Elsevier

Journal of Controlled Release

Volume 332, 10 April 2021, Pages 460-492
Journal of Controlled Release

Review article
The triad of nanotechnology, cell signalling, and scaffold implantation for the successful repair of damaged organs: An overview on soft-tissue engineering

https://doi.org/10.1016/j.jconrel.2021.02.036Get rights and content

Highlights

  • The main goal of soft tissue regeneration is to facilitate efficient tissue repair and offer relevant tissue models.

  • Nano-biomaterials provide astounding developments in soft tissue healing at the nanoscale.

  • Synthetic biomaterials have attracted great interest due to high tunability, versatility, and facile functionalization.

  • Hydrogels have been applied in biomedical fields owing to their admirable biocompatibility and high content of water.

  • Scaffolds are regularly constructed from biodegradable polymeric materials categorized as synthetic and natural polymers.

Abstract

As a milestone in therapeutic fields, tissue engineering has offered an alternative strategy to address unmet clinical needs for the repair and replacement of human damaged organs. The premise of regenerative medicine follows an essential triad of cells, substrates, and physiologically active biomolecules to generate advanced therapeutic methods for tissue repair. Biomedical usages of nanotechnology in regenerative medicine are considerably growing. Dynamic three-dimensional nano-environments can deliver bioactive molecular substrates to accelerate the recovery of damaged tissues by inducing the preservation, proliferation, and differentiation of healthy cells. Nanotechnology provides the possibility to optimize the characteristics of scaffolds and tune their biological functionality (e.g., cellular attachment, electrical conductivity, biocompatibility, and cell-differentiation inducing effect). In addition, nanoscale substances can supply scaffolds via releasing several loaded drugs and triggering cellular proliferation to deliver efficient repair of various organs such as bone, cornea, cartilage, and the heart. Overall, the nature of damaged tissues, as well as scaffolds' composition, porous structure, degradability, and biocompatibility are determinant factors for successful tissue engineering. This review has addressed the most recent advances in the tissue engineering of various organs with a focus on the applications of nanomaterials in this field.

Introduction

Organ implantation is restricted by the shortage of accessible donors and expensive processes, leaving numerous patients on transplant waiting lists, many of whom expire before receiving any organ [1]. Lately, tissue engineering has developed as an interdisciplinary field incorporating principles from engineering, material, and life sciences to enhance functional alternatives for injured organs and tissues [2]. Instead of incorporating cells into a defected part to regenerate a tissue and/or return its function, cells are typically embedded in or seeded onto biomaterials prior to transplantation [3]. These samples act as degradable scaffolds and redefine cellular rearrangements to create a functional tissue [4]. The macro-porous structure of the substrates applied in tissue regeneration imitates the conformational features of the matrix itself (artificial or natural). Extracellular matrix (ECM) acts as an appropriate cellular substrate, and morphogenesis is passively regulated by determining tissue boundaries [5]. For efficient tissue regeneration, well-designed engineering, enhancing mass transfer to the core of the tissue, and designing biodegradable and biocompatible platforms with proper mechanical characteristics for engineering different tissues are among the main concerns[6]. The role of scaffolds' biological properties in regulating the function of several types of cells has been suggested [7]. A problem in current tissue regeneration approaches is that most commonly used mats do not recapitulate tissues' microenvironments. This is important as ECM is a hierarchically and dynamically arranged nanocomposite structure that controls vital cellular functions such as migration, proliferation, morphogenesis, adhesion, and differentiation [8]. As a result, researchers are seeking novel nano-technological devices for tissue regeneration to provide innovative nanocomposite frameworks that can imitate ECMs and finally assemble larger and more complicated functional tissues [[9], [10], [11], [12]]. To explore the link between nanotechnology and tissue regeneration, we here first explain the nanostructure of ECMs and then explore its impacts on functional tissue properties. We also address various nano-scale based methods and materials for designing ECMs for different engineered tissues [13].

