Historical perspective
Graphene nanosheets as reinforcement and cell-instructive material in soft tissue scaffolds

https://doi.org/10.1016/j.cis.2020.102167Get rights and content

Highlights

  • Polymeric scaffolds deteriorate quickly due to poor mechanical strength.

  • Graphene sheets can impart desirable strength and porosity to the scaffolds.

  • High surface area enables strong interaction of sheets with the polymers.

  • With a corrugated structure, sheets mediate physiological signals relevant to regeneration.

Abstract

Mechanical strength of polymeric scaffolds deteriorates quickly in the physiological mileu. This can be minimized by reinforcing the polymeric matrix with graphene, a planar two-dimensional material with unique physicochemical and biological properties. Association between the sheet and polymer chains offers a range of porosity commensurate with tissue requirements. Besides, studies suggest that corrugated structure of graphene offers desirable bio-mechanical cues for tissue regeneration. This review covers three important aspects of graphene-polymer composites, (a) the opportunity on reinforcing the polymer matrix with graphene, (b) challenges associated with limited aqueous processability of graphene, and (c) physiological signaling in the presence of graphene. Among numerous graphene materials, our discussion is limited to graphene oxide (GO) and reduced graphene oxide (rGO) nanosheets. Challenges associated with limited dispersity of hydrophobic sheets within the polymeric matrix have been discussed at molecular level.

Introduction

Surgical resection is regarded as the mainstay treatment modality for localized solid tumors showing no signs of regional or distant metastasis. Accompanying damage to the surrounding tissues may cause major functional deficits. Lack of evidences on endogenous tissue regeneration affirms that underlying mechanisms remain conserved in human beings [1]. It necessitates the means of re-configuring and restoring the lost structure following major surgeries. The approach involving transplantation of auto- or allografts is constrained by donor site morbidity, poor immunogenicity and graft resorption [[2], [3], [4]]. Alternatively, microenvironment of damaged tissues can be modulated locally for driving the regenerative process. This has fostered the exploration of polymeric hydrogels (scaffolds), capable of allowing infiltration, division and differentiation of seeded cells [5,6]. Polymeric scaffolds are attractive because of their excellent water-holding ability and structural resemblance to the extracellular matrix (ECM) [[7], [8], [9], [10], [11]]. Their degradation kinetics can be synchronized with the augmentative effects in order to drive the regeneration of scarless tissue. This eliminates the need of secondary surgical procedures for removing the degenerated scaffold [12,13].

Over the past three decades, research on soft tissue scaffolds has evolved to improve the mechanical integrity, biocompatibility and architecture [3,[14], [15], [16], [17]]. Specialized techniques such as lithography, photo-polymerization and micro-robotic techniques have been employed to create the nanoscopic features within the scaffold [3,[17], [18], [19]]. Scaffolds patterned with ordered channels offer superior cell homing as the interconnections allow the diffusion of nutrients, waste, morphogenetic factors and oxygen during regeneration [20,21]. These channels guide uniform expansion of cells, and contribute to reconstitution of a vasculature identical to that of the native tissue. Bioactivity of scaffolds can further be amplified by co-loading peptides, proteins or bioactive molecules to be released independently and guide tissue formation. The network of scaffold minimizes the adverse events and inadequate healing related to quick release of growth factors [[22], [23], [24], [25], [26]]. A number of polymeric materials, both from natural and synthetic origins, have been investigated for scaffold development. These polymers can be processed in aqueous vehicles and desirable biological properties within the scaffold can be attained by blending the components of specific molecular properties. The scaffolds, however, possess limited mechanical strength and undergo quick deterioration in the physiological mileu [11]. This can be mitigated with the use of reinforcement materials, including metal nanoparticles [27], carbon nanotubes [28] and other inorganic carriers [[29], [30], [31]]. Association between the filler and polymer chains offer a range of porosity without damaging biological properties of the scaffold [9].

In this review, we have addressed the mechanical reinforcement of scaffolds using graphene nanosheets. Although a number of graphene materials are known [32], our discussion is limited to graphene oxide (GO) and reduced graphene oxide (rGO). While reviewing the trends on reinforcing soft tissue scaffolds with GO and rGO nanosheets, challenges associated with limited dispersity of sheets within the polymeric matrix have been discussed at molecular level. Next, we have elaborated the functional aspects of sheet incorporation, such as mobilization of growth components, and transmission of physiological signals.

Section snippets

Graphene as reinforcement material

Graphene, a form of sp2 hybridized carbon monolayers, is the strongest material known. It consists of a two dimensional atomic sheet of carbon (C-C distance: 1.42 Å), distributed over the vertices of regular hexagons [33]. Large quantity of graphene sheets can be prepared employing top-down or bottom-up approaches [34]. Methods have been modified to attain novel material properties in context to application of sheets in light emitting devices and biosensors [[35], [36], [37], [38], [39]].

Graphene-polymer interaction

Interfacial interaction between sheets and polymer is dictated by two factors; (i) affinity of sheets for the polymeric groups, and (ii) distribution and physical alignment of sheets along the polymer backbone. Agglomerated graphene colloids may create non-homogeneous association points and weak network islands. This may lead to non-uniform stress distribution within the scaffold. A superior interface can be attained by allowing specific molecular interactions between GO and polymer chain [57].

Cell-instructive roles of graphene

Biochemical response of cells during regenerative events is modulated through chemical and physical signaling cues [80,[104], [105], [106]]. It is thus pertinent to evaluate the instructive role of graphene, apart from its well-described reinforcement effect. With its inherent corrugated structure, graphene can be a potential alternative to expensive lithographic techniques for creating nanoscale topographies [107,108]. Studies suggest that graphene amplifies the biological properties of seeded

Conclusion & perspectives

The research on regenerative applications of graphene-based scaffolds is expanding exponentially. Composites of graphene materials with natural and synthetic polymers tested thus far clearly highlight the role of graphene in improving the mechanical properties. With a high specific area and unique surface chemistry, graphene engages with polymer units to develop dense interconnections. Interfacial interactions can further be modulated through functionalization with small organic moieties,

Declaration of Competing Interest

Authors declare no conflict of interest.

Acknowledgements

ST is thankful to the Science & Engineering Research Board (SERB), India, for funding support under ECRA scheme (#ECR/2017/000903).

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