Natural-origin polymers as carriers and scaffolds for biomolecules and cell delivery in tissue engineering applications

The present paper intends to overview a wide range of natural-origin polymers with special focus on proteins and polysaccharides (the systems more inspired on the extracellular matrix) that are being used in research, or might be potentially useful as carriers systems for active biomolecules or as cell carriers with application in the tissue engineering field targeting several biological tissues. The combination of both applications into a single material has proven to be very challenging though. The paper presents also some examples of commercially available natural-origin polymers with applications in research or in clinical use in several applications. As it is recognized, this class of polymers is being widely used due to their similarities with the extracellular matrix, high chemical versatility, typically good biological performance and inherent cellular interaction and, also very significant, the cell or enzyme-controlled degradability. These biocharacteristics classify the natural-origin polymers as one of the most attractive options to be used in the tissue engineering field and drug delivery applications.     

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.     

Drug delivery’s quest for polymers: Where are the frontiers?

Since the legendary 1964 article of Folkman and Long entitled “The use of silicone rubber as a carrier for prolonged drug therapy” the role of polymers in controlled drug delivery has come a long way. Today it is evident that polymers play a crucial if not the prime role in this field. The latest boost owes to the interest in drug delivery for the purpose of tissue engineering in regenerative medicine. The focus of this commentary is on a selection of general and personal observations that are characteristic for the current state of polymer therapeutics and carriers. It briefly highlights selected examples for the long march of synthetic polymer–drug conjugates from bench to bedside, comments on the ambivalence of selected polymers as inert excipients versus biological response modifiers, and on the yet unsolved dilemma of cationic polymers for the delivery of nucleic acid therapeutics. Further subjects are the complex design of multifunctional polymeric carriers including recent concepts towards functional supramolecular polymers, as well as observations on stimuli-sensitive polymers and the currently ongoing trend towards natural and naturally-derived biopolymers. The final topic is the discovery and early development of a novel type of biodegradable polyesters for parenteral use. Altogether, it is not the basic and applied research in polymer therapeutics and carriers, but the translational process that is the key hurdle to proceed towards an authoritative approval of new polymer therapeutics and carriers.     

Contribution of poly(amino acids) to advances in pharmaceutical biotechnology

Recently, protein biotechnology generates tremendous impacts in therapeutic products. These products include enzymes, antibodies, hormones, blood factors, growth factors and regulatory factors. Protein, vaccine and gene therapy drugs could be formulated with suitable biomaterials to deliver active agents to their target sites at the right time and maintain therapeutic effects for proper durations. In this review article, we focus on poly(amino acids) or polymerized amino acids for their applications in drug delivery systems, vaccines, and gene therapy. The nomenclatures of poly(amino acids) are briefly introduced to systematically express synthetic polypeptides. In drug delivery systems, we introduce two applications of poly(amino acids) in pharmaceutical biotechnology, either as carriers to facilitate drug delivery, or as biomaterials to be formulated as suitable delivery systems for application in tissue engineering. Many short polypeptides are mapped from antigen motifs and used for vaccination. These poly(amino acids) provide protective effects in animal challenge tests and potential application in vaccine development to be briefly introduced. Finally, some reports related to new developed poly(amino acids) as DNA carriers for achieving gene delivery are also described in the text.     

Strategies for controlled delivery of growth factors and cells for bone regeneration

The controlled delivery of growth factors and cells within biomaterial carriers can enhance and accelerate functional bone formation. The carrier system can be designed with pre-programmed release kinetics to deliver bioactive molecules in a localized, spatiotemporal manner most similar to the natural wound healing process. The carrier can also act as an extracellular matrix-mimicking substrate for promoting osteoprogenitor cellular infiltration and proliferation for integrative tissue repair. This review discusses the role of various regenerative factors involved in bone healing and their appropriate combinations with different delivery systems for augmenting bone regeneration. The general requirements of protein, cell and gene therapy are described, with elaboration on how the selection of materials, configurations and processing affects growth factor and cell delivery and regenerative efficacy in both in vitro and in vivo applications for bone tissue engineering.     

The future perspectives of natural materials for pulmonary drug delivery and lung tissue engineering

Introduction: Search for new, functional biomaterials that can be used to synergistically deliver a drug, enhance its adsorption and stimulate the post-injury recovery of tissue function, is one of the priorities in biomedicine. Currently used materials for drug delivery fail to satisfy one or more of these functionalities, thus they have limited potential and new classes of materials are urgently needed.

Areas covered: Natural materials, due to their origin, physical and chemical structure can potentially fulfill these requirements and there is already strong evidence of their usefulness in drug delivery. They are increasingly utilized in various therapeutic applications due to the obvious advantages over synthetic materials. Particularly in pulmonary drug delivery, there have been limitations in the use of synthetic materials such as polymers and lipids, leading to an increase in the use of natural and protein-based materials such as silk, keratin, elastin and collagen. Literature search in each specialized field, namely, silk, keratin and collagen was conducted, and the benefits of each material for future application in pulmonary drug delivery are highlighted.

Expert opinion: The natural materials discussed in this review have been well established in their use for other applications, yet further studies are required in the application of pulmonary drug delivery. The properties exhibited by these natural materials seem positive for their application in lung tissue engineering, which may allow for more extensive testing for validation of pulmonary drug delivery systems.     

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 targeting by surface cationization

Cationization of drug products and carriers involves a direct modification or attachment of conveying or accompanying components, either of which cause a charge modification. Cationization of macromolecules such as proteins and nucleotides and particulate drug carriers generally enhances their cellular uptake by endocytosis. The most common use of cationization today is in gene delivery. This is undertaken by either employing cationic polymers or entraping nucleotides in cationic carriers such as cationic liposomes. Cationized delivery systems are also used to overcome biological barriers and are suggested for drug targeting, in a nonspecific manner, to a variety of body organs, including brain, eyes, nose, and inflamed intestinal epithelium. Protein cationization is also suggested both for tumor immunotherapy and as a diagnostic tool in cancer therapy. Cationization has proven itself to be a straightforward tool for targeting to cells, tissues, and selected organs. This article reviews the extensive range of applications of cationization for improving drug and gene delivery and summarizes major technologies employed for that purpose.     

Bio-inspired, bioengineered and biomimetic drug delivery carriers

Synthetic carriers such as polymer and lipid particles often struggle to meet clinical expectations. Natural particulates - that range from pathogens to mammalian cells - are therefore worth examining in more depth, as they are highly optimized for their specific functions in vivo and possess features that are often desired in drug delivery carriers. With a better understanding of these biological systems, in conjunction with the availability of advanced biotechnology tools that are useful for re-engineering the various natural systems, researchers have started to exploit natural particulates for multiple applications in the delivery of proteins, small interfering RNA and other therapeutic agents. Here, we review the natural drug delivery carriers that have provided the basis and inspiration for new drug delivery systems.     

Matrices and scaffolds for delivery of bioactive molecules in bone and cartilage tissue engineering

Regeneration of bone and cartilage defects can be accelerated by localized delivery of appropriate growth factors incorporated within biodegradable carriers. The carrier essentially allows the impregnated growth factor to release at a desirable rate and concentration, and to linger at injury sites for a sufficient time to recruit progenitors and stimulate tissue healing processes. In addition, the carrier can be formulated to have particular structure to facilitate cellular infiltration and growth. In this review, we present a summary of growth factor delivery carrier systems for bone and cartilage tissue engineering. Firstly, we describe a list of growth factors implicated in repair and regeneration of bone and cartilage by addressing their biological effects at different stages of the healing process. General requirements for localized growth factor delivery carriers are then discussed. We also provide selective examples of material types (natural and synthetic polymers, inorganic materials, and their composites) and fabricated forms of the carrier (porous scaffolds, microparticles, and hydrogels), highlighting the dose-dependent efficacy, release kinetics, animal models, and restored tissue types. Extensive discussion on issues involving currently investigated carriers for bone and cartilage tissue engineering approaches may illustrate future paths toward the development of an ideal growth factor delivery system.     