Nanomaterials have permitted tissue engineering substrates to represent higher mechanical strength and to improve cellular proliferation and differentiation [14]. Carbon-based nanomaterials, such as graphene oxide (GO) [15], fullerenes, carbon nanotubes (CNTs) [16], carbon dots (CDs) [17], graphene [18] composite scaffolds, and nanoparticles have attracted much attention in soft tissue engineering[19]. These materials have unique mechanical, dimensional, optical, and conductive features that provide new opportunities for enhanced soft tissue engineering. Several groups have established various functionalization techniques for carbonic nanomaterials to attain better biocompatibility, as well as cellular attachment capability and differentiation. Artificial cell substrates for soft tissue regeneration and healing are needed to be comparable with natural ECM structures in terms of mechanical properties, chemical composition, and physical properties. Moreover, the electrical conducting properties of carbon-based nanocomposite scaffolds can be applied to offer electrical cues to tissues [20,21].

Some conducting nanomaterials such as nanocomposite bioinks have been applied for biofabrication purposes. For example, bioactive DNA-coated single-wall CNT is a conductive bioink used for three-dimensional (3D) printing of conductive flexible electronics via a two-step procedure on various supportive platforms [22]. A 3D-printed model of “cardiac organs-on-chip” is another example of the applications of nanoinks (applying carbon black nanoparticles-laden thermoplastic poly urethane as a conductive ink in combination with other inks) [23]. The constructs printed in this manner have several features such as piezoresistivity, high conductance, and great biocompatibility. In another study, researchers used the nanoinks comprising graphene and poly(lactide-co-glycolide) (PLGA) for printing a 3D model of neuronal conduits to enhance neural regeneration [24]. Chief biopolymers for neural regeneration include polysaccharides, natural proteins, and ECM derivatives. Biocompatible materials are used for nerve conduits preparation. These materials serve as substrates for inducing cellular proliferation and delivering molecular signals during neural regeneration. Biocompatibility, mechanical compatibility, and histocompatibility are considered as essential factors for successful neural regeneration both in vivo and in vitro. Treatment with either oxygen or plasma can be used to synthesize polymers with weak protein adsorption capacities and acceptable biocompatibility. In this regard, laminin which has excellent biocompatibility, in association with chitosan and PLGA, has been shown to improve cells' adhesive and proliferative functions [25].

Moreover, nanomaterials can be used to boost the in vivo efficiency of growth factors along with extending their local release and protecting them from proteolytic degradation. A broad range of nano-delivery systems have been considered to improve wound healing, mostly nanofibrous structures, lipid NPs, and polymeric NPs. Recently, biocompatible polymeric systems have been investigated for optimizing the controlled release of biological compounds including growth factors [26,27]. The role of nanomedicine in tissue engineering has been summarized in Fig. 1, and some of the biomaterials commonly used in tissue engineering have been reviewed in Table 1. We will discuss the effects of nanostructures on scaffolds' features and their applications in controlling the attributes of engineered tissues. At the end, we provide some perspectives on the future of nanotechnology in tissue engineering and regeneration.

Section snippets

Skin tissue engineering

Acute dermal injuries such as serious burns and diabetic wounds, in which pathogens have sufficient time to colonize, are the salient causes of mortality around the world. Rapid closure of chronic wounds is crucial for the prevention of hypertrophic scarring. Appropriate coverage and rapid treatments are vital steps to prolong the survival of people with extensive burns and to avoid widespread scarring and long-term physiological defects. Using split thickness autografts, as a current therapy,

Nanomaterials in neural tissue engineering

Nerves form one of the vital systems of the body, and defects in these cells lead to significant morbidities and even mortality. According to annual American statistics, about 250,000–400,000 patients are buckled under neural diseases every year [172].

Nerves' gaps and neurons' injuries are claimed to be the main neural defects which couldn't be spontaneously restored by natural biological mechanisms. By means of tissue engineering, neural regeneration works out for neural repairing. The neural

Nanomaterials in ocular tissue engineering

Ocular tissue engineering focuses on the defects of three main parts including the cornea, lens, and stroma. Current therapies have limitations such as the shortage of donors, rejection, and inflammatory responses. Tissue engineering solves these problems and provides efficient therapies to regenerate synthetic and functional corneal prosthesis [265]; however, the clinical translation of this has not been yet proved. In this regard, as a troubleshooting approach, 3D bioprinting has been used to

