Composite polymer-bioceramic scaffolds with drug delivery capability for bone tissue engineering

Introduction: Next-generation scaffolds for bone tissue engineering (BTE) should exhibit the appropriate combination of mechanical support and morphological guidance for cell proliferation and attachment while at the same time serving as matrices for sustained delivery of therapeutic drugs and/or biomolecular signals, such as growth factors. Drug delivery from BTE scaffolds to induce the formation of functional tissues, which may need to vary temporally and spatially, represents a versatile approach to manipulating the local environment for directing cell function and/or to treat common bone diseases or local infection. In addition, drug delivery from BTE is proposed to either increase the expression of tissue inductive factors or to block the expression of others factors that could inhibit bone tissue formation. Composite scaffolds which combine biopolymers and bioactive ceramics in mechanically competent 3D structures, including also organic–inorganic hybrids, are being widely developed for BTE, where the affinity and interaction between biomaterials and therapeutic drugs or biomolecular signals play a decisive role in controlling the release rate.

Areas covered: This review covers current developments and applications of 3D composite scaffolds for BTE which exhibit the added capability of controlled delivery of therapeutic drugs or growth factors. A summary of drugs and biomolecules incorporated in composite scaffolds and approaches developed to combine biopolymers and bioceramics in composites for drug delivery systems for BTE is presented. Special attention is given to identify the main challenges and unmet needs of current designs and technologies for developing such multifunctional 3D composite scaffolds for BTE.

Expert opinion: One of the major challenges for developing composite scaffolds for BTE is the incorporation of a drug delivery function of sufficient complexity to be able to induce the release patterns that may be necessary for effective osseointegration, vascularization and bone regeneration. Loading 3D scaffolds with different biomolecular agents should produce a codelivery system with different, predetermined release profiles. It is also envisaged that the number of relevant bioactive agents that can be loaded onto scaffolds will be increased, whilst the composite scaffold design should exploit synergistically the different degradation profiles of the organic and inorganic components.     

Thermosensitive hydrogels for drug delivery

Introduction: Controlled drug delivery has been widely applied in areas such as cancer therapy and tissue regeneration. Thermosensitive hydrogel-based drug delivery systems have increasingly attracted the attention of the drug delivery community, as the drugs can be readily encapsulated and released by the hydrogels.

Areas covered: Thermosensitive hydrogels that can serve as drug carriers are discussed in this paper. Strategies used to control hydrogel properties, in order to tailor drug release kinetics, are also reviewed. This paper also introduces applications of the thermosensitive hydrogel-based drug delivery systems in cancer therapy and tissue regeneration.

Expert opinion: When designing a drug delivery system using thermosensitive hydrogels, one needs to consider what type of thermosensitive hydrogel needs to be used, and how to manipulate its properties to meet the desired drug release kinetics. For material selection, both naturally derived and synthetic thermosensitive polymers can be used. Various methods can be used to tailor thermosensitive hydrogel properties in order to achieve the desired drug release profile.     

Bisphosphonate-modified biomaterials for drug delivery and bone tissue engineering

Introduction: Bisphosphonates (BPs) were introduced 45 years ago as anti-osteoporotic drugs and during the last decade have been utilized as bone-targeting groups in systemic treatment of bone diseases. Very recently, strategies of chemical immobilization of BPs in hydrogels and nanocomposites for bone tissue engineering emerged. These strategies opened new applications of BPs in bone tissue engineering.

Areas covered: Conjugates of BPs to different drug molecules, imaging agents, proteins and polymers are discussed in terms of specific targeting to bone and therapeutic affect induced by the resulting prodrugs in comparison with the parent drugs. Conversion of these conjugates into hydrogel scaffolds is also presented along with the application of the resulting materials for bone tissue engineering.

Expert opinion: Calcium-binding properties of BPs can be successfully extended via different conjugation strategies not only for purposes of bone targeting, but also in supramolecular assembly affording either new nanocarriers or bulk nanocomposite scaffolds. Interaction between carrier-linked BPs and drug molecules should also be considered for the control of release of these molecules and their optimized delivery. Bone-targeting properties of BP-functionalized nanomaterials should correspond to bone adhesive properties of their bulk analogs.     

Aerosol drug delivery in lung transplant recipients

Background: Inhaled drug delivery after lung transplantation provides a unique opportunity for direct treatment of a solid organ transplant. At present, no inhaled therapies are approved for this population though several have received some development. Primary potential applications include inhaled immunosuppressive and anti-infective drugs. Objectives: The objective of this article is to review potential applications of inhaled medications for lung transplant recipients, the techniques used to develop inhaled drugs and the challenges of aerosol delivery in this specific population. Methods: The results of relevant studies are reviewed and two developmental examples are presented. Results/conclusions: Inhaled medications may provide significant advantages for lung transplant recipients. Past studies with inhaled cyclosporine and amphotericin-B provide useful guidance for clinical development of new preparations.     

Molecularly imprinted polymers in drug delivery: state of art and future perspectives

Introduction: Molecularly imprinted polymers (MIPs) are synthetic receptors, characterized by a high selectivity for the selected template. Among the different applications of MIPs, their use as controlled/sustained drug delivery devices has been extensively explored, even though the optimization of such devices needs to be performed before they are applied in clinical practice.

Areas covered: Within drug delivery, one of the most promising fields is the possibility to modulate the drug release profile in response to a specific external stimulus; MIPs represent potentially suitable vehicles, because of the possibility to insert a stimuli-responsive co-monomer in their structure. This review discusses recent advances in the use of external stimuli to modulate drug release, as well as the synthetic strategies devoted to increase the water compatibility of these systems, which is a base requirement for their application in biomedicine.

Expert opinion: Although it is easy to imagine imprinted polymers for biomedical applications, several aspects have to be further investigated, such as the in vivo studies, efficiency and biocompatibility. However, we think that in the next few years it will possible to see unprecedented progress in the preparation of such systems and the translational application of these intelligent structures in medicine.     

Nanotechnology controlled drug delivery for treating bone diseases

Rapid developments at the intersection of nanotechnology and controlled drug delivery have triggered exceptional growth in treating various bone diseases. As a result, over the past decade, nanotechnology has contributed tremendously to controlling drug delivery for treating various bone diseases, and in many cases, has led to increased bone regeneration. In this review paper, the recent experimental progress towards using nanotechnology to treat bone-specific diseases is reviewed. Novel applications of different types of nanomaterials (from nanoparticles to 3D nanostructured scaffolds) for treating bone diseases are summarized. In addition, fundamental principles for utilizing nanomaterials to create better drug delivery systems, especially for treating bone diseases and regenerating bone, are emphasized.     

Controlled local drug delivery strategies from chitosan hydrogels for wound healing

Introduction: The main target of tissue engineering is the preparation and application of adequate materials for the design and production of scaffolds, that possess properties promoting cell adhesion, proliferation and differentiation. The use of natural polysaccharides, such as chitosan, to prepare hydrogels for wound healing and controlled drug delivery is a research topic of wide and increasing interest.

Areas covered: This review presents the latest results and challenges in the preparation of chitosan and chitosan-based scaffold/hydrogel for wound healing applications. A detailed overview of their behavior in terms of controlled drug delivery, divided by drug categories, and efficacy was provided and critically discussed.

Expert opinion: The need to establish and exploit the advantages of natural biomaterials in combination with active compounds is playing a pivotal role in the regenerative medicine fields. The challenges posed by the many variables affecting tissue repair and regeneration need to be standardized and adhere to recognized guidelines to improve the quality of evidence in the wound healing process. Currently, different methodologies are followed to prepare innovative scaffold formulations and structures. Innovative technologies such as 3D printing or bio-electrospray are promising to create chitosan-based scaffolds with finely controlled structures with customizable shape porosity and thickness. Chitosan scaffolds could be designed in combination with a variety of polysaccharides or active compounds with selected and reproducible spacial distribution, providing active wound dressing with highly tunable controlled drug delivery.     

