Nano Today
Volume 6, Issue 4, August 2011, Pages 332-338
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Shaky foundations of hierarchical biological materials

https://doi.org/10.1016/j.nantod.2011.07.001Get rights and content

Summary

It is popular stance that successful growth – be it structural, economic or biological – requires a stable foundation. The hierarchical structure of native biological materials and tissues introduces variations in form and function across a multitude of scales. Yet, many synthetic scaffolds and substrates in which such materials are assembled, the foundation, are designed at a single scale. The result is an uncertain or shaky foundation for material assembly and tissue growth, where changes in the scaffold properties and architecture result in unpredictable behaviors in tissue development, and proven, reliable scaffolds for one tissue type may be completely unsuitable for another. This is in contrast to the behavior of foundations for civil engineering structures, which provide a decoupling of the foundation from the building design since different foundations can support equivalent functional structures. Current advancements in the design of biologically active foundations shed light on proven scaffolds and substrates, but cannot be used to design and predict success from the bottom-up. This is because while the phenomenological coupling between materials and substrates has been well investigated and has yielded methodologies for biomaterial synthesis, the underlying mechanisms of self-assembly and growth are not fully understood. A potential solution lies in the utilization of hierarchical material foundations, with molecular, fibrillar and other interactions designed across all length- and time-scales with engineered, predictive, and repeatable outcomes. The potential to realize such hierarchical multiscale scaffolds can be found in the exploitation of responsive, or mutable, polymer systems that exhibit precise control and variegated chemical functionalities for applications in diverse areas such as regenerative medicine, cancer treatment or drug delivery.

Highlights

► Successful growth, be it structural, economic or biological, requires a stable foundation. ► The hierarchical structure of biological tissues introduces variations across many scales. ► Many synthetic scaffolds and substrates, the foundations, are often designed at a single scale. ► A potential solution lies in the multiscale design and utilization of hierarchical foundations. ► Such hierarchical, responsive and mutable materials enable applications in diverse areas.

Introduction

The design and assembly of any safe structure requires a thorough knowledge of the foundation. No structural engineer would approve the construction of a skyscraper without a complete geotechnical report, where the stability of the foundation below supports the building above. Yet, at the macroscale, the groundwork and the structure are sufficiently decoupled. As long as the foundation satisfies minimum requirements, there is no adverse effect on the overlying structure. What the building “sees” is limited to a single scale and characterized by the design parameters of the foundation, including settlement restrictions and bearing capacity and such phenomena are at the same scale as the structural system. Assuming that the critical parameters are met, more detailed and smaller scale properties (such as material type or microstructure) have no external affect on the borne structure, and different engineered foundations can support equivalent functional structures. One can design and construct a building independent of the structural foundation, as long as it is assumed a priori that the foundation has satisfied the required design parameters such as maximum settlement and bearing capacity. On a more complex level, one may also consider seismic and slope stability, pore water pressure variation, and other parameters. The point being is that the foundation is designed independently of the structure – one need not know the details of either for a successful design, only the design requirements (Fig. 1a). In the development of biological tissues, however, this fundamental relationship changes. The foundation for nano- and microscale assembly – the material substrate, scaffold, or matrix that will support cellular processes and mechanical requirements – is no longer disassociated from the assembled system; they interact intimately. Consider this: when you walk into a building, be it a residential complex or a shopping mall, can you tell what type of foundation it is built on? The answer, without any other cues, is clearly no. For biological tissues, however, cellular processes recognize the foundation properties at multiple levels, and they are inextricably linked as the details of the foundation define what tissue grows.

Indeed, different substrates induce different affects, are not transferable, and are more complex. The complexity (and hence challenge) arises from the multiscale and hierarchical nature of this relation. Changes can easily be made for system-level properties (such as stiffness, porosity, etc.), but the changes have effects that subsequently cascade downward from the system-level to the fundamental molecular interactions at the nanoscale (Fig. 1b). From a cursory perspective, they are uncertain – or shaky – foundations for assembly. This shaky attribute is a result of a single-scale perspective in the current design paradigm and one that can potentially be remedied if we had the fundamental knowledge to exploit them (both in theory and in practice). Currently, there is no single set of “design parameters” that will satisfy more than the most rudimentary system. Interactions between the functional system and material substrates or scaffolds are inevitably complicated by the multiscale processes that are involved. Tissues and biological materials are commonly hierarchical as there is underlying structure and function at a multitude of diverse scales [1], [2], [3]. As a result, slight variations at a lower scale, such as scaffold topology or material choice, can propagate and express at larger scales, typically to the detriment of the growth or assembly of the system. This is in contrast to macroscale engineered systems, in which structural details, such as spacing of piers for example, do not affect the above structure (assuming alternate designs have equivalent mechanical performance). Likewise, material details, such as the choice of reinforced concrete or structural steel components, do not affect the borne structure. The overlaying structure does not “care” what supports it – it will function the same. Thus, a fundamental challenge of tissue engineering and biological material synthesis lies within the understanding of material–substrate interactions across all scales, from individual atoms, to molecules, to subsequent tissues and entire organisms. Continuing the analogy with foundation engineering, not only do you have to analyze properties of the soil, in the case of biological tissues you have to know the behavior of each individual rock, mineral, and grain.

Certainly, for the construction of a building, the foundation is of little importance to the overlying structure – a post-and-pier foundation on bedrock provides a similar platform to a slab-on-grade over clay, and a home built atop does not change functionality based on the foundation below. On the other hand, it is well known in tissue engineering that different substrates can result in different materials. One important difference is that the tissue grows itself whereas a building is “grown” by the external means (typically construction personnel). In the case of biological tissues the same cells can develop into different tissues depending on the substrate (foundation) they live. For construction, a structure can be designed independently from the foundation, whereas in biology, the foundation may dictate the structure! For example, a promising candidate for a tissue-engineering scaffold is the use of extracellular matrix (ECM), which is a key component in the natural regeneration and maintenance of tissues and organs [4]. Methods of producing ECM-inspired tissue platforms have been successful in replicating the required physiochemical properties and structural features of their natural analogs, but, in most cases, do not match the mechanical properties of the tissue to be regenerated. Yet, the elasticity of the matrix can determine stem cell differentiation: soft matrices are neurogenic, stiffer matrices are myogenic, and rigid matrices are osteogenic [5], [6]. This example focused on a simple and single parameter, stiffness, clearly shows that the properties of the foundation affect the resulting structure.

We must also account for the geometry of the foundation. At the microscale, for example, the advance of rapid prototyping techniques has significantly improved control over the pore network architecture (e.g. pore size, channel geometry) of tissue-engineering scaffolds, which are known to influence the signal expression and subsequent differentiation of a transplanted cell population [7], [8]. Indeed, the interconnectivity of pores, permeability, confinement, and other geometric properties have been shown to affect the transport of oxygen and nutrients throughout tissue scaffolds [7]. There is a multitude of known design parameters considered important to achieve a successful synergy between material and substrate (cell and scaffold), including porosity, interconnectivity, surface properties, mechanical strength, the amounts and types of filler material, cell seeding density, and other exogenous growth factors [9], [10], [11]. The common aspect of such design parameters is that they are typically considered at a single scale. While the results of such property variations are known, the underlying protein/substrate interactions are not fully understood. Be that as it may, such ad hoc approaches are quite advanced and ingenious, and have been successful in delineating appropriate substrates and scaffolds for particular tissues (such as collagen or bone [12]) and biological macromolecular structures (such as amyloid films [13]). However, the specific molecular mechanisms resulting in successful tissue generation remain largely unknown. Often, synthesis is achieved by experimental trials and screening, and the continuous refinement of previous insights. Such steps are necessary for the progression and immediate application to tissue engineering. At this time, a mechanistic framework from the molecules up is not yet practical, but can be attained in the near future.

Section snippets

Challenges and opportunities

The fundamental challenge lies in the complex hierarchical structure of the tissues and materials, where changes at the molecular level propagate and are expressed in unpredictable ways [14], [15]. What a cell (with a diameter of 10–30 μm) in a collagen tissue “sees” can be very different in a natural system than in most currently used tissue-engineering scaffolding biomaterials. The structure and properties of the implemented scaffold are typically designed on the scale of tissue assembly,

Examples and applications

Potential candidates for such mutable materials are stimuli-responsive macromolecular nanostructures. Scaffolds currently used in tissue engineering and cell therapy are mostly passive in that they deliver biological agents mainly through mechanisms involving molecular diffusion, material degradation, and cell migration, which do not allow for dynamic external regulations. Responsive polymer systems exhibit similar features as biological materials, and are capable of conformational and chemical

Conclusion

A fundamental understanding of cross-scale interactions and mechanisms in self-assembly and tissue growth can be used to exploit the process for both biological and synthetic materials. If assembly and growth is dictated by material-substrate interactions, an ability to dynamically tune substrate properties provides vast potential for control across all scales. With increasing complexity, such systems start to resemble their biological counterparts (e.g. adaptation to their surrounding

Acknowledgements

This work was supported by the NSF-MRSEC program and NSF-CAREER. Additional support provided by DOD-PECASE and ONR.

Steven W. Cranford is a Ph.D. candidate in the Department of Civil and Environmental Engineering at the Massachusetts Institute of Technology and a member of the Laboratory for Atomistic and Molecular Mechanics. Cranford's research interests are advanced and novel structural materials at the continuum and atomistic scale, and the incorporation of biological design principles into engineering design at all scales. He holds a Bachelor of Engineering Degree from Memorial University in St. John's

References (44)

  • P. Fratzl et al.

    Progress in Materials Science

    (2007)
  • M.J. Buehler et al.

    Progress in Materials Science

    (2008)
  • A.J. Engler et al.

    Cell

    (2006)
  • F.P.W. Melchels et al.

    Acta Biomaterialia

    (2010)
  • K. Kim et al.

    Biomaterials

    (2011)
  • J.L. Drury et al.

    Biomaterials

    (2003)
  • N.M. Pugno

    Materials Today

    (2010)
  • H. Shin et al.

    Biomaterials

    (2003)
  • G. Chan et al.

    Trends in Biotechnology

    (2008)
  • J.P. Fisher et al.

    Biomaterials

    (2002)
  • R.W. Sands et al.

    Current Opinion in Biotechnology

    (2007)
  • K.S. Brammer et al.

    Acta Biomaterialia

    (2011)
  • H.J. Kim et al.

    Bone

    (2008)
  • B.B. Mandal et al.

    Biomaterials

    (2009)
  • N.M. Pugno

    Nanotechnology

    (2006)
  • H. Fernandes et al.

    Journal of Materials Chemistry

    (2009)
  • D.E. Discher et al.

    Science

    (2005)
  • K. Kim et al.

    Tissue Engineering Part B – Reviews

    (2010)
  • X. Liu et al.

    Nature Materials

    (2011)
  • A. Nandakumar et al.

    Langmuir

    (2010)
  • T.P.J. Knowles et al.

    Nature Nanotechnology

    (2010)
  • N.M. Pugno et al.

    Small

    (2008)
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    Steven W. Cranford is a Ph.D. candidate in the Department of Civil and Environmental Engineering at the Massachusetts Institute of Technology and a member of the Laboratory for Atomistic and Molecular Mechanics. Cranford's research interests are advanced and novel structural materials at the continuum and atomistic scale, and the incorporation of biological design principles into engineering design at all scales. He holds a Bachelor of Engineering Degree from Memorial University in St. John's (Canada) and a Master of Science in Civil Engineering from Stanford University. He received several medals and awards, including a Schoettler Fellowship at MIT, the University Medal in Civil Engineering at Memorial University and the PEG-NL Award of Excellence at Memorial University.

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