Structure and functionalization of mesoporous bioceramics for bone tissue regeneration and local drug delivery

This review article describes the importance of structure and functionalization in the performance of mesoporous silica bioceramics for bone tissue regeneration and local drug delivery purposes. Herein, we summarize the pivotal features of mesoporous bioactive glasses, also known as 'templated glasses' (TGs), which present chemical compositions similar to those of conventional bioactive sol-gel glasses and the added value of an ordered mesopore arrangement. An in-depth study concerning the possibility of tailoring the structural and textural characteristics of TGs at the nanometric scale and their influence on bioactive behaviour is discussed. The highly ordered mesoporous arrangement of cavities allows these materials to confine drugs to be subsequently released, acting as drug delivery devices. The functionalization of mesoporous silica walls has been revealed as the cornerstone in the performance of these materials as controlled release systems. The synergy between the improved bioactive behaviour and local sustained drug release capability of mesostructured materials makes them suitable to manufacture three-dimensional macroporous scaffolds for bone tissue engineering. Finally, this review tackles the possibility of covalently grafting different osteoinductive agents to the scaffold surface that act as attracting signals for bone cells to promote the bone regeneration process.     

Nanocrystalline calcium phosphate ceramics in biomedical engineering

Nanocrystalline calcium phosphate based bioceramics are the new rage in biomaterials research. Conventionally, calcium phosphates based materials are preferred as bone grafts in hard tissue engineering because of their superior biocompatibility and bioactivity. However, this group of bioceramics exhibits poor mechanical performance, which restricts their uses in load bearing applications. The recent trend in bioceramic research is mainly concentrated on bioactive and bioresorbable ceramics, i.e. hydroxyapatite, bioactive glasses, tricalcium phosphates and biphasic calcium phosphates as they exhibit superior biological properties over other materials. In recent times, the arena of nanotechnology has been extensively studied by various researchers to overcome the existing limitations of calcium phosphates, mainly hydroxyapatite, as well as to fabricate nanostructured scaffolds to mimic structural and dimensional details of natural bone. The bone mineral consists of tiny HAp crystals in the nano-regime. It is found that nanocrystalline HAp powders improve sinterability and densification due to greater surface area, which could improve the fracture toughness and other mechanical properties. Nano-HAp is also expected to have better bioactivity than coarser crystals. Nanocrystalline calcium phosphate has the potential to revolutionize the field of hard tissue engineering from bone repair and augmentation to controlled drug delivery devices. This paper reviews the current state of knowledge and recent developments of various nanocrystalline calcium phosphate based bioceramics from synthesis to characterization.     

Progress on Electrospun Composite Fibers Incorporating Bioactive Glass: An Overview

Electrospinning is a promising approach for the development of fibrous tissue engineering (TE) scaffolds suitable for hard and soft tissues. Apart from physicomechanical properties, electrospun fibers are required to incorporate bioactive cues to control cellular functions, including facilitating biomineralization and osteogenic differentiation in case of bone TE, as well as vascularization, to support successful tissue regeneration. In recent years, bioactive glass (BG) addition to electrospun biopolymer fibers has shown promising results in enhancing the properties of fibers, including the improvement of biological performance. In this article, a comprehensive overview of BG-containing electrospun polymer composite fibers is presented, identifying the parameters that affect the mechanical properties as well as the biological response in vivo and in vitro. Subsequently, the effects of BG addition on the properties of the scaffolds are discussed. Recent developments in the fields of bone regeneration, wound healing, and drug delivery using BG-containing electrospun fibrous scaffolds are described in detail. Essential aspects related to BG-polymer composite fibers for translational research in TE are highlighted for future research in this field.     

Sol–gel-derived manganese-releasing bioactive glass as a therapeutic approach for bone tissue engineering

Sol–gel processing allows the production of bioactive glasses (BG) with flexible compositions and the incorporation of different metallic ions with therapeutic benefits into the glass network. Manganese is among several previously studied therapeutically beneficial ions and has been shown to favour osteogenic differentiation, in addition to playing an important role in cell adhesion. The incorporation of Mn into bioactive glasses for tissue engineering has been previously conducted using the conventional melting route, whereas the sol–gel route has not yet been explored. Sol–gel technology has great versatility, allowing the preparation of BG with various compositions, sizes, morphologies and a large surface area that could provide improved cellular responses and enhanced bioactivity when compared to melt-derived glasses. In this context, this work developed new compositions of sol–gel bioactive glasses (on the SiO₂–P₂O₅–CaO–MnO system) and explored the effects of incorporating MnO on the structure, texture, in vitro bioactivity and cytocompatibility of these materials. Our results show that Mn-containing bioactive glasses present an amorphous character, high surface area and mesoporous structure. The formation of a hydroxycarbonate apatite (HCA) layer after immersion in simulated body fluid (SBF) revealed the high bioactivity of the glasses. Ion release evaluation indicated that the Si, Ca, P and Mn release levels could be adjusted within therapeutic limits, and cytotoxic analysis demonstrated that the ionic products of all samples generated a cell-friendly environment. Therefore, Mn incorporation into the bioactive glass network appears to be a potential strategy to develop superior materials with sustained ion release for tissue engineering.     

Bivalent cationic ions doped bioactive glasses: the influence of magnesium,zinc, strontium and copper on the physical and biological properties

Bioactive glass and glass ceramic materials are widely used as substitutes for bone augmentation and restoration, in orthopaedic, dental and maxillofacial surgery and in the tissue engineering field. Indeed, these materials are bioactive, biocompatible, mechanically stable, biodegradable and favour osteointegration, being able to promote bone tissue formation at their surface and to bond to surrounding living tissues when implanted in the human body. It has been demonstrated that bioglass (BG) ionic dissolution products (e.g. Si, Ca, P and Na) are able to induce and stimulate the expressions of genes related to the osteoblastic differentiation and bone formation, to stimulate angiogenesis in vitro and in vivo, as well as to play possible antibacterial and anti-inflammatory actions. Thus, it is possible to tailor BGs properties properly formulating their chemical composition and adding selected ions with specific functional and biological role. In this perspective, Hench proposed a new generation of genetically designed glasses, on the basis of their ability to activate specific genes involved in in situ tissue regeneration, by doping silicate and phosphate glasses with several active ions, particularly metallic ions with therapeutic effects. In this framework, the present review is aimed to provide an overview about the effect of selected cationic substitutions (i.e. magnesium, zinc, strontium and copper), incorporated within the bioglasses structure, on the physical and biological properties of these materials, since the comprehension of the influence of the most employed metallic ions has to be considered pivotal to address the formulation of more promising and performing glasses.     

Historic and current strategies in bone tissue engineering: Do we have a hope in Hench?

Professors Larry Hench and Julia Polak formed the Tissue Engineering and Regenerative Medicine Centre (TERM) at Imperial College London to foster collaborations between biologists and materials scientists. Early work at the center elucidated the biomolecular interactions between primary human osteoblasts and 45S5 Bioglass . As research efforts expanded, the team discovered that the dissolution products of both 45S5 Bioglass and 58S sol-gel bioactive glasses had osteoblastic stimulatory properties. To address the shortage of appropriate cells for bone tissue engineering applications, TERM scientists also demonstrated the differentiation of embryonic stem (ES) cells to osteoblasts when treated with the dissolution products of bioactive glasses. They also found that the soluble factors ascorbic acid, beta -glycerophosphate, and dexamethasone preferentially differentiated ES cells to osteoblasts, and their combination with the dissolution products of bioactive glasses stimulated differentiation even further. Taken together, these results demonstrate the suitability of bioactive glasses as scaffolds for bone tissue engineering as they not only provide an osteoconductive and osteoproductive substrate, but also actively stimulate cells to express appropriate osteoblastic phenotypes. Professor Hench's vision to pioneer regenerative medicine research continues with the aim of developing novel therapeutics to treat musculoskeletal disability.     

Fabrication of porous bioactive glass particles by one step sintering

In this study, we reported a facile method to prepare porous bioactive glass microparticles. Porous particles were synthesized by sintering hollow bioactive glass microspheres obtained using a sol-gel co-template technology. The results showed that porous bioactive glass particles possessed a narrow particle size distribution, a relatively porous surface morphology and a hollow structure. It is worth to say that the resulting microparticles present an amorphous structure although the sintering temperature was improved compared to hollow microspheres. The presence of macropore on the shell may provide an efficient method to carry drugs in the hollow cores. Considering the high deposit rate of nanoscale apatite for bioactive glass materials, the porous microparticles should have potential applications in drug and bioactive molecules delivery, in addition to bone tissue regeneration.     

Promising trends of bioceramics in the biomaterials field

Biomedical scientific community is currently demanding new advances in the designing of 3rd generation bioceramics, which promote bone tissue regeneration. In the last years, the development of supramolecular chemistry and the application of organic-inorganic hybrid materials in the biomedical field have resulted in a new generation of advanced bioceramics, which exhibit fascinating properties for regenerative purposes together with the possibility of being used as carriers of biologically active molecules. This communication overviews the evolution occurred from the first silica based bioceramics to the last advances in the synthesis of bioceramics for bone tissue regeneration. A critical review concerning the first bioactive glasses as well as the newest hybrid bioactive materials and templated mesoporous bioactive systems, will be performed from the point of view of their potential applications as replacement materials in bone repair and regeneration.     

Bioactive glass-containing cranial implants: an overview

Although metals have successfully been used as implants for decades, devices made out of metals do not meet all clinical requirements. For example, metal objects may interfere with some medical imaging systems (computer tomography, magnetic resonance imaging), while their stiffness also differs from natural bone and may cause stress-shielding and over-loading of bone. There has been a lot of development in the field of composite biomaterial research, which has focused to a large extent on biodegradable composites. This overview article reviews the rationale of using glass fiber-reinforced composite–bioactive glass (FRC–BG) in cranial implants. For this overview, published scientific articles with the search term “bioactive glass cranial implant” were collected for having basis to introduce a novel design of composite implant, which contains bioactive glass. Additional scientific information was based on articles in the fields of chemistry, engineering sciences and dentistry. Published articles of the material properties, biocompatibility and possibility to add bioactive glass to the FRC–BG implants alongside with the clinical experience as far suggest that there is a clinical need for bioactive nonmetallic implants. In the FRC–BG implants, biostable glass fibers are responsible for the load-bearing capacity of the implant, while the dissolution of the bioactive glass particles supports osteogenesis and vascularization and provides antimicrobial properties for the implant. Material combination of FRC–BG has been used clinically in cranioplasty and cranio-maxillo-facial implants, and they have been investigated also as oral and orthopedic implants. Material combination of FRC–BG has successfully been introduced to be a potential implant material in cranial surgery.     

Polyelectrolyte multilayers for bio‐applications: recent advancements

The synergistic relationship between structure and the bulk properties of polyelectrolyte multilayer (PEM) films has generated tremendous interest in their application for loading and release of bioactive species. Layer‐by‐layer assembly is the simplest, cost effective process for fabrication of such PEMs films, leading to one of the most widely accepted platforms for incorporating biological molecules with nanometre precision. The bulk reservoir properties of PEM films render them a potential candidate for applications such as biosensing, drug delivery and tissue engineering. Various biomolecules such as proteins, DNA, RNA or other desired molecules can be incorporated into the PEM stack via electrostatic interactions and various other secondary interactions such as hydrophobic interactions. The location and availability of the biological molecules within the PEM stack mediates its applicability in various fields of biomedical engineering such as programmed drug delivery. The development of advanced technologies for biomedical applications using PEM films has seen rapid progress recently. This review briefly summarises the recent successes of PEM being utilised for diverse bio‐applications.Inspec keywords: polymer electrolytes, multilayers, polymer films, molecular biophysics, biomedical materials, biochemistryOther keywords: bioapplications, polyelectrolyte multilayer films, bioactive species, layer‐by‐layer assembly, biological molecules, biosensing, drug delivery, tissue engineering, biomolecules, proteins, DNA, RNA, electrostatic interactions, secondary interactions, hydrophobic interactions, biomedical engineering, programmed drug delivery, biomedical applications, PEM films     

Structure,thermal properties,dissolution behaviour and biomedical applications of phosphate glasses and fibres: a review

For the last few decades, there has been a growing interest in using glasses for biomedical applications. Bioactive glasses are a group of surface reactive glasses which can initiate a range of biological responses by releasing ions into the local environment. Silicate, borate and phosphate glasses are known to show good bioactive characteristics and could be potentially used as favourable templates for bone-tissue formation. Phosphate glasses are unique group of materials that offer great potential for hard and soft tissue engineering over other types of bioactive glasses due to their fully resorbable characteristics, with some formulations possessing chemical composition similar to the mineral phase of natural bone. Moreover, these phosphate glasses can be prepared as fibres which could be used for soft tissue engineering and as fibrous reinforcement for resorbable polymers such as poly-(lactic acid) for fracture fixation applications. This review details some of the properties of phosphate glasses, such as thermal, viscosity/temperature, dissolution and biocompatibility of and how different factors can effectively alter these properties. The effect of the addition of different modifier oxides on the structure in terms of chain length is included. This review also reports on the manufacturing process, mechanical properties and biomedical application of phosphate glass fibres. A brief comparison between three different types of bioactive glasses has also been presented in this review. The main aim of this review is to present the factors affecting the properties of phosphate glasses and glass fibres and how these may be exploited in the design of a biomaterial.     

激活基因的玻璃

三十年前发现，生物玻璃能与骨形成骨键结合。这种特殊的材料已经有超过15年的临床应用，并在数以千计的成功病例。研究表明，骨的键合及骨再生和修复（骨形成作用）涉及玻璃表面的离子快速交换反应、生物活性表面反应层的成核和生长、由可溶硅和钙组成的临界浓度的离子溶解产物的释放。生物活性玻璃的分子生物学机理研究表明，它的生物活性响应看起来是由基因控制的。具有骨促进作用的A类生物活性玻璃通过直接对那些调节诱发细胞周期开始和进程的基因的直接控制，从而加强了其骨形成和促进作用。不能够形成新骨的细胞从细胞总体中被消除，这一特征是当成骨细胞在生物惰性材料或者B类生物活性材料培养时所没有的。骨前细胞细胞周期的基因调控生物学结果是成骨细胞的快速繁殖和分裂，这也导致了骨的迅速再生。对生物活性玻璃基因基础的理解，可以为设计新一代活化基因的玻璃材料，以及新一代活化基因的组织工程用生物降解支架提供重要的依据。如果我们能用玻璃激活基因，可以肯定，有一天我们就能用玻璃来控制基因。     

Bone tissue engineering therapeutics: controlled drug delivery in three-dimensional scaffolds

This paper provides an extensive overview of published studies on the development and applications of three-dimensional bone tissue engineering (TE) scaffolds with potential capability for the controlled delivery of therapeutic drugs. Typical drugs considered include gentamicin and other antibiotics generally used to combat osteomyelitis, as well as anti-inflammatory drugs and bisphosphonates, but delivery of growth factors is not covered in this review. In each case reviewed, special attention has been given to the technology used for controlling the release of the loaded drugs. The possibility of designing multifunctional three-dimensional bone TE scaffolds for the emerging field of bone TE therapeutics is discussed. A detailed summary of drugs included in three-dimensional scaffolds and the several approaches developed to combine bioceramics with various polymeric biomaterials in composites for drug-delivery systems is included. The main results presented in the literature are discussed and the remaining challenges in the field are summarized with suggestions for future research directions.     

Controlling ion release from bioactive glass foam scaffolds with antibacterial properties

Bioactive glass scaffolds have been produced, which meet many of the criteria for an ideal scaffold for bone tissue engineering applications, by foaming sol-gel derived bioactive glasses. The scaffolds have a hierarchical pore structure that is very similar to that of cancellous bone. The degradation products of bioactive glasses have been found to stimulate the genes in osteoblasts. This effect has been found to be dose dependent. The addition of silver ions to bioactive glasses has also been investigated to produce glasses with bactericidal properties. This paper discusses how changes in the hierarchical pore structure affect the dissolution of the glass and therefore its bioactivity and rate of ion delivery and demonstrates that silver containing bioactive glass foam scaffolds can be synthesised. It was found that the rate of release of Si and Ca ions was more rapid for pore structures with a larger modal pore diameter, although the effect of tailoring the textural porosity on the rate of ion release was more pronounced. Bioactive glass scaffolds, containing 2 mol% silver, released silver ions at a rate that was similar to that which has previously been found to be bactericidal but not high enough to be cytotoxic to bone cells.     

Applications of Nanomaterials in Cell Stem Therapies and the Onset of Nanomedicine

Stem cells hold enormous potential in the treatment of diseases such as diabetes, arthritis, cirrhosis, spinal cord injury, and Alzheimer's disease, due to their unique ability to differentiate into various cell lines and tissues and integrate seamlessly into damaged or diseased tissue. The use of nanoparticles as bioactive molecules is still considered a nascent science, but their unique physical and chemical properties hold great hopes for drug delivery, cancer targeting, and bioimaging. There is active worldwide ongoing research to generate advanced therapeutic compounds for incurable diseases, combining the unique properties of nanomaterials and stem cells. The present review will cover emerging areas of nanotechnology applications in stem cell therapy, one of the next frontiers of medical science.     

Polymer-bioceramic composites for tissue engineering scaffolds

Designing tissue engineering scaffolds with the required mechanical properties and favourable microstructure to promote cell attachment, growth and new tissue formation is one of the key challenges facing the tissue engineering field. An important class of scaffolds for bone tissue engineering is based on bioceramics and bioactive glasses, including: hydroxyapatite, bioactive glass (e.g. Bioglass^®), alumina, TiO₂ and calcium phosphates. The primary disadvantage of these materials is their low resistance to fracture under loads and their high brittleness. These drawbacks are exacerbated by the fact that optimal scaffolds must be highly porous (>90% porosity). Several approaches are being explored to enhance the structural integrity, fracture strength and toughness of bioceramic scaffolds. This paper reviews recent proposed approaches based on developing bioactive composites by introducing polymer coatings or by forming interpenetrating polymer-bioceramic microstructures which mimic the composite structure of bone. Several systems are analysed and scaffold fabrication processes, microstructure development and mechanical properties are discussed. The analysis of the literature suggests that the scaffolds reviewed here might represent the optimal solution and be the scaffolds of choice for bone regeneration strategies.     

Functional Microgels: Recent Advances in Their Biomedical Applications

Here, a spotlight is shown on aqueous microgel particles which exhibit a great potential for various biomedical applications such as drug delivery, cell imaging, and tissue engineering. Herein, different synthetic methods to develop microgels with desirable functionality and properties along with degradable strategies to ensure their renal clearance are briefly presented. A special focus is given on the ability of microgels to respond to various stimuli such as temperature, pH, redox potential, magnetic field, light, etc., which helps not only to adjust their physical and chemical properties, and degradability on demand, but also the release of encapsulated bioactive molecules and thus making them suitable for drug delivery. Furthermore, recent developments in using the functional microgels for cell imaging and tissue regeneration are reviewed. The results reviewed here encourage the development of a new class of microgels which are able to intelligently perform in a complex biological environment. Finally, various challenges and possibilities are discussed in order to achieve their successful clinical use in future.     

One‐step method for the preparation of poly(methyl methacrylate) modified titanium‐bioactive glass three‐dimensional scaffolds for bone tissue engineering

A novel three‐dimensional (3D) titanium (Ti)‐doping meso‐macroporous bioactive glasses (BGs)/poly(methyl methacrylate) (PMMA) composite was synthesised using PMMA and EO₂₀ PO₇₀ EO₂₀ (P₁₂₃) as the macroporous and mesoporous templates, respectively. Unlike the usual calcination method, the acid steam technique was used to improve the polycondensation of Ti‐BGs, and then PMMA was partially extracted via chloroform to induce the macroporous structure. Simultaneously, the residual PMMA which remained in the wall enhanced the compressive strength to 2.4 MPa (0.3 MPa for pure BGs). It is a simple and green method to prepare the macro‐mesoporous Ti‐BGs/PMMA. The materials showed the 3D interconnected hierarchical structure (250 and 3.4 nm), making the fast inducing‐hydroxyapatite growth and the controlled drug release. Besides mentioned above, the good antimicrobial property and biocompatible of the scaffold also ensure it is further of clinical use. Herein, the fabricated materials are expected to have potential application on bone tissue regeneration.Inspec keywords: titanium, bone, tissue engineering, glass, materials preparation, biomedical materials, polymers, porous materials, drug delivery systems, nanomedicineOther keywords: poly(methyl methacrylate), PMMA preparation, 3D titanium‐bioactive glass scaffold, bone tissue engineering, titanium‐doping mesomacroporous bioactive glass, bioactive glass‐PMMA composite, macroporous template, mesoporous template, calcination method, acid steam technique, titanium‐bioactive glass polycondensation, macroporous structure, green method, macromesoporous titanium‐bioactive glass‐PMMA, 3D interconnected hierarchical structure, fast inducing‐hydroxyapatite growth, controlled drug release, bone tissue regeneration, Ti     

Local drug delivery system for the treatment of osteomyelitis: In vitro evaluation

Local antimicrobial delivery is a potential area of research conceptualized to provide alternative and better methods of treatment for cases, as osteomyelitis where avascular zones prevent the delivery of drugs from conventional routes of administration. Drug-loaded polymers and calcium phosphates as hydroxyapatites have been tried earlier. Bioactive glasses are bone-filling materials used for space management in orthopedic and dental surgery. A new bioactive glass (SSS2) was synthesized and fabricated into porous scaffold with a view to provide prolonged local delivery of gatifloxacin and fluconazole as suitable for the treatment of osteomyelitis. The new SSS2 was characterized by Fourier transform infrared (FTIR) and X-ray diffraction (XRD) analyses. In addition, the bioactivity of the SSS2 glass and resulting scaffold was examined by in vitro acellular method and ascertained by FTIR and XRD. The pore size distribution was analysed by mercury intrusion porosimetry and the release of drugs from scaffolds were studied in vitro. The glass and the resulting scaffolds were bioactive indicating that they can bond with bone in vivo. The scaffolds were porous with pores predominantly in the range of 10-60 μm, released the drugs effectively for 6 weeks and deemed suitable for local delivery of drugs to treat osteomyelitis.     

Noncoding RNAs and Their Potential Therapeutic Applications in Tissue Engineering

Tissue engineering is a relatively new but rapidly developing field in the medical sciences. Noncoding RNAs (ncRNAs) are functional RNA molecules without a protein-coding function; they can regulate cellular behavior and change the biological milieu of the tissue. The application of ncRNAs in tissue engineering is starting to attract increasing attention as a means of resolving a large number of unmet healthcare needs, although ncRNA-based approaches have not yet entered clinical practice. In-depth research on the regulation and delivery of ncRNAs may improve their application in tissue engineering. The aim of this review is: to outline essential ncRNAs that are related to tissue engineering for the repair and regeneration of nerve, skin, liver, vascular system, and muscle tissue; to discuss their regulation and delivery; and to anticipate their potential therapeutic applications.