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Advanced Drug Delivery Reviews
Journal Prestige (SJR): 4.09
Citation Impact (citeScore): 13
Number of Followers: 142  
 
  Hybrid Journal Hybrid journal (It can contain Open Access articles)
ISSN (Print) 0169-409X
Published by Elsevier Homepage  [3159 journals]
  • Challenges and innovations of delivering medicines to older adults
    • Abstract: Publication date: Available online 15 August 2018Source: Advanced Drug Delivery ReviewsAuthor(s): Danijela Gnjidic, Andy Husband, Adam Todd Older adults with multimorbidity, polypharmacy, and complex health needs are the major consumer of health care. Ensuring that medicines are used safely, effectively, and delivered efficiently in this population is challenging. In this context, the approach to medicines delivery should seek to overcome some of the difficulties of delivering medicines to older people, and ensure each medication is delivered by the optimal and most convenient route for the patient in question. However, this poses significant obstacles, as the development of medicines suitable for use in older populations does not often account for complex health needs, potential challenges in relation to drug disposition, safety of excipients and limitations with practical usability of dosage forms. The objective of this review is to summarise and discuss current challenges and novel approaches to delivering medications to older adults.
       
  • Muscle fibrosis in the soft palate: Delivery of cells, growth factors and
           anti-fibrotics
    • Abstract: Publication date: Available online 11 August 2018Source: Advanced Drug Delivery ReviewsAuthor(s): Johannes W. Von den Hoff, Paola L. Carvajal Monroy, Edwin M. Ongkosuwito, Toin H. van Kuppevelt, Willeke F. Daamen The healing of skeletal muscle injuries after major trauma or surgical reconstruction is often complicated by the development of fibrosis leading to impaired function. Research in the field of muscle regeneration is mainly focused on the restoration of muscle mass while far less attention is paid to the prevention of fibrosis. In this review, we take as an example the reconstruction of the muscles in the soft palate of cleft palate patients. After surgical closure of the soft palate, muscle function during speech is often impaired by a shortage of muscle tissue as well as the development of fibrosis. We will give a short overview of the most common approaches to generate muscle mass and then focus on strategies to prevent fibrosis. These include anti-fibrotic strategies that have been developed for muscle and other organs by the delivery of small molecules, decorin and miRNAs. Anti-fibrotic compounds should be delivered in aligned constructs in order to obtain the organized architecture of muscle tissue. The available techniques for the preparation of aligned muscle constructs will be discussed. The combination of approaches to generate muscle mass with anti-fibrotic components in an aligned muscle construct may greatly improve the functional outcome of regenerative therapies for muscle injuries.Graphical abstractUnlabelled Image
       
  • Phage therapy for respiratory infections
    • Abstract: Publication date: Available online 7 August 2018Source: Advanced Drug Delivery ReviewsAuthor(s): Rachel Yoon Kyung Chang, Martin Wallin, Yu Lin, Sharon Sui Yee Leung, Hui Wang, Sandra Morales, Hak-Kim Chan A respiratory infection caused by antibiotic-resistant bacteria can be life-threatening. In recent years, there has been tremendous effort put towards therapeutic application of bacteriophages (phages) as an alternative or supplementary treatment option over conventional antibiotics. Phages are natural parasitic viruses of bacteria that can kill the bacterial host, including those that are resistant to antibiotics. Inhaled phage therapy involves the development of stable phage formulations suitable for aerosol delivery followed by preclinical and clinical studies for assessment of efficacy, pharmacokinetics and safety. We presented an overview of recent advances in phage formulation for aerosol delivery and their efficacy in acute and chronic rodent lung infection models. We have reviewed and presented on the prospects of inhaled phage therapy as a complementary treatment option with current antibiotics and as a preventative means. Inhaled phage therapy has the potential to transform the prevention and treatment of bacterial respiratory infections, including those caused by antibiotic-resistant bacteria.Graphical abstractUnlabelled Image
       
  • Acellular and cellular approaches to improve diabetic wound healing
    • Abstract: Publication date: Available online 1 August 2018Source: Advanced Drug Delivery ReviewsAuthor(s): Hongkwan Cho, Michael R. Blatchley, Elia J. Duh, Sharon Gerecht Chronic diabetic wounds represent a huge socioeconomic burden for both affected individuals and the entire healthcare system. Although the number of available treatment options as well as our understanding of wound healing mechanisms associated with diabetes has vastly improved over the past decades, there still remains a great need for additional therapeutic options. Tissue engineering and regenerative medicine approaches provide great advantages over conventional treatment options, which are mainly aimed at wound closure rather than addressing the underlying pathophysiology of diabetic wounds. Recent advances in biomaterials and stem cell research presented in this review provide novel ways to tackle different molecular and cellular culprits responsible for chronic and nonhealing wounds by delivering therapeutic agents in direct or indirect ways. Careful integration of different approaches presented in the current article could lead to the development of new therapeutic platforms that can address multiple pathophysiologic abnormalities and facilitate wound healing in patients with diabetes.Graphical abstractUnlabelled Image
       
  • Computational modelling of drug delivery to solid tumour: Understanding
           the interplay between chemotherapeutics and biological system for
           optimised delivery system
    • Abstract: Publication date: Available online 29 July 2018Source: Advanced Drug Delivery ReviewsAuthor(s): Wenbo Zhan, Moath Alamer, Xiao Yun Xu Drug delivery to solid tumour involves multiple physiological, biochemical and biophysical processes taking place across a wide range of length and time scales. The therapeutic efficacy of anticancer drugs is influenced by the complex interplays among the intrinsic properties of tumours, biophysical aspects of drug transport and cellular uptake. Mathematical and computational modelling allows for a well-controlled study on the individual and combined effects of a wide range of parameters on drug transport and therapeutic efficacy, which would not be possible or economically viable through experimental means. A wide spectrum of mathematical models has been developed for the simulation of drug transport and delivery in solid tumours, including PK/PD-based compartmental models, microscopic and macroscopic transport models, and molecular dynamics drug loading and release models. These models have been used as a tool to identify the limiting factors and for optimal design of efficient drug delivery systems. This article gives an overview of the currently available computational models for drug transport in solid tumours, together with their applications to novel drug delivery systems, such as nanoparticle-mediated drug delivery and convection-enhanced delivery.Graphical abstractUnlabelled Image
       
  • Strategies to overcome the polycation dilemma in drug delivery
    • Abstract: Publication date: Available online 29 July 2018Source: Advanced Drug Delivery ReviewsAuthor(s): Andreas Bernkop-Schnürch Because of polycationic auxiliary agents such as chitosan, polyethyleneimine and cell penetrating peptides as well as cationic lipids assembling to polycationic systems, drug carriers can tightly interact with cell membranes exhibiting a high-density anionic charge. Because of these interactions the cell membrane is depolarized and becomes vulnerable to various uptake mechanisms. On their way to the target site, however, the polycationic character of all these drug carriers is eliminated by polyanionic macromolecules such as mucus glycoproteins, serum proteins, proteoglycans of the extracellular matrix (ECM) and polyanionic surface substructures of non-target cells such as red blood cells. Strategies to overcome this polycation dilemma are focusing on a pH-, redox- or enzyme-triggered charge conversion at the target site. The pH-triggered systems are making use of a slight acidic environment at the target site such as in case of solid tumors, inflammatory tissue and ischemic tissue. Due to a pH shift from 7.2 to slightly acidic mainly amino substructures of polymeric excipients are protonated or shielding groups such as 2,3 dimethylmaleic acid are cleaved off unleashing the underlying cationic character. Redox-triggered systems are utilizing disulfide linkages to bulky side chains such as PEGs masking the polycationic character. Under mild reducing conditions such as in the tumor microenvironment these disulfide bonds are cleaved. Enzyme-triggered systems are targeting enzymes such as alkaline phosphatase, matrix metalloproteinases or hyaluronidase in order to eliminate anionic moieties via enzymatic cleavage resulting in a charge conversion from negative to positive. Within this review an overview about the pros and cons of these systems is provided.Graphical abstractUnlabelled Image
       
  • Harnessing albumin as a carrier for cancer therapies
    • Abstract: Publication date: Available online 27 July 2018Source: Advanced Drug Delivery ReviewsAuthor(s): Ella N. Hoogenboezem, Craig L. Duvall Serum albumin, a natural ligand carrier that is highly concentrated and long-circulating in the blood, has shown remarkable promise as a carrier for anti-cancer agents. Albumin is able to prolong the circulation half-life of otherwise rapidly cleared drugs and, importantly, promote their accumulation within tumors. The applications for using albumin as a cancer drug carrier are broad and include both traditional cancer chemotherapeutics and new classes of biologics. Strategies for leveraging albumin for drug delivery can be classified broadly into exogenous and in situ binding formulations that utilize covalent attachment, non-covalent association, or encapsulation in albumin-based nanoparticles. These methods have shown remarkable preclinical and clinical successes that are examined in this review.Graphical abstractUnlabelled Image
       
  • 3D bioprinting of skin tissue: From pre-processing to final product
           evaluation
    • Abstract: Publication date: Available online 26 July 2018Source: Advanced Drug Delivery ReviewsAuthor(s): Wei-Cheng Yan, Pooya Davoodi, S. Vijayavenkataraman, Yuan Tian, Wei Cheng Ng, Jerry Y.H. Fuh, Kim Samirah Robinson, Chi-Hwa Wang Bioprinted skin tissue has the potential for aiding drug screening, formulation development, clinical transplantation, chemical and cosmetic testing, as well as basic research. Limitations of conventional skin tissue engineering approaches have driven the development of biomimetic skin equivalent via 3D bioprinting. A key hope for bioprinting skin is the improved tissue authenticity over conventional skin equivalent construction, enabling the precise localization of multiple cell types and appendages within a construct. The printing of skin faces challenges broadly associated with general 3D bioprinting, including the selection of cell types and biomaterials, and additionally requires in vitro culture formats that allow for growth at an air-liquid interface. This paper provides a thorough review of current 3D bioprinting technologies used to engineer human skin constructs and presents the overall pipelines of designing a biomimetic artificial skin via 3D bioprinting from the design phase (i.e. pre-processing phase) through the tissue maturation phase (i.e. post-processing) and into final product evaluation for drug screening, development, and drug delivery applications.Graphical abstractUnlabelled Image
       
  • Stem cell-based Lung-on-Chips: The best of both worlds'
    • Abstract: Publication date: Available online 25 July 2018Source: Advanced Drug Delivery ReviewsAuthor(s): Janna C. Nawroth, Riccardo Barrile, David Conegliano, Sander van Riet, Pieter S. Hiemstra, Remi Villenave Pathologies of the respiratory system such as lung infections, chronic inflammatory lung diseases, and lung cancer are among the leading causes of morbidity and mortality, killing one in six people worldwide. Development of more effective treatments is hindered by the lack of preclinical models of the human lung that can capture the disease complexity, highly heterogeneous disease phenotypes, and pharmacokinetics and pharmacodynamics observed in patients. The merger of two novel technologies, Organs-on-Chips and human stem cell engineering, has the potential to deliver such urgently needed models. Organs-on-Chips, which are microengineered bioinspired tissue systems, recapitulate the mechanochemical environment and physiological functions of human organs while concurrent advances in generating and differentiating human stem cells promise a renewable supply of patient-specific cells for personalized and precision medicine. Here, we discuss the challenges of modeling human lung pathophysiology in vitro, evaluate past and current models including Organs-on-Chips, review the current status of lung tissue modeling using human pluripotent stem cells, explore in depth how stem-cell based Lung-on-Chips may advance disease modeling and drug testing, and summarize practical consideration for the design of Lung-on-Chips for academic and industry applications.Graphical abstractUnlabelled Image
       
  • The quest for mechanically and biologically functional soft biomaterials
           via soft network composites
    • Abstract: Publication date: Available online 24 July 2018Source: Advanced Drug Delivery ReviewsAuthor(s): Onur Bas, Elena M. De-Juan-Pardo, Isabelle Catelas, Dietmar W. Hutmacher Developing multifunctional soft biomaterials capable of addressing all of the requirements of the complex tissue regeneration process is a multifaceted problem. In order to tackle the current challenges, recent research efforts are increasingly being directed towards biomimetic design concepts that can be translated into soft biomaterials via advanced manufacturing technologies. Among those, soft network composites consisting of a continuous hydrogel matrix and a reinforcing fibrous network closely resemble native soft biological materials from the design, composition and physicochemical point of view. This article reviews soft network composite systems with a particular emphasis on the design, biomaterial and fabrication aspects within the context of soft tissue engineering and drug delivery applications.Graphical abstractUnlabelled Image
       
  • 3D bioprinting for cardiovascular regeneration and pharmacology
    • Abstract: Publication date: Available online 24 July 2018Source: Advanced Drug Delivery ReviewsAuthor(s): Haitao Cui, Shida Miao, Timothy Esworthy, Xuan Zhou, Se-jun Lee, Chengyu Liu, Zu-xi Yu, John P. Fisher, Muhammad Mohiuddin, Lijie Grace Zhang Cardiovascular disease (CVD) is a major cause of morbidity and mortality worldwide. Compared to traditional therapeutic strategies, three-dimensional (3D) bioprinting is one of the most advanced techniques for creating complicated cardiovascular implants with biomimetic features, which are capable of recapitulating both the native physiochemical and biomechanical characteristics of the cardiovascular system. The present review provides an overview of the cardiovascular system, as well as describes the principles of, and recent advances in, 3D bioprinting cardiovascular tissues and models. Moreover, this review will focus on the applications of 3D bioprinting technology in cardiovascular repair/regeneration and pharmacological modeling, further discussing current challenges and perspectives.Graphical abstractUnlabelled Image
       
  • Top-down fabrication of shape-controlled, monodisperse nanoparticles for
           biomedical applications
    • Abstract: Publication date: Available online 23 July 2018Source: Advanced Drug Delivery ReviewsAuthor(s): Xinxin Fu, Jingxuan Cai, Xiang Zhang, Wen-Di Li, Haixiong Ge, Yong Hu Nanoparticles for biomedical applications are generally formed by bottom-up approaches such as self-assembly, emulsification and precipitation. But these methods usually have critical limitations in fabrication of nanoparticles with controllable morphologies and monodispersed size. Compared with bottom-up methods, top-down nanofabrication techniques offer advantages of high fidelity and high controllability. This review focuses on top-down nanofabrication techniques for engineering particles along with their biomedical applications. We present several commonly used top-down nanofabrication techniques that have the potential to fabricate nanoparticles, including photolithography, interference lithography, electron beam lithography, mold-based lithography (nanoimprint lithography and soft lithography), nanostencil lithography, and nanosphere lithography. Varieties of current and emerging applications are also covered: (i) targeting, (ii) drug and gene delivery, (iii) imaging, and (iv) therapy. Finally, a future perspective of the nanoparticles fabricated by the top-down techniques in biomedicine is also addressed.Graphical abstractUnlabelled Image
       
  • Battle of GLP-1 delivery technologies
    • Abstract: Publication date: Available online 21 July 2018Source: Advanced Drug Delivery ReviewsAuthor(s): Minzhi Yu, Mason M. Benjamin, Santhanakrishnan Srinivasan, Emily E. Morin, Ekaterina I. Shishatskaya, Steven P. Schwendeman, Anna Schwendeman Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) belong to an important therapeutic class for treatment of type 2 diabetes. Six GLP-1 RAs, each utilizing a unique drug delivery strategy, are now approved by the Food and Drug Administration (FDA) and additional, novel GLP-1 RAs are still under development, making for a crowded marketplace and fierce competition among the manufacturers of these products. As rapid elimination is a major challenge for clinical application of GLP-1 RAs, various half-life extension strategies have been successfully employed including sequential modification, attachment of fatty-acid to peptide, fusion with human serum albumin, fusion with the fragment crystallizable (Fc) region of a monoclonal antibody, sustained drug delivery systems, and PEGylation. In this review, we discuss the scientific rationale of the various half-life extension strategies used for GLP-1 RA development. By analyzing and comparing different approved GLP-1 RAs and those in development, we focus on assessing how half-life extending strategies impact the pharmacokinetics, pharmacodynamics, safety, patient usability and ultimately, the commercial success of GLP-1 RA products. We also anticipate future GLP-1 RA development trends. Since similar drug delivery strategies are also applied for developing other therapeutic peptides, we expect this case study of GLP-1 RAs will provide generalizable concepts for the rational design of therapeutic peptides products with extended duration of action.Graphical abstractUnlabelled Image
       
  • A review on core–shell structured unimolecular nanoparticles for
           biomedical applications
    • Abstract: Publication date: Available online 20 July 2018Source: Advanced Drug Delivery ReviewsAuthor(s): Guojun Chen, Yuyuan Wang, Ruosen Xie, Shaoqin Gong Polymeric unimolecular nanoparticles (NPs) exhibiting a core-shell structure and formed by a single multi-arm molecule containing only covalent bonds have attracted increasing attention for numerous biomedical applications. This unique single-molecular architecture provides the unimolecular NP with superior stability both in vitro and in vivo, a high drug loading capacity, as well as versatile surface chemistry, thereby making it a desirable nanoplatform for therapeutic and diagnostic applications. In this review, we surveyed the architecture of various types of polymeric unimolecular NPs, including water-dispersible unimolecular micelles and water-soluble unimolecular NPs used for the delivery of hydrophobic and hydrophilic agents, respectively, as well as their diverse biomedical applications. Future opportunities and challenges of unimolecular NPs were also briefly discussed.Graphical abstractUnlabelled Image
       
  • Electrohydrodynamic atomization and spray-drying for the production of
           pure drug nanocrystals and co-crystals
    • Abstract: Publication date: Available online 20 July 2018Source: Advanced Drug Delivery ReviewsAuthor(s): Roni Sverdlov Arzi, Alejandro Sosnik In recent years, nanotechnology has offered attractive opportunities to overcome the (bio)pharmaceutical drawbacks of most drugs such as low aqueous solubility and bioavailability. Among the numerous methodologies that have been applied to improve drug performance, a special emphasis has been made on those that increase the dissolution rate and the saturation solubility by the reduction of the particle size of pure drugs to the nanoscale and the associated increase of the specific surface area. Different top-down and bottom-up methods have been implemented, each one with its own pros and cons. Over the last years, the latter that rely on the dissolution of the drug in a proper solvent and its crystallization or co-crystallization by precipitation in an anti-solvent or, conversely, by solvent evaporation have gained remarkable impulse owing to the ability to features such as size, size distribution, morphology and to control the amorphous/crystalline nature of the product. In this framework, electrohydrodynamic atomization (also called electrospraying) and spray-drying excel due to their simplicity and potential scalability. Moreover, they do not necessarily need suspension stabilizers and dry products are often produced during the formation of the nanoparticles what ensures physicochemical stability for longer times than liquid products. This review overviews the potential of these two technologies for the production of pure drug nanocrystals and co-crystals and discusses the recent technological advances and challenges for their implementation in pharmaceutical research and development.Graphical abstractUnlabelled Image
       
  • Tumor targeting via EPR: Strategies to enhance patient responses
    • Abstract: Publication date: Available online 19 July 2018Source: Advanced Drug Delivery ReviewsAuthor(s): Susanne K. Golombek, Jan-Niklas May, Benjamin Theek, Lia Appold, Natascha Drude, Fabian Kiessling, Twan Lammers The tumor accumulation of nanomedicines relies on the enhanced permeability and retention (EPR) effect. In the last 5–10 years, it has been increasingly recognized that there is a large inter- and intra-individual heterogeneity in EPR-mediated tumor targeting, explaining the heterogeneous outcomes of clinical trials in which nanomedicine formulations have been evaluated. To address this heterogeneity, as in other areas of oncology drug development, we have to move away from a one-size-fits-all tumor targeting approach, towards methods that can be employed to individualize and improve nanomedicine treatments. To this end, efforts have to be invested in better understanding the nature, the complexity and the heterogeneity of the EPR effect, and in establishing systems and strategies to enhance, combine, bypass and image EPR-based tumor targeting. In the present manuscript, we summarize key studies in which these strategies are explored, and we discuss how these approaches can be employed to enhance patient responses.Graphical abstractUnlabelled Image
       
  • Supercritical carbon dioxide-based technologies for the production of drug
           nanoparticles/nanocrystals – A comprehensive review
    • Abstract: Publication date: Available online 17 July 2018Source: Advanced Drug Delivery ReviewsAuthor(s): Luís Padrela, Miguel A. Rodrigues, Andreia Duarte, Ana M.A. Dias, Mara E.M. Braga, Hermínio C. de Sousa Low drug bioavailability, which is mostly a result of poor aqueous drug solubilities and of inadequate drug dissolution rates, is one of the most significant challenges that pharmaceutical companies are currently facing, since this may limit the therapeutic efficacy of marketed drugs, or even result in the discard of potential highly effective drug candidates during developmental stages. Two of the main approaches that have been implemented in recent years to overcome poor drug solubility/dissolution issues have frequently involved drug particle size reduction (i.e., micronization/nanonization) and/or the modification of some of the physicochemical and structural properties of poorly water soluble drugs. A large number of particle engineering methodologies have been developed, tested, and applied in the synthesis and control of particle size/particle-size distributions, crystallinities, and polymorphic purities of drug micro- and nano-particles/crystals. In recent years pharmaceutical processing using supercritical fluids (SCF), in general, and supercritical carbon dioxide (scCO2), in particular, have attracted a great attention from the pharmaceutical industry. This is mostly due to the several well-known advantageous technical features of these processes, as well as to other increasingly important subjects for the pharmaceutical industry, namely their “green”, sustainable, safe and “environmentally-friendly” intrinsic characteristics.In this work, it is presented a comprehensive state-of-the-art review on scCO2-based processes focused on the formation and on the control of the physicochemical, structural and morphological properties of amorphous/crystalline pure drug nanoparticles. It is presented and discussed the most relevant scCO2, scCO2-based fluids and drug physicochemical properties that are pertinent for the development of successful pharmaceutical products, namely those that are critical in the selection of an adequate scCO2-based method to produce pure drug nanoparticles/nanocrystals. scCO2-based nanoparticle formation methodologies are classified in three main families, and in terms of the most important role played by scCO2 in particle formation processes: as a solvent; as an antisolvent or a co-antisolvent; and as a “high mobility” additive (a solute, a co-solute, or a co-solvent). Specific particle formation methods belonging to each one of these families are presented, discussed and compared. Some selected amorphous/crystalline drug nanoparticles that were prepared by these methods are compiled and presented, namely those studied in the last 10–15 years. A special emphasis is given to the formation of drug cocrystals. It is also discussed the fundamental knowledge and the main mechanisms in which the scCO2-based particle formation methods rely on, as well as the current status and urgent needs in terms of reliable experimental data and of robust modeling approaches. Other addressed and discussed topics include the currently available and the most adequate physicochemical, morphological and biological characterization methods required for pure drug nanoparticles/nanocrystals, some of the current nanometrology and regulatory issues associated to the use of these methods, as well as some scale-up, post-processing and pharmaceutical regulatory subjects related to the industrial implementation of these scCO2-based processes. Finally, it is also discussed the current status of these techniques, as well as their future major perspectives and opportunities for industrial implementation in the upcoming years.Graphical abstractUnlabelled Image
       
  • 3D bioprinting of tissues and organs for regenerative medicine
    • Abstract: Publication date: Available online 7 July 2018Source: Advanced Drug Delivery ReviewsAuthor(s): Sanjairaj Vijayavenkataraman, Wei-Cheng Yan, Wen Feng Lu, Chi-Hwa Wang, Jerry Ying Hsi Fuh 3D bioprinting is a pioneering technology that enables fabrication of biomimetic, multiscale, multi-cellular tissues with highly complex tissue microenvironment, intricate cytoarchitecture, structure-function hierarchy, and tissue-specific compositional and mechanical heterogeneity. Given the huge demand for organ transplantation, coupled with limited organ donors, bioprinting is a potential technology that could solve this crisis of organ shortage by fabrication of fully-functional whole organs. Though organ bioprinting is a far-fetched goal, there has been a considerable and commendable progress in the field of bioprinting that could be used as transplantable tissues in regenerative medicine. This paper presents a first-time review of 3D bioprinting in regenerative medicine, where the current status and contemporary issues of 3D bioprinting pertaining to the eleven organ systems of the human body including skeletal, muscular, nervous, lymphatic, endocrine, reproductive, integumentary, respiratory, digestive, urinary, and circulatory systems were critically reviewed. The implications of 3D bioprinting in drug discovery, development, and delivery systems are also briefly discussed, in terms of in vitro drug testing models, and personalized medicine. While there is a substantial progress in the field of bioprinting in the recent past, there is still a long way to go to fully realize the translational potential of this technology. Computational studies for study of tissue growth or tissue fusion post-printing, improving the scalability of this technology to fabricate human-scale tissues, development of hybrid systems with integration of different bioprinting modalities, formulation of new bioinks with tuneable mechanical and rheological properties, mechanobiological studies on cell-bioink interaction, 4D bioprinting with smart (stimuli-responsive) hydrogels, and addressing the ethical, social, and regulatory issues concerning bioprinting are potential futuristic focus areas that would aid in successful clinical translation of this technology.
       
  • Aptamers: Uptake mechanisms and intracellular applications
    • Abstract: Publication date: Available online 6 July 2018Source: Advanced Drug Delivery ReviewsAuthor(s): Sorah Yoon, John J. Rossi The structural flexibility and small size of aptamers enable precise recognition of cellular elements for imaging and therapeutic applications. The process by which aptamers are taken into cells depends on their targets but is typically clathrin-mediated endocytosis or macropinocytosis. After internalization, most aptamers are transported to endosomes, lysosomes, endoplasmic reticulum, Golgi apparatus, and occasionally mitochondria and autophagosomes. Intracellular aptamers, or “intramers,” have versatile functions ranging from intracellular RNA imaging, gene regulation, and therapeutics to allosteric modulation, which we discuss in this review. Immune responses to therapeutic aptamers and the effects of G-quadruplex structure on aptamer function are also discussed.Graphical abstractUnlabelled Image
       
  • Bacteriophage T4 nanoparticles for vaccine delivery against infectious
           diseases
    • Abstract: Publication date: Available online 6 July 2018Source: Advanced Drug Delivery ReviewsAuthor(s): Pan Tao, Jingen Zhu, Marthandan Mahalingam, Himanshu Batra, Venigalla B. Rao Subunit vaccines containing one or more target antigens from pathogenic organisms represent safer alternatives to whole pathogen vaccines. However, the antigens by themselves are not sufficiently immunogenic and require additives known as adjuvants to enhance immunogenicity and protective efficacy. Assembly of the antigens into virus-like nanoparticles (VLPs) is a better approach as it allows presentation of the epitopes in a more native context. The repetitive, symmetrical, and high density display of antigens on the VLPs mimic pathogen-associated molecular patterns seen on bacteria and viruses. The antigens, thus, might be better presented to stimulate host's innate as well as adaptive immune systems thereby eliciting both humoral and cellular immune responses. Bacteriophages such as phage T4 provide excellent platforms to generate the nanoparticle vaccines. The T4 capsid containing two non-essential outer proteins Soc and Hoc allow high density array of antigen epitopes in the form of peptides, domains, full-length proteins, or even multi-subunit complexes. Co-delivery of DNAs, targeting molecules, and/or molecular adjuvants provides additional advantages. Recent studies demonstrate that the phage T4 VLPs are highly immunogenic, do not need an adjuvant, and provide complete protection against bacterial and viral pathogens. Thus, phage T4 could potentially be developed as a “universal” VLP platform to design future multivalent vaccines against complex and emerging pathogens.Graphical abstractUnlabelled Image
       
  • Drug delivery systems for programmed and on-demand release
    • Abstract: Publication date: Available online 6 July 2018Source: Advanced Drug Delivery ReviewsAuthor(s): Pooya Davoodi, Lai Yeng Lee, Qingxing Xu, Vishnu Sunil, Yajuan Sun, Siowling Soh, Chi-Hwa Wang With the advancement in medical science and understanding the importance of biodistribution and pharmacokinetics of therapeutic agents, modern drug delivery research strives to utilize novel materials and fabrication technologies for the preparation of robust drug delivery systems to combat acute and chronic diseases. Compared to traditional drug carriers, which could only control the release of the agents in a monotonic manner, the new drug carriers are able to provide a precise control over the release time and the quantity of drug introduced into the patient's body. To achieve this goal, scientists have introduced “programmed” and “on-demand” approaches. The former provides delivery systems with a sophisticated architecture to precisely tune the release rate for a definite time period, while the latter includes systems directly controlled by an operator/practitioner, perhaps with a remote device triggering/affecting the implanted or injected drug carrier. Ideally, such devices can determine flexible release pattern and intensify the efficacy of a therapy via controlling time, duration, dosage, and location of drug release in a predictable, repeatable, and reliable manner. This review sheds light on the past and current techniques available for fabricating and remotely controlling drug delivery systems and addresses the application of new technologies (e.g. 3D printing) in this field.Graphical abstractUnlabelled Image
       
  • Re-epithelialization of adult skin wounds: Cellular mechanisms and
           therapeutic strategies
    • Abstract: Publication date: Available online 5 July 2018Source: Advanced Drug Delivery ReviewsAuthor(s): Patricia Rousselle, Fabienne Braye, Guila Dayan Cutaneous wound healing in adult mammals is a complex multi-step process involving overlapping stages of blood clot formation, inflammation, re-epithelialization, granulation tