Graphene-based materials for tissue engineering

Cellulose of bacterial origin, known as bacterial cellulose (BC), is one of the most versatile biomaterials that has a huge potential in tissue engineering due to its favourable mechanical properties, high hydrophilicity, crystallinity, and purity. Additional properties such as porous nano-fibrillar 3D structure and a high degree of polymerisation of BC mimic the properties of the native extracellular matrix (ECM), making it an excellent material for the fabrication of composite scaffolds suitable for cell growth and tissue development. Recently, the fabrication of BC-based scaffolds, including composites and blends with nanomaterials, and other biocompatible polymers has received particular attention owing to their desirable properties for tissue engineering. These have proven to be promising advanced materials in hard and soft tissue engineering. This review presents the latest state-of-the-art modified/functionalised BC-based composites and blends as advanced materials in tissue engineering. Their applicability as an ideal biomaterial in targeted tissue repair including bone, cartilage, vascular, skin, nerve, and cardiac tissue has been discussed. Additionally, this review briefly summarises the latest updates on the production strategies and characterisation of BC and its composites and blends. Finally, the challenges in the future development and the direction of future research are also discussed.

Tissue engineering involves materials science, bioengineering, and regenerative medicine and many other disciplines. In the early stage, it aims to develop functional biological alternatives that improve, or maintain the function of lost or damaged tissue by combining the scaffold, cells, and biological molecules (such as growth factors). In addition, the ultimate goal of tissue engineering is to regenerate or repair damaged tissues with the help of the biological substitutes. Therefore, the tissue engineering scaffold should mimic the property, structure of the damaged tissue and mimic the extracellular matrix to support cell survival and growth to improve the tissue function. Moreover, the scaffold should also enhance cell proliferation and guide differentiation to regenerate or repair damaged tissues. Over the years, numerous studies have demonstrated that electrical signals can influence cellular behavior and function and conductive materials can enhance cell proliferation and guide differentiation of stem cells through promoting intercellular signaling. Traditional polymers have good process property, biodegradability, and good biocompatibility. So they are most widely used in tissue engineering, but traditional polymers are insulators, which cannot respond to signal transmission between cells to further control cellular activities, such as cell proliferation, migration and differentiation. However, researchers have discovered a variety of electrically conducting polymers in recent decades, such as polyaniline (PANi), polypyrrole (PPy), polythiophene, and their derivatives (mainly aniline oligomers and poly(3,4-ethylenedioxythiophene)) which have good biocompatibility and excellent electrical conductivity. They have been widely used in biomedical fields including drug delivery systems, biosensors, neural implants, and biological actuator, mostly used in the field of tissue engineering scaffolds. Moreover, their excellent electrical conductivity can promote cell adhesion and proliferation at the interface between the polymer and tissue by electrical stimulation, thereby promoting tissue growth. Therefore, the field of tissue engineering by conductive polymeric biomaterials has received more and more attention. However, the pure conductive polymers are brittle and their poor processability limits their applications in tissue engineering. Therefore, composite conductive polymeric biomaterials have been developed based on the above-mentioned conductive polymers and biocompatible degradable polymers, which have excellent biocompatibility, electrical conductivity, and processability. This review will summarize a variety of composite conductive polymeric biomaterials used in tissue engineering, such as pure conducting polymers, conducting blends or composite films, conducting copolymer films, conducting nanofibers, conducting hydrogels, and conducting composite three-dimensional (3D) scaffolds. In addition, recent research in tissue engineering has found that these conductive polymeric biomaterials can be used in various electrical signal sensitive tissues engineering including bone, muscle, nerve and cardiac tissue engineering. The above aspects will be discussed in detail in this paper.

Surface modification of polymers by plasma treatments for the enhancement of biocompatibility and controlled drug release

Polysaccharide-based hydrogels have emerged as indispensable materials in tissue engineering and wound healing, offering a unique combination of biocompatibility, biodegradability, and structural versatility. Indeed, their three-dimensional polymeric network and high water content closely resemble the natural extracellular matrix, creating a microenvironment for cell growth, differentiation, and tissue regeneration. Moreover, their intrinsic biodegradability, tunable chemical structure, non-toxicity, and minimal immunogenicity make them optimal candidates for prolonged drug delivery systems. Notwithstanding numerous advantages, these polysaccharide-based hydrogels are confronted with setbacks such as variability in material qualities depending on their source, susceptibility to microbial contamination, unregulated water absorption, inadequate mechanical strength, and unpredictable degradation patterns which limit their efficacy in real-world applications. This review summarizes recent advancements in the application of polysaccharide-based hydrogels, including cellulose, starch, pectin, zein, dextran, pullulan and hyaluronic acid as innovative solutions in wound healing, drug delivery, tissue engineering, and regenerative medicine. Future research should concentrate on optimizing hydrogel formulations to enhance their effectiveness in regenerative medicine and antimicrobial therapy.

In cardiovascular surgery, reconstruction and replacement of cardiac and vascular structures are routinely performed. Prosthetic or biological materials traditionally used for this purpose cannot be considered ideal substitutes as they have limited durability and no growth or regeneration potential. Tissue engineering aims to create materials having normal tissue function including capacity for growth and self-repair. These advanced materials can potentially overcome the shortcomings of conventionally used materials, and, if successfully passing all phases of product development, they might provide a better option for both the pediatric and adult patient population requiring cardiovascular interventions. This short review article overviews the most important cardiovascular pathologies where tissue engineered materials could be used, briefly summarizes the main directions of development of these materials, and discusses the hurdles in their clinical translation. At its beginnings in the 1980s, tissue engineering (TE) was defined as “an interdisciplinary field that applies the principles of engineering and the life sciences toward the development of biological substitutes that restore, maintain, or improve tissue function” (1). Currently, the utility of TE products and materials are being investigated in several fields of human medicine, ranging from orthopedics to cardiovascular surgery (2–5). In cardiovascular surgery, reconstruction and replacement of cardiac and vascular structures are routinely performed. Considering the shortcomings of traditionally used materials, the need for advanced materials that can “restore, maintain or improve tissue function” are evident. Tissue engineered substitutes, having growth and regenerative capacity, could fundamentally change the specialty (6). This article overviews the most important cardiovascular pathologies where TE materials could be used, briefly summarizes the main directions of development of TE materials along with their advantages and shortcomings, and discusses the hurdles in their clinical translation.

Transcriptomic profiling of neural stem cell differentiation on graphene substrates

Recently, tissue engineering and regenerative medicine, especially bone tissue engineering and regenerative medicine have developed rapidly. Bone tissue engineering is a complicated and dynamic bone remodeling process that starts with recruitment and migration of osteoblasts and then regulates their proliferation, differentiation, and mineralization. Scaffold is typically biodegradable material that plays a crucial role as one of the three elements of bone tissue engineering and regenerative medicine. Bone scaffold provides the mechanical support during reformation and repair of damaged or diseased bone. For more than a decade, a large amount of research work has been carried out on the designing of scaffolds, processing techniques, performance assessment, and medical application. Significant progress has been made toward scaffold materials for structural support for desired osteogenesis and angiogenesis abilities. To date, depending on the advanced technologies, the bioresorbable scaffolds possess controlled porosity and high mechanical properties are possible used as bone scaffold. Natural bone has delicate architectural structure that spans nanoscale to macroscopic dimensions, which determine the unique mechanical properties of bone. The hierarchical structure of natural bone can be defined as a nanocomposite consisting of inorganic nanocrystalline hydroxyapatite (HA), organic components (mostly are collagens) and water. The outside proteins assemble together to form an extracellular matrix (ECM) with nanostructured which influences the adhesion, proliferation, differentiation, and mineralization of several cell types, such as bone lining cell, mesenchymal stem cells, osteoblasts, osteocytes, and osteoclasts. To better mimic the nanostructure in natural ECM, many research groups over the past decade developed nano-based scaffolds (nanotubes, nanofibers, nanoparticles, and hydrogel) to resemble the ECM for promising candidates in replacing defective tissues. The high biomimetic properties and excellent mechanical features of nano-based scaffolds plays a vital role in stimulating cell adhesion and proliferation, as well as directing bone tissue formation through mimetic the nanometer dimension of natural bone tissue. Besides, mechanical properties are key factors for bone regeneration and bone local function. Nowadays, a large number of research groups have tried to manipulate the mechanical properties of scaffolds through designing the different nanosturctures, including nanofiber, nanoparticle, polymer matrices to mimic the nanocomposite structure of natural bone. These materials have highly stiffness, strength, and toughness properties that are promising in bone tissue engineering. Nanobiomaterials, especially inorganic nanobiomaterials, have excellent mechanical properties and biocompatibility, and are ideal for the preparation of scaffold materials for bone tissue engineering and regenerative medicine, showing a broad application prospect. In this article, we systematically review the application of inorganic nanomaterials, including hydroxyapatite, silicon-based nanomaterials, carbon-containing nanomaterials and several metal nanomaterials in bone tissue engineering and regenerative medicine. Although nanotechnology represents a major frontier with potential to significantly advance the field of bone tissue engineering, the application in the clinical regenerative engineering has limited. Currently, there are several limitations in regenerative strategies, including low efficient cellular proliferation, differentiation and mineralization, insufficient mechanical strength of scaffolds, and limited production of growth factors necessary for efficient osteogenesis. Therefore, there are still some issues on the nano-based scaffold should be cleared: (1) The interaction of nano-based scaffold and bioactive molecules, growth factors, and genetic material, (2) the biocomptibility, cytotoxicity, and biodegradation of nano-based scaffold, and (3) nano-based scaffold mechanical stability, cellular survival, and molecular mechanism of inducing bone formation. As the development of nanotechnology, ultimate translation to the clinical application may allow for improved therapeutic outcomes in patients with large bone deficits and osteodegenerative diseases.

Decellularized tissues are widely used as promising materials in tissue engineering and regenerative medicine. Research on the microstructure and components of the extracellular matrix (ECM) was conducted to improve the current understanding of decellularized tissue functionality. The presence of matrix-bound nanovesicles (MBVs) embedded within the ECM was recently reported. Results of a previous experimental investigation revealed that decellularized tissues prepared using high hydrostatic pressure (HHP) exhibited good in vivo performance. In the current study, according to the hypothesis that MBVs are one of the functional components in HHP-decellularized tissue, we investigated the extraction of MBVs and the associated effects on vascular endothelial cells. Using nanoparticle tracking assay (NTA), transmission electron microscopy (TEM), and RNA analysis, nanosized (100–300 nm) and membranous particles containing small RNA were detected in MBVs derived from HHP-decellularized small intestinal submucosa (SIS), urinary bladder matrix (UBM), and liver. To evaluate the effect on the growth of vascular endothelial cells, which are important in the tissue regeneration process, isolated SIS-derived MBVs were exposed to vascular endothelial cells to induce cell proliferation. These results indicate that MBVs can be extracted from HHP-decellularized tissues and may play a significant role in tissue remodeling.

Hyaluronic acid (HA) is a naturally occurring glycosaminoglycan widely recognised for its biocompatibility, biodegradability, and unique viscoelastic properties. Its structural versatility enables the formation of hydrogels with tuneable physicochemical characteristics, making it a valuable biomaterial in drug delivery and regenerative medicine. This review outlines HA properties, gel-forming approaches, and modern medicine and bioengineering applications. It provides a comprehensive overview of advances in HA production strategies, including microbial fermentation, animal tissue extraction, and production in vitro. Particular attention is given to gel-forming mechanisms, emphasising physical and chemical crosslinking methods like carbodiimide crosslinking, radical polymerisation, and enzymatic crosslinking. Advances in HA-based drug delivery systems and applications of HA-based materials in tissue engineering are also discussed, focusing on HA-based hydrogels with conjugates and combinations with compounds like collagen, alginate, and chitosan.

Graphene, a truly two-dimensional (2D) and fully π-conjugated honeycomb network, exhibits many unique physical and chemical properties that are interesting in a wide range of areas. Since its discovery in 2004, graphene has been extensively studied in many different fields including nano-electronics, composite materials, energy research, catalysis and so on. Based on the fascinating action of members in the carbon family, notably zero dimensional (0D) fullerenes and one dimensional (1D) carbon nanotubes (CNTs) in biomedical areas, increasing number of reports have explored the potential of graphene for different biomedical and biotechnical applications since 2008. This manuscript aims to provide a summary of current research progress of graphene-based carbon materials in biosensing, drug (gene) delivery and tissue engineering, and discusses the opportunities and challenges in this rapidly growing field.

6 - Toxicology of nanoformulations and materials in tissue engineering

Articular cartilage defects and degeneration can be caused by multiple factors, and the current clinical treatment schemes for pathological changes are relatively limited. Engineered cartilage tissue represents an alternative therapy for repairing cartilage defects in regenerative medicine. The scaffold material is considered the framework of tissue engineering; thus, scaffold material selection plays a crucial role in the therapy outcome. Polycaprolactone (PCL)-hydroxyapatite (HA) has been applied as a scaffold material for bone and cartilage tissue engineering with nontoxic, harmless metabolites and proper physical properties. The extracellular matrix (ECM) is mainly composed of collagen and proteoglycan, as well as a large number of growth factors and cytokines, which provide a tissue-specific microenvironment for host cells. Adipose-derived stem cells are pluripotent stem cells, and transforming growth factor-β3 (TGF-β3) enables mesenchymal stem cells to promote ECM production. This study, via in vitro and in vivo experiments, elucidated that the synovium mesenchymal stem cells (SMSCs) + chondrocytes + ECM-PCL-HA repair system, which is constructed upon the ECM-PCL-HA scaffold material, exhibits an adequate chondrogenic ability and reparatory effect. Overall, ECM-PCL-HA can be defined as a biofunctional scaffold material. The SMSCs + chondrocytes + ECM-PCL-HA repair system showed good confluency between the new cartilage and the surface, as well as the interface of the adjacent host cartilage. Furthermore, the structure of new cartilage tissue is consistent with adjacency. Thus, it can be used as a preferred plan for articular cartilage defect repair. Impact statement Studies investigating the chondrogenic ability and reparatory effect of the synovium mesenchymal stem cells (SMSCs) + chondrocytes + extracellular matrix (ECM)-polycaprolactone (PCL)-hydroxyapatite (HA) repair system provided a theoretical and practical basis for choosing ECM-PCL-HA as the scaffold material for cartilage tissue engineering. In this study, the transforming growth factor-β3 (TGF-β3) gene was introduced into adipose-derived stem cells (ADSCs) using a lentiviral vector to enhance ECM production. The decellularized ADSCs-ECM-PCL-HA acted as a biofunctional scaffold material with suitable physicochemical properties, which was advantageous for SMSC and chondrocyte adhesion and growth. Lastly, the SMSCs + chondrocytes + ECM-PCL-HA repair system showed excellent capability in the flush fusion state of the prosthetic surface and interface.

With the development of tissue engineering, the application of decellularized adipose matrix as scaffold material in tissue engineering has been intensively explored due to its wide source and excellent potential in tissue regeneration. Decellularized adipose matrix is a promising candidate for adipose tissue regeneration, while modification of decellularized adipose matrix scaffold can also allow it to transcend the limitations of adipose tissue source properties and applied to other tissue engineering fields, including cartilage and bone tissue engineering, neural tissue engineering, and skin tissue engineering. In this review, we summarized the development of the applications of decellularized adipose matrix in different tissue engineering and present future perspectives.Level of Evidence III This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

Tissue engineering is a promising approach in replacing or improving tissues lost or has become nonviable due to disease or trauma by the use of scaffold materials by combining engineering and biochemical/physicochemical methods. Its purpose is to create suitable matrices that support cell differentiation and proliferation toward the formation of new and functional tissue.Marine-based natural compounds are potential scaffold feedstock material in tissue engineering owing to their biocompatibility and biodegradability while providing excellent biochemical/physicochemical properties. Numerous application areas and various fabrication routes techniques described in the literature attest to the importance of these materials in tissue regeneration. This review has been carried to merge the information from a large number of studies on the marine-based scaffold materials in tissue engineering into a coherent summary.KeywordsMarineBiomaterial(s)Tissue engineeringScaffold(s)

During the past decades, photo-crosslinked gelatin hydrogel (methacrylated gelatin, GelMA) has gained a lot of attention due to its remarkable application in the biomedical field. It has been widely used in cell transplantation, cell culture and drug delivery, based on its crosslinking to form hydrogels with tunable mechanical properties and excellent bio-compatibility when exposed to light irradiation to mimic the micro-environment of native extracellular matrix (ECM). Because of its unique biofunctionality and mechanical tenability, it has also been widely applied in the repair and regeneration of bone, heart, cornea, epidermal tissue, cartilage, vascular, peripheral nerve, oral mucosa, and skeletal muscle et al. The purpose of this review is to summarize the recent application of GelMA in drug delivery and tissue engineering field. Moreover, this review article will briefly introduce both the development of GelMA and the characterization of GelMA. Finally, we discuss the challenges and future development prospects of GelMA as a tissue engineering material and drug or gene delivery carrier, hoping to contribute to accelerating the development of GelMA in the biomedical field.Graphical abstract