Emerging pressure-release materials for drug delivery

Drug delivery systems for non-specialist uses and application under field conditions are required for medical action in disaster situations and in developing countries. A possible solution for drug delivery under those conditions might be provided by mechanical manipulation of host–guest interactions that could allow drug release control by simple human actions such as hand motion. This editorial article presents recent research developments on control of molecular recognition, capture and release involving macroscopic mechanical motions. In particular, pressure-induced drug release from a cyclodextrin-linked gel has been used to realize controlled release of entrapped drugs upon applying an easy-to-perform mechanical procedure. These easy-action-based drug delivery systems can be applied at will by unskilled staff or patients and are expected to be used to assist medically patients in less-favorable environments anywhere in the world.     

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.     

基因药物肺部递送系统的研究进展

哮喘、肺气肿、囊性纤维化、肺部病毒感染和肺癌等多种肺部疾病严重影响人类的健康.基因治疗为肺部疾病治疗开辟了一个新的治疗途径.但因裸露的治疗基因易被降解、靶向能力差,因此需要安全有效的传递系统.本文将对基因药物在体内递送至肺部的给药屏障及可行性方法进行讨论.     

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.     

Interpenetrating Polymer Networks polysaccharide hydrogels for drug delivery and tissue engineering

The ever increasing improvements of pharmaceutical formulations have been often obtained by means of the use of hydrogels. In particular, environmentally sensitive hydrogels have been investigated as “smart” delivery systems capable to release, at the appropriate time and site of action, entrapped drugs in response to specific physiological triggers. At the same time the progress in the tissue engineering research area was possible because of significant innovations in the field of hydrogels. In recent years multicomponent hydrogels, such as semi-Interpenetrating Polymer Networks (semi-IPNs) and Interpenetrating Polymer Networks (IPNs) have emerged as innovative biomaterials for drug delivery and as scaffolds for tissue engineering. These interpenetrated hydrogel networks, which can be obtained by either chemical or physical crosslinking, in most cases show physico-chemical properties that can remarkably differ from those of the macromolecular constituents. Among the synthetic and natural polymers that have been used for the preparation of semi-IPNs and IPNs, polysaccharides represent a class of macromolecules of particular interest because they are usually abundant, available from renewable sources and have a large variety of composition and properties that may allow appropriately tailored chemical modifications. Sometimes both macromolecular systems are based on polysaccharides but often also synthetic polymers are present together with polysaccharide chains.     

Nanostructured self assembled lipid materials for drug delivery and tissue engineering

Every living organism comprises of lipids as basic building blocks in addition to other components. Utilizing these lipids for pharmaceutical and biomedical applications can overcome biocompatibility and biodegradability issues. A well known example is liposomes (lipids arranged in lamellar structures), but other than that there are additional unique mesophasic structures of lipids formed as a result of lipid polymorphisms, which include cubic-, hexagonal- or sponge-phase structures. These structures provide the advantages of stability and production feasibility compared with liposomes. Cubosomes, which exist in a cubic structure, have improved stability, bioadhesivity and biocompatibility. Hexagonal phases or hexosomes exhibit hexagonal arrangements and can encapsulate different drugs with high stability. Lipids also forms tube-like structures known as tubules and ribbons that are also utilized in different biomedical applications, especially in tissue engineering. Immune stimulating complexes are nanocage-like structures formed as a result of interactions of lipid, antigen and Quillaja saponin. These lipidic mesophasic structures have been utilized for gene, vaccine and drug delivery. This article addresses lipid self-assembled supramolecular nanostructures, including cubosomes, hexosomes, tubules, ribbons, cochleates, lipoplexes and immune stimulating complexes and their biomedical applications.     

Recent progress in drug delivery of pluronic P123: pharmaceutical perspectives

This review focuses on recent investigations that used Pluronic P123 (P123) as pharmaceutical ingredients in vesicle, micelle, mixed micelle, in situ gel, tablet and emulsion. The main results from these studies show that P123 can significantly increase the stability of incorporated hydrophobic drugs with enhanced in vitro cytotoxicity and cellular uptake of anticancer drugs. Moreover, modified forms of P123 with RGD, folate or other targeted marker have shown its therapeutic potentials in various types of tumors and cancers. Furthermore, modified forms of P123 alone and/or mixed with other copolymers have less toxic effects and more tumor-specific delivery of anticancer drugs. They are promising materials as a nanoplatform for the drug delivery. Finally, the future perspectives of the field are briefly discussed.     

Intrathecal drug delivery for pain management: recent advances and future developments

ABSTRACT

Introduction: Chronic pain conditions of malignant and non-malignant etiology afflict a large group of the population and pose a vast economic burden on society. Intrathecal drug therapy is a viable treatment option in such patients who have failed conservative medical measures and less invasive pain management procedures. However, the clinical growth of intrathecal therapy in managing intractable chronic pain conditions continues to face many challenges and is likely underutilized secondary to its high-complexity and lack of understanding.

Areas covered: This review will briefly discuss the history of intrathecal drug delivery systems (IDDS), cerebrospinal fluid (CSF) flow dynamics, types of IDDS, indications and patient profile suitable for this therapy, and risks and complications related to IDDS. We will also discuss challenges faced by physicians utilizing this therapy and the future changes that are needed for making this treatment modality more efficacious.

Expert opinion: IDDS offer an effective therapy for pain control in patients suffering from chronic intractable pain conditions. These devices provide a safer alternative to oral opioid medications with reduced systemic side effects. Adherence to best practices and continued clinical and basic science research is important to ensure continuing success of this therapy.     

Towards crystal engineering via simulated pulmonary surfactant monolayers to optimise inhaled drug delivery

Purpose

To generate theophylline monohydrate crystals underneath Langmuir monolayers composed of material expressed at the alveolar air-liquid interface. Such monolayers can act as nucleation sites to direct crystallisation. The approach offers a novel route to rationally engineer therapeutic crystals and thereby optimise inhaled drug delivery.

Methods

Langmuir monolayers consisting of either dipalmitoylphosphatidylcholine (DPPC) or a surfactant mix reflecting pulmonary surfactant were supported on an aqueous theophylline (5.7 mg/ml) subphase. The monolayers were compressed to surface pressures reflecting inhalation and exhalation (i.e. 5 mN m⁻¹ or 55 mN m⁻¹) with a period of 16 h to allow crystallisation. Analysis involved scanning electron microscopy (SEM), atomic force microscopy (AFM) and powder X-ray diffraction (PXRD).

Results

Condensed isotherms were acquired, which signified surfactant-theophylline interaction. Theophylline monohydrate crystals were obtained and exhibited needle-like morphology. SEM and AFM data highlighted regions of roughened growth along with smooth, stepwise growth on the same crystal face. The surfactant monolayers appeared to influence crystal morphology over time.

Conclusions

The data indicate a favourable interaction between each species. The principal mechanism of interaction is thought to be an ion-dipole association. This approach may be applied to generate material with improved complementarity with pulmonary surfactant thus enhancing the interaction between inhaled drug particles and internal lung surfaces.     

Hierarchical pulmonary target nanoparticles via inhaled administration for anticancer drug delivery

Inhalation administration, compared with intravenous administration, significantly enhances chemotherapeutic drug exposure to the lung tissue and may increase the therapeutic effect for pulmonary anticancer. However, further identification of cancer cells after lung deposition of inhaled drugs is necessary to avoid side effects on normal lung tissue and to maximize drug efficacy. Moreover, as the action site of the major drug was intracellular organelles, drug target to the specific organelle is the final key for accurate drug delivery. Here, we designed a novel multifunctional nanoparticles (MNPs) for pulmonary antitumor and the material was well-designed for hierarchical target involved lung tissue target, cancer cell target, and mitochondrial target. The biodistribution in vivo determined by UHPLC–MS/MS method was employed to verify the drug concentration overwhelmingly increasing in lung tissue through inhaled administration compared with intravenous administration. Cellular uptake assay using A549 cells proved the efficient receptor-mediated cell endocytosis. Confocal laser scanning microscopy observation showed the location of MNPs in cells was mitochondria. All results confirmed the intelligent material can progressively play hierarchical target functions, which could induce more cell apoptosis related to mitochondrial damage. It provides a smart and efficient nanocarrier platform for hierarchical targeting of pulmonary anticancer drug. So far, this kind of material for pulmonary mitochondrial-target has not been seen in other reports.     

Modification of apatite materials for bone tissue engineering and drug delivery carriers

Apatite-related calcium phosphate, the main component of biological hard tissue, has good biocompatibility and is an economical material. Methods for the synthesis of apatite materials including hydroxyapatite (HAp) have previously been established. Therefore, for many years, apatite materials have been utilized as substitute materials for bone in orthopedic and dental fields. Such types of conventional substitute materials, which are implanted in the human body, should ostensibly be chemically stable to maintain their quality over time. However, recent advances in tissue engineering have altered this concept. Physicians and researchers now seek to identify materials that alter their properties temporally and spatially to achieve ideal tissue regeneration. In order to use apatite materials for tissue engineering and as drug delivery systems, the materials require both a high affinity for cells, tissues and/or functional molecules (e.g. growth factors and genes) and controllable bioabsorbability. To achieve these properties, various physicochemical modifications of apatite materials have been attempted. In addition, fabrication desiring three-dimensional structures (e.g. size, morphology and porosity) of apatite materials for implant sites could be one of the crucial techniques used to obtain ideal prognoses. In this review, the latest research trends relating to the techniques for the fabrication and modification of apatite materials are introduced.     

Polydioxanone-based bio-materials for tissue engineering and drug/gene delivery applications

Since the commercialization of polydioxanone (PDX) as a biodegradable monofilament suture by Ethicon in 1981, the polymer has received only limited interest until recently. The limitations of polylactide-co-glycolide (PLGA) coupled with the growing need for materials with enhanced features and the advent of new fabrication techniques such as electrospinning have revived interest for PDX in medical devices, tissue engineering and drug delivery applications. Electrospun PDX mats show comparable mechanical properties as the major structural components of native vascular extracellular matrix (ECM) i.e. collagen and elastin. In addition, PDX’s unique shape memory property provides rebound and kink resistance when fabricated into vascular conduits. The synthesis of methyl dioxanone (MeDX) monomer and copolymers of dioxanone (DX) and MeDX have opened up new perspectives for poly(ester-ether)s, enabling the design of the next generation of tissue engineering scaffolds for application in regenerating such tissues as arteries, peripheral nerve and bone. Tailoring of polymer properties and their formulation as nanoparticles, nanomicelles or nanofibers have brought along important developments in the area of controlled drug or gene delivery.This paper reviews the synthesis of PDX and its copolymers and provides for the first time an exhaustive account of its applications in the (bio)medical field with focus on tissue engineering and drug/gene delivery.     

Stimuli-sensitive drug delivery systems for site-specific antibiotic release

Site-specific delivery of antibiotics has always been a high-priority area in pharmaceutical research. Conventionally used antibiotics suffer several limitations, such as low accumulation and penetration in diseased cells/tissues, limited bioavailability of drugs, drug resistance, and off-target toxicity. To overcome these limitations, several strategies have been exploited for delivering antibiotics to the site of infection, such as the use of stimuli-responsive antibiotic delivery systems, which can release antibiotics in a controlled and timely fashion. These stimuli can either be exogenous (light, magnetism, ultrasound, and electrical) or endogenous (pH, redox reactions, and enzymatic). In this review, we present a summary of recent developments in the field of stimuli-based targeted drug delivery systems for the site-specific release of antibiotics.