Natural polymers for gene delivery and tissue engineering

Although the field of gene delivery is dominated by viral vectors and synthetic polymeric or lipid gene carriers, natural polymers offer distinct advantages and may help advance the field of non-viral gene therapy. Natural polymers, such as chitosan, have been successful in oral and nasal delivery due to their mucoadhesive properties. Collagen has broad utility as gene activated matrices, capable of delivering large quantities of DNA in a direct, localized manner. Most natural polymers contain reactive sites amenable for ligand conjugation, cross-linking, and other modifications that can render the polymer tailored for a range of clinical applications. Natural polymers also often possess good cytocompatibility, making them popular choices for tissue engineering scaffolding applications. The marriage of gene therapy and tissue engineering exploits the power of genetic cell engineering to provide the biochemical signals to influence proliferation or differentiation of cells. Natural polymers with their ability to serve as gene carriers and tissue engineering scaffolds are poised to play an important role in the field of regenerative medicine. This review highlights the past and present research on various applications of natural polymers as particulate and matrix delivery vehicles for gene delivery.     

Surface-functionalized electrospun nanofibers for tissue engineering and drug delivery

Electrospun nanofibers with a high surface area to volume ratio have received much attention because of their potential applications for biomedical devices, tissue engineering scaffolds, and drug delivery carriers. In order to develop electrospun nanofibers as useful nanobiomaterials, surfaces of electrospun nanofibers have been chemically functionalized for achieving sustained delivery through physical adsorption of diverse bioactive molecules. Surface modification of nanofibers includes plasma treatment, wet chemical method, surface graft polymerization, and co-electrospinning of surface active agents and polymers. A variety of bioactive molecules including anti-cancer drugs, enzymes, cytokines, and polysaccharides were entrapped within the interior or physically immobilized on the surface for controlled drug delivery. Surfaces of electrospun nanofibers were also chemically modified with immobilizing cell specific bioactive ligands to enhance cell adhesion, proliferation, and differentiation by mimicking morphology and biological functions of extracellular matrix. This review summarizes surface modification strategies of electrospun polymeric nanofibers for controlled drug delivery and tissue engineering.     

Studies on thermoresponsive polymers: Phase behaviour,drug delivery and biomedical applications

The present review aims to highlight the applications of thermoresponsive polymers. Thermo-responsive polymers show a sharp change in properties upon a small or modest change in temperature. This behaviour can be utilized for the preparation of so-called ‘smart’ drug delivery systems, which mimic biological response behaviour to a certain extent. Such materials are used in the development of several applications, such as drug delivery systems, tissue engineering scaffolds and gene delivery. Advances in this field are particularly relevant to applications in the areas of regenerative medicine and drug delivery. This review addresses summary of the main applications of thermoresponsive polymers which are categorized based on their 3-dimensional structure; hydrogels, interpenetrating networks, micelles, films and particles. The physico-chemical behaviour underlying the phase transition is also discussed in brief.     

Polymer carriers for drug delivery in tissue engineering

Growing demand for tissues and organs for transplantation and the inability to meet this need using by autogeneic (from the host) or allogeneic (from the same species) sources has led to the rapid development of tissue engineering as an alternative. Tissue engineering aims to replace or facilitate the regrowth of damaged or diseased tissue by applying a combination of biomaterials, cells and bioactive molecules. This review focuses on synthetic polymers that have been used for tissue growth scaffold fabrication and their applications in both cell and extracellular matrix support and controlling the release of cell growth and differentiation supporting drugs.     

Biopolymeric colloidal carriers for encapsulation or controlled release applications

Biopolymers represent an interesting alternative to synthetic polymers in order to be used as structured carriers for controlled release and encapsulation applications. In particular, the ability of these carriers to entrap both hydrophilic and hydrophobic drugs may be very promising for many applications. In addition, the absence of chemical compounds and organic solvents used to produce biopolymeric matrices could be very interesting for some industrial applications. Simple or complex coacervation methods involving proteins or protein and polysaccharide mixtures were used to create new matrices dedicated to controlled release applications. Controlled release experiments with model compounds were conducted in order to evaluate the performance of such matrices. An alternative and promising research field deals with particles obtained from hydrogel systems. Totally transparent solid matrices resulting from the dehydration of new protein gels were formed and swelling capacities of these matrices were studied.     

Carbon nanotubes: Their potential and pitfalls for bone tissue regeneration and engineering

The extracellular environment which supports cell life is composed of a hierarchy of maintenance, force and regulatory systems which integrate from the nano- through to macroscale. For this reason, strategies to recreate cell supporting environments have been investigating the use of nanocomposite biomaterials. Here, we review the use of carbon nanotubes as part of a bottom-up approach for use in bone tissue engineering. We evaluate the properties of carbon nanotubes in the context of synthetic tissue substrates and contrast them with the nanoscale features of the extracellular environment. Key studies are evaluated with an emphasis on understanding the mechanisms through which carbon nanotubes interact with biological systems. This includes an examination of how the different properties of carbon nanotubes affect tissue growth, how these properties and variation to them might be leveraged in regenerative tissue therapies and how impurities or contaminates affect their toxicity and biological interaction.From the Clinical EditorIn this comprehensive review, the authors describe the status and potential applications of carbon nanotubes in bone tissue engineering.     

The potential of recombinant human elastin-like polypeptides for drug delivery

Mimicking the structure of natural proteins by recombinant biopolymers is a useful approach for the development of novel bioactive biomaterials with desired properties, that help elucidate molecular interactions in biological systems and elaborate strategies for tissue engineering and drug delivery purposes. Structurally based on elastin repeated motifs, recombinant human elastin-like polypeptides (HELPs) represent excellent examples of bio-inspired polymers proposed for tissue engineering, and recently exploited also for drug delivery applications. This Editorial reports on the latest advances in the research on HELP biopolymers for drug delivery and targeting applications. The main findings will be summarized with emphasis on the ‘smart’ properties of HELPs, which render this class of biopolymers particularly interesting in the whole biomedicine field. Considerations about further improvements of the current HELP-based systems will be provided, and a demonstration of the huge potential of HELPs in becoming leading material for drug delivery will be attempted.     

Micro- and nanoscale technologies for tissue engineering and drug discovery applications

Micro- and nanoscale technologies are emerging as powerful enabling tools for tissue engineering and drug discovery. In tissue engineering, micro- and nanotechnologies can be used to fabricate biomimetic scaffolds with increased complexity and vascularization. Furthermore, these technologies can be used to control the cellular microenvironment (i.e., cell–cell, cell–matrix and cell–soluble factor interactions) in a reproducible manner and with high temporal and spatial resolution. In drug discovery, miniaturized platforms based on micro- and nanotechnology can be used to precisely control the fluid flow, enable high-throughput screening, and minimize sample or reagent volumes. In addition, these systems enhance reproducibility and significantly reduce reaction times. This paper reviews the recent developments in the field of micro- and nanoscale technology and gives examples of their tissue engineering and drug discovery applications.     

3D in vitro technology for drug discovery

Three-dimensional (3D) in vitro systems that can mimic organ and tissue structure and function in vivo, will be of great benefit for a variety of biological applications from basic biology to toxicity testing and drug discovery. There have been several attempts to generate 3D tissue models but most of these models require costly equipment, and the most serious disadvantage in them is that they are too far from the mature human organs in vivo. Because of these problems, research and development in drug discovery, toxicity testing and biotech industries are highly expensive, and involve sacrifice of countless animals and it takes several years to bring a single drug/product to the market or to find the toxicity or otherwise of chemical entities. Our group has been actively working on several alternative models by merging biomaterials science, nanotechnology and biological principles to generate 3D in vitro living organs, to be called "Human Organs-on-Chip", to mimic natural organ/tissues, in order to reduce animal testing and clinical trials. We have fabricated a novel type of mechanically and biologically bio-mimicking collagen-based hydrogel that would provide for interconnected mini-wells in which 3D cell/organ culture of human samples in a manner similar to human organs with extracellular matrix (ECM) molecules would be possible. These products mimic the physical, chemical, and biological properties of natural organs and tissues at different scales. This paper will review the outcome of our several experiments so far in this direction and the future perspectives.     

Mathematical modeling of polymer erosion: consequences for drug delivery

Bioerodible polymers have been extensively used as carriers for drug delivery and as scaffolds for tissue engineering. The ability to model and predict erosion behavior can enable the rational design and optimization of biomaterials for various biomedical applications in vivo. This review examines critically the current approaches in mathematical modeling of the erosion of synthetic polymers. The models are classified broadly based on whether they use phenomenological, probabilistic, or empirical approaches. An analysis of the various physical, chemical, and biological factors affecting polymer erosion and the classes of bioerodible polymers to which these analyses have been applied are discussed. The key features and assumptions associated with each of the models are described, and information is provided on the limitations of the models and the various approaches. The review concludes with several directions for future models of polymer erosion.     

Ceramic composites as matrices and scaffolds for drug delivery in tissue engineering

Ceramic composites and scaffolds are popular implant materials in the field of dentistry, orthopedics and plastic surgery. For bone tissue engineering especially CaP-ceramics or cements and bioactive glass are suitable implant materials due to their osteoconductive properties. In this review the applicability of these ceramics but also of ceramic/polymer composites for bone tissue engineering is discussed, and in particular their use as drug delivery systems. Overall, the high density and slow biodegradability of ceramics is not beneficial for tissue engineering purposes. To address these issues, macroporosity can be introduced often in combination with osteoinductive growth factors and cells. Ceramics are good carriers for drugs, in which release patterns are strongly dependent on the chemical consistency of the ceramic, type of drug and drug loading. Biodegradable polymers like polylactic acid, gelatin or chitosan are used as matrices for ceramic particles or as adjuvant to calcium phosphate cements. The use of these polymers can introduce a tailored biodegradation/drug release to the ceramic material.     

Drug delivery systems: 3A. Role of polymers in drug delivery

At present, polymers represent a class of ubiquitous materials. They are being used for a multitude of purposes and the almost inexhaustible varieties of molecular architecture that macromolecular materials can possess provides the possibility for a myriad of applications. Because of the increased interest being shown in the macromolecules by the pharmaceutical industry for the fabrication of drug delivery systems, numerous polymers have been synthesized and successfully used in drug delivery devices. The necessary conditions for developing the concept of pharmaceutically applicable polymers depend upon delineating a detailed knowledge of the relationship between the structure and properties of polymer networks. A number of polymers have been studied systematically from this point of view and there is every indication that the systems described have the potential to become clinically valuable and therefore marketable drug delivery systems. The potential of these promising polymers is still far from being exhausted and there is a strong possibility that many important developments will be forthcoming in this field in the future. In the current review article, polymers for controlled release have been divided into four major categories: diffusion-controlled systems; chemically controlled systems; solvent-activated systems; and magnetically controlled systems. Polymers as drug carriers also have been divided into various subgroups: soluble, biodegradable, mucoadhesive and other polymeric systems. The latter group includes polymers containing pendant bioactive substituents, matrix systems, heparin-releasing polymers, ionic polymers, oligomers and miscellaneous. At an introductory and fundamental level, an overview of these polymers and the materials science for the design of drug delivery systems will be discussed.     

Biodegradable polymeric drug delivery systems

The use of biodegradable polymeric materials as drug carriers is a relatively new dimension in polymeric drug delivery systems. A number of biodegradable or bioerodible polymers, such as poly (lactic/glycolic acid) copolymer, poly(α-amino acid), polyanhydride, and poly (ortho ester) are currently being investigated for this purpose. These polymers are useful for matrix and reservoir-type delivery devices. In addition, when chemical functional groups are introduced to the biodegradable polymer backbone, such as poly (N-(2-hydroxypropy) methacrylamide), the therapeutic agent can be covalently bound directly orvia spacer to the backbone polymer. These polymer/drug conjugates represent another new dimension in biodegradable polymeric drug delivery systems. In this paper, major emphasis is placed on clinical applications of biodegradable polymeric delivery systems. In addition, examples of biodegradable polymeric durg delivery systems currently being investigated will be discussed for the purpose of demonstrating the potential importance of this new field.     

Protein delivery: from conventional drug delivery carriers to polymeric nanoreactors

Due to their low bioavailability, many naturally occurring proteins can not be used in their native form in diseases caused by insufficient amounts or inactive variants of those proteins. The strategy of delivering proteins to biological compartments using carriers represents the most promising approach to improve protein bioavailability. A large variety of systems have been developed to protect and deliver proteins, based on lipids, polymers or conjugates. Here we present the current progress of the carriers design criteria with the help of recent specific examples in the literature ranging from conventional liposomes to polymeric nanoreactors, with sizes from micrometer to nanometer scale, and having various morphologies. The design and optimisation of carriers in the dual way of addressing questions of a particular application and of keeping them very flexible and reliable for general applications represent an important step in protein delivery approaches, which influence considerably the therapeutic efficacy. We examine several options currently under exploration for creating suitable protein carriers, discuss their advantages and limitations that induced the need to develop alternative ways to deliver proteins to biological compartments. We consider that only tailored systems can serve to improve proteins bioavailability, and thus solve specific pathological situations. This can be accomplished by developing nanocarriers and nanoreactors based on biocompatible, biodegradable and non-toxic polymer systems, adapted sizes and surface properties, and multifunctionality to cope with the complexity of the in-vivo biological conditions.     

Genetically engineered polymers for drug delivery

Genetic engineering methodology offers the ability to synthesize protein-based polymers with precisely controlled structures. Protein-based polymers synthesized by recombinant techniques have a well-defined monomer composition and sequence, stereochemistry, and a narrow molecular weight distribution. The structure of the polymeric carrier at the molecular level influences its biological disposition and drug release profile. Current methodologies of polymer synthesis (chemical polymerization) result in the production of polymers with heterogeneous molecular weights, and with monomer sequences and compositions defined in terms of statistical distributions. Genetic engineering methodologies can be used to design new polymeric drug carriers with improved properties, such as better-defined biorecognition, pharmacokinetic, biodegradation, and drug release profiles. In this review article the rationale and methodology of polymer synthesis using genetic engineering techniques, the status of such polymers in drug delivery to-date, and the potential of these polymers for the development of new systems in the future are discussed.     

Biodegradable ‘intelligent’ materials in response to chemical stimuli for biomedical applications

Background: Biodegradable stimuli-responsive materials, which exhibit large and sharp physical–chemical changes in response to small physical or chemical stimuli, are attracting increasing interests because of their potential applications in biomedical fields, such as transient implants, drug delivery carriers, and tissue engineering scaffolds. Our previous review (see page 493 of issue 4) summarized those biodegradable ‘intelligent’ materials that respond to physical stimuli, such as temperature, ultrasound, and magnetic field. Biodegradable ‘intelligent’ materials that could respond to chemical stimuli, such as pH and specific molecules, have also been studied intensively and significant progress in this field has been achieved. As a single stimulus-responsive property would limit practical application, multi-stimuli-responsive materials are receiving increasing interest and considerable attention. Objective/methods: This review summarizes the development of biodegradable ‘intelligent’ materials in response to chemical stimuli and to dual stimuli; their potential biomedical applications are also introduced. A detailed analysis of publications and patents on such materials in recent years is presented. Results/conclusion: Most of biodegradable stimuli-responsive materials are currently still at a developmental research stage. Further work is required to improve the responsive properties between the materials and the biological environments, so that the clinical applicability of such devices could be successful. We hope that our review will be helpful in the future development of new stimuli-responsive biodegradable polymers or polymeric systems that can be used reliably in real-life applications.     

Biodegradable ‘intelligent’ materials in response to physical stimuli for biomedical applications

Background: Stimuli-responsive materials that undergo dramatic changes in physical–chemical properties in response to mild physical changes in environmental conditions are attracting increasing interest because of their potential application in biomedical fields. Biodegradable materials are highly desired for most biomedical applications in vivo, such as transient implants, drug-delivery carriers, and tissue engineering scaffolds. Biomedical systems that are both biodegradable and stimuli-responsive have therefore been studied intensively and significant progress in this field has been achieved. Objective/methods: This review summarizes the development of biodegradable ‘intelligent’ materials in response to physical stimuli and their potential biomedical applications. A detailed analysis of publications and patents on such materials in recent years is presented. Results/conclusion: Although biodegradable stimuli-responsive materials are highly attractive for biomedical applications, most such materials are currently at a developmental research stage. Additionally, single stimulus-responsive property limits the practical applications of these materials. To achieve more favorable applications for these materials, further efforts are still necessary, especially for developing multi-stimuli-responsive functions of materials and improving the stimuli-responsive properties of such materials in a biological environment. Bearing in mind the great prospect of these biodegradable stimuli-responsive materials, we hope that this review will help in the future development of stimuli-responsive polymers or systems that could be reliably employed in biomedical applications.     

New intelligent and targetted drug delivery systems. Pharmaceutical and biomedical applications

Biomaterials are widely used in numerous medical applications. Chemical engineering has played a central role in this research and development. We review herein polymers as biomaterials, materials and approaches used in drug and protein delivery systems, materials used as scaffolds in tissue engineering, and nanotechnology and microfabrication techniques applied to biomaterials.     

Electrospun silk biomaterial scaffolds for regenerative medicine

Electrospinning is a versatile technique that enables the development of nanofiber-based biomaterial scaffolds. Scaffolds can be generated that are useful for tissue engineering and regenerative medicine since they mimic the nanoscale properties of certain fibrous components of the native extracellular matrix in tissues. Silk is a natural protein with excellent biocompatibility, remarkable mechanical properties as well as tailorable degradability. Integrating these protein polymer advantages with electrospinning results in scaffolds with combined biochemical, topographical and mechanical cues with versatility for a range of biomaterial, cell and tissue studies and applications. This review covers research related to electrospinning of silk, including process parameters, post treatment of the spun fibers, functionalization of nanofibers, and the potential applications for these material systems in regenerative medicine. Research challenges and future trends are also discussed.     

MicroRNAs in liver tissue engineering — New promises for failing organs

miRNA-based technologies provide attractive tools for several liver tissue engineering approaches. Herein, we review the current state of miRNA applications in liver tissue engineering. Several miRNAs have been implicated in hepatic disease and proper hepatocyte function. However, the clinical translation of these findings into tissue engineering has just begun. miRNAs have been successfully used to induce proliferation of mature hepatocytes and improve the differentiation of hepatic precursor cells. Nonetheless, miRNA-based approaches beyond cell generation have not yet entered preclinical or clinical investigations. Moreover, miRNA-based concepts for the biliary tree have yet to be developed. Further research on miRNA based modifications, however, holds the promise of enabling significant improvements to liver tissue engineering approaches due to their ability to regulate and fine-tune all biological processes relevant to hepatic tissue engineering, such as proliferation, differentiation, growth, and cell function.