 321–331. R. Riahi, Y. Yang, D.D. Zhang, P.K. Wong, Advances in wound-healing assays for probing collective cell migration, J. Lab. Autom. 17 (2012) 59–65. W.S. Wong, P.T. Yung, Characterization of a nanoscale S-layer protein based template for biomolecular patterning, in: Conf. Proc. IEEE Eng. Med. Biol. Soc., 2014, pp. 2781–2784. B.M. Paegel, G.F. Joyce, Darwinian evolution on a chip, PLoS Biol. 6 (2008) e85. B. Harink, S. Le Gac, R. Truckenmuller, C. van Blitterswiijk, P. Habibovic, Regeneration-on-a-chip? The perspectives on use of microfluidics in regenerative medicine, Lab Chip 13 (2013) 3512–3528. A.M. Taylor, D.C. Dieterich, H.T. Ito, S.A. Kim, E.M. Schuman, Microfluidic local perfusion chambers for the visualization and manipulation of synapses, Neuron 66 (2010) 57–68. L.S. Zweifel, R. Kuruvilla, D.D. Ginty, Functions and mechanisms of retrograde neurotrophin signalling, Nat. Rev. Neurosci. 6 (2005) 615–625. R.J. Tsai, L.M. Li, J.K. Chen, Reconstruction of damaged corneas by transplantation of autologous limbal epithelial cells, N. Engl. J. Med. 343 (2000) 86–93. P. Macchiarini, P. Jungebluth, T. Go, M.A. Asnaghi, L.E. Rees, T.A. Cogan, A. Dodson, J. Martorell, S. Bellini, P.P. Parnigotto, S.C. Dickinson, A.P. Hollander, S. Mantero, M.T. Conconi, M.A. Birchall, Clinical transplantation of a tissueengineered airway, Lancet 372 (2008) 2023–2030. A. Atala, S.B. Bauer, S. Soker, J.J. Yoo, A.B. Retik, Tissue-engineered autologous bladders for patients needing cystoplasty, Lancet 367 (2006) 1241–1246. P. Brun, S.C. Dickinson, B. Zavan, R. Cortivo, A.P. Hollander, G. Abatangelo, Characteristics of repair tissue in second-look and third-look biopsies from patients treated with engineered cartilage: relationship to symptomatology and time after implantation, Arthritis Res. Ther. 10 (2008) R132. R. Quarto, M. Mastrogiacomo, R. Cancedda, S.M. Kutepov, V. Mukhachev, A. Lavroukov, E. Kon, M. Marcacci, Repair of large bone defects with the use of autologous bone marrow stromal cells, N. Engl. J. Med. 344 (2001) 385–386.

Please cite this article in press as: D.W. Green et al., Diversification and enrichment of clinical biomaterials inspired by Darwinian evolution, Acta Biomater. (2016), http://dx.doi.org/10.1016/j.actbio.2016.06.039