Nanomaterials for liver tissue engineering

The liver is a vital organ in the body, and its disorders are among the main causes of mortality and morbidity worldwide. The aim of novel therapies is to replace the failed organ with functional in vitro models and alternatives as the shortage of donors and increasing drug-induced injuries have restricted the applicability of current transplantation methods [360]. The nature of cultured stem cells, scaffolds' properties (i.e., the type of constructed materials, porous structure, 3D design,

Conclusion

Using autografts and allografts to correct tissue injuries suffers from some limitations such as shortage of donors and unwanted inflammatory responses. As a novel alternative therapeutic method, tissue engineering has been widely studied to regenerate tissues. This approach aims to simulate natural organs both in vitro and in vivo. Cells are cultured on appropriate scaffolds and under specific growth factors to support their differentiation. The porous structures of scaffolds are essential for

Declaration of competing interest

The authors hereby declare that there was no conflict of interest in the present study.

Acknowledgments

The authors would like to thank Tabriz University of Medical Sciences, Tabriz, Iran and North Khorasan University of Medical Sciences, Bojnurd, Iran.

References (381)

  • R. Eivazzadeh-Keihan et al.

    Carbon based nanomaterials for tissue engineering of bone: building new bone on small black scaffolds: a review

    J. Adv. Res.

    (2019)
  • S. Kargozar et al.

    “Hard” ceramics for “Soft” tissue engineering: paradox or opportunity?

    Acta Biomater.

    (2020)
  • L. Cui et al.

    Electroactive composite scaffold with locally expressed osteoinductive factor for synergistic bone repair upon electrical stimulation

    Biomaterials

    (2020)
  • P.K. Chandra et al.

    Chapter 1 - Tissue engineering: current status and future perspectives

  • I. Garcia-Orue et al.

    Chapter 2 - Nanotechnology approaches for skin wound regeneration using drug-delivery systems

  • M.E. Astaneh et al.

    Chitosan/gelatin hydrogel and endometrial stem cells with subsequent atorvastatin injection impact in regenerating spinal cord tissue

    J. Drug Deliv. Sci. Technol.

    (2020)
  • R. Rajalekshmi et al.

    Scaffold for liver tissue engineering: exploring the potential of fibrin incorporated alginate dialdehyde–gelatin hydrogel

    Int. J. Biol. Macromol.

    (2021)
  • Y. Zhang et al.

    A collagen hydrogel loaded with HDAC7-derived peptide promotes the regeneration of infarcted myocardium with functional improvement in a rodent model

    Acta Biomater.

    (2019)
  • H. Goodarzi et al.

    Preparation and in vitro characterization of cross-linked collagen–gelatin hydrogel using EDC/NHS for corneal tissue engineering applications

    Int. J. Biol. Macromol.

    (2019)
  • S. Khodabakhsh Aghdam et al.

    Collagen modulates functional activity of hepatic cells inside alginate-galactosylated chitosan hydrogel microcapsules

    Int. J. Biol. Macromol.

    (2020)
  • H. Samadian et al.

    Sophisticated polycaprolactone/gelatin nanofibrous nerve guided conduit containing platelet-rich plasma and citicoline for peripheral nerve regeneration: In vitro and in vivo study

    Int. J. Biol. Macromol.

    (2020)
  • L.-K. Zhang et al.

    Bone marrow stem cells combined with polycaprolactone-polylactic acid-polypropylene amine scaffolds for the treatment of acute liver failure

    Chem. Eng. J.

    (2019)
  • A. Abedi et al.

    Concurrent application of conductive biopolymeric chitosan/polyvinyl alcohol/MWCNTs nanofibers, intracellular signaling manipulating molecules and electrical stimulation for more effective cardiac tissue engineering

    Mater. Chem. Phys.

    (2021)
  • C. Kengla et al.

    11 - 3-D bioprinting technologies for tissue engineering applications

  • S. Liu et al.

    Chapter 14 - Hydrogels and hydrogel composites for 3D and 4D printing applications

  • O. Ogunlade et al.

    Monitoring neovascularization and integration of decellularized human scaffolds using photoacoustic imaging

    Photoacoustics

    (2019)
  • T. Zhu et al.

    Engineered three-dimensional scaffolds for enhanced bone regeneration in osteonecrosis

    Bioact. Mater.

    (2020)
  • G. Ramanathan et al.

    Design and characterization of 3D hybrid collagen matrixes as a dermal substitute in skin tissue engineering

    Mater. Sci. Eng. C

    (2017)
  • P. Choudhury et al.

    Hydroxyethyl methacrylate grafted carboxy methyl tamarind (CMT-g-HEMA) polysaccharide based matrix as a suitable scaffold for skin tissue engineering

    Carbohydr. Polym.

    (2018)
  • S. Yang et al.

    Preparation and characterization of antibacterial electrospun chitosan/poly (vinyl alcohol)/graphene oxide composite nanofibrous membrane

    Appl. Surf. Sci.

    (2018)
  • A.M. Pandele et al.

    Synthesis, characterization, and in vitro studies of graphene oxide/chitosan–polyvinyl alcohol films

    Carbohydr. Polym.

    (2014)
  • R. Scaffaro et al.

    Electrospun PCL/GO-g-PEG structures: processing-morphology-properties relationships

    Compos. A: Appl. Sci. Manuf.

    (2017)
  • N. Abzan et al.

    Development of three-dimensional piezoelectric polyvinylidene fluoride-graphene oxide scaffold by non-solvent induced phase separation method for nerve tissue engineering

    Mater. Des.

    (2019)
  • N. Padmavathy et al.

    Oligomer-grafted graphene in a soft nanocomposite augments mechanical properties and biological activity

    Mater. Des.

    (2017)
  • M. Ionita et al.

    Sodium alginate/graphene oxide composite films with enhanced thermal and mechanical properties

    Carbohydr. Polym.

    (2013)
  • E. Correa et al.

    Characterization of polycaprolactone/rGO nanocomposite scaffolds obtained by electrospinning

    Mater. Sci. Eng. C

    (2019)
  • Y. Lee et al.

    A conducting composite microfiber containing graphene/silver nanowires in an agarose matrix with fast humidity sensing ability

    Polymer

    (2019)
  • H.G. de Oliveira Barud et al.

    A multipurpose natural and renewable polymer in medical applications: bacterial cellulose

    Carbohydr. Polym.

    (2016)
  • D. Lankveld et al.

    The kinetics of the tissue distribution of silver nanoparticles of different sizes

    Biomaterials

    (2010)
  • W. Xiao et al.

    The impact of protein corona on the behavior and targeting capability of nanoparticle-based delivery system

    Int. J. Pharm.

    (2018)
  • K.B. Narayanan et al.

    Electrospun poly(vinyl alcohol)/reduced graphene oxide nanofibrous scaffolds for skin tissue engineering

    Colloids Surf. B: Biointerfaces

    (2020)
  • S.-W. Kim et al.

    Stretchable and electrically conductive polyurethane- silver/graphene composite fibers prepared by wet-spinning process

    Compos. Part B

    (2019)
  • N.A. Ismail et al.

    Novel gellan gum incorporated TiO2 nanotubes film for skin tissue engineering

    Mater. Lett.

    (2018)
  • K. Ghosal et al.

    Electrospinning tissue engineering and wound dressing scaffolds from polymer-titanium dioxide nanocomposites

    Chem. Eng. J.

    (2019)
  • N.S. El-Sayed et al.

    New approach for immobilization of 3-aminopropyltrimethoxysilane and TiO2 nanoparticles into cellulose for BJ1 skin cells proliferation

    Carbohydr. Polym.

    (2018)
  • W. Zhu et al.

    3D printing of functional biomaterials for tissue engineering

    Curr. Opin. Biotechnol.

    (2016)
  • R. Singla et al.

    Nanomaterials as potential and versatile platform for next generation tissue engineering applications

    J. Biomed. Mater. Res. B Appl. Biomater.

    (2019)
  • M. Fathi-Achachelouei et al.

    Use of nanoparticles in tissue engineering and regenerative medicine

    Front. Bioeng. Biotechnol.

    (2019)
  • E. Abbasi et al.

    Silver nanoparticles: synthesis methods, bio-applications and properties

    Crit. Rev. Microbiol.

    (2016)
  • J. Yi et al.

    Graphene oxide-incorporated hydrogels for biomedical applications

    Polym. J.

    (2020)
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