Overview on zein protein: a promising pharmaceutical excipient in drug delivery systems and tissue engineering

Introduction: Natural pharmaceutical excipients have been applied extensively in the past decades owing to their safety and biocompatibility. Zein, a natural protein of plant origin offers great benefit over other synthetic polymers used in controlled drug and biomedical delivery systems. It was used in a variety of medical fields including pharmaceutical and biomedical drug targeting, vaccine, tissue engineering, and gene delivery. Being biodegradable and biocompatible, the current review focuses on the history and the medical application of zein as an attractive still promising biopolymer.

Areas covered: The current review gives a broadscope on zein as a still promising protein excipient in different fields. Zein- based drug and biomedical delivery systems are discussed with special focus on current and potential application in controlled drug delivery systems, and tissue engineering.

Expert opinion: Zein as a protein of natural origin can still be considered a promising polymer in the field of drug delivery systems as well as in tissue engineering. Although different researchers spotted light on zein application in different industrial fields extensively, the feasibility of its use in the field of drug delivery replenished by investigators in recent years has not yet been fully approached.     

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.     

The role of the disulfide group in disulfide-based polymeric gene carriers

Background: An essential prerequisite for successful gene therapy is the development of safe and efficient gene delivery carriers. For this purpose, cationic polymers have been widely studied as non-viral carriers, but they generally suffer from low transfection efficiency and/or high cytotoxicity. To address these problems, disulfide-based cationic polymers have been designed as intelligent gene carriers that are capable of inducing highly efficient gene transfection with low cytotoxicity. Objective: The present review discusses the effects of the disulfide linker on the gene delivery properties of cationic polymers in relation to various gene delivery barriers. Methods: The literature regarding the gene delivery barriers encountered by polymeric gene delivery is reviewed and discussed in relation to the presence of the disulfide moiety in these gene carriers. Conclusions: The presence of disulfide linkages in cationic polymers can in many aspects favorably influence the gene delivery properties, such as increasing DNA binding ability, enabling de-shielding of ‘stealth’ (PEG) groups, fine-tuning of the buffer capacity for enhanced endosomal escape, improving carrier-unpacking and decreasing cytotoxicity. Therefore, disulfide-based cationic polymers are promising candidates for the next generation of non-viral carriers.     

Delivering DNA with polymer matrices: applications in tissue engineering and gene therapy

DNA delivery from polymers is currently being applied to the multidisciplinary science of gene therapy and tissue engineering. This is motivated by the potential of treating a wide range of diseases and the provision of alternatives to tissue and organ transplantation. The combination of these fields involves the incorporation of genes into polymeric matrices that can be injected or implanted to promote tissue regeneration. This review presents an overview of current and developing polymer systems for gene delivery and tissue engineering.     

Bone tissue engineering by gene delivery

Recombinant human bone morphogenetic protein-2 and -7 were recently granted United States Food and Drug Administration approval for select clinical applications in bone repair. While significant progress has been made in the delivery of recombinant osteogenic factor to promote bone healing, the short half-life and instability of the protein requires the delivery of milligram quantities of factor or multiple dosages. The potential of gene therapy for bone regeneration is the delivery of physiological levels of therapeutic protein using natural cellular mechanisms. Experimental investigations have demonstrated this approach uses lower dosages of factor to yield bone healing equivalent to that achieved via the administration of recombinant factor or use of bone grafts. The current states of gene delivery for bone tissue engineering applications and challenges to be met are presented in this review. Over the past couple of years, studies have continued to examine the delivery of the osteogenic factor bone morphogenetic protein using gene therapies. The importance of angiogenesis to bone formation has prompted the development of vascular endothelial growth factor gene expression systems for bone regeneration. Viral vectors, in combination with allograft bone, have been investigated to improve existing surgical care. Newly constructed vectors with reduced immunogenicity and regulated gene expression systems provide a greater degree of control over the timing and level of gene expression. Several advances have allowed bone tissue engineering by gene delivery to advance beyond serving as a potential treatment for isolated bone defects and fractures to a gene therapy approach for the treatment of genetic based bone diseases, such as osteogenesis imperfecta.     

Targeted filamentous bacteriophages as therapeutic agents

Bacteriophages (phages) have been used for therapy of bacterial infections, for genetic research, as tools for the discovery of specific target binding proteins and for vaccine development. The aim of this article is to present advances in genetic and chemical engineering of filamentous bacteriophages that facilitated their application for therapeutic purposes. We review studies where phages were applied for in vivo imaging, as gene delivery vehicles and as drug carriers. Target specificity is based on peptides or proteins displayed on the phage coat. The cargo may be a packaged gene incorporated into the phage genome for gene delivery applications, or imaging agents or cytotoxic drugs chemically conjugated at high density onto the phage coat. We believe that the combination of those separately developed methodologies would result in clinical applications of phage-based therapeutics.     

Chitosan microspheres in novel drug delivery systems

The main aim in the drug therapy of any disease is to attain the desired therapeutic concentration of the drug in plasma or at the site of action and maintain it for the entire duration of treatment. A drug on being used in conventional dosage forms leads to unavoidable fluctuations in the drug concentration leading to under medication or overmedication and increased frequency of dose administration as well as poor patient compliance. To minimize drug degradation and loss, to prevent harmful side effects and to increase drug bioavailability various drug delivery and drug targeting systems are currently under development. Handling the treatment of severe disease conditions has necessitated the development of innovative ideas to modify drug delivery techniques. Drug targeting means delivery of the drug-loaded system to the site of interest. Drug carrier systems include polymers, micelles, microcapsules, liposomes and lipoproteins to name some. Different polymer carriers exert different effects on drug delivery. Synthetic polymers are usually non-biocompatible, non-biodegradable and expensive. Natural polymers such as chitin and chitosan are devoid of such problems. Chitosan comes from the deacetylation of chitin, a natural biopolymer originating from crustacean shells. Chitosan is a biocompatible, biodegradable, and nontoxic natural polymer with excellent film-forming ability. Being of cationic character, chitosan is able to react with polyanions giving rise to polyelectrolyte complexes. Hence chitosan has become a promising natural polymer for the preparation of microspheres/nanospheres and microcapsules. The techniques employed to microencapsulate with chitosan include ionotropic gelation, spray drying, emulsion phase separation, simple and complex coacervation. This review focuses on the preparation, characterization of chitosan microspheres and their role in novel drug delivery systems.     

Recent development of nonviral gene delivery systems with virus-like structures and mechanisms

The concept of gene therapy includes not only the addition of normal genes to genetically deficient cells, but also the use of transgenes encoding several peptides that function to enhance the capacity of normal cells or to regulate cell differentiation. The application of gene therapy has been widely considered for various diseases, as well as for the field of tissue engineering. To overcome the problems with viral vectors, a broad range of nonviral systems for gene delivery have been developed, including systems composed of cationic lipids (lipoplexes) and cationic polymers (polyplexes). However, most of these systems are still much less efficient than viral vectors, especially for in vivo gene delivery. Paradoxically, to achieve a maximum transgene expression in the targeted cells, there is no question that natural viruses are the most effective nanocarriers. In this article, we highlight the approaches currently being taken to improve nonviral gene delivery systems so that they better replicate the typical structures and mechanisms of viruses, such as DNA (RNA) condensation in the core, surrounding structures with targeting molecules for specific receptors, as well as the toxic and immunogenic problems which should be avoided, with the ultimate goal of bringing these systems into a clinical setting.     

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.     

Polyphosphates and other phosphorus-containing polymers for drug delivery applications

Poly(phosphate ester)s, polyphosphonates, and polyphosphazenes are three classes of phosphorus-containing polymers that have received wide attention over the past decade for their utility in biomedicine and tissue engineering. These three families of polymers can lead to a number of subclasses of polymers with varied properties. Significant research in this area has led to niche polymers with morphologies ranging from viscous gels to amorphous microparticles for utility in drug delivery. Furthermore, the pentavalency of phosphorus offers the potential for covalent linking of the drug. The classes of polymers discussed in this review are being explored in human clinical trials for vaccine delivery as well as delivery of oncolytic and CNS therapeutics. More applications in the areas of DNA delivery and tissue engineering are also being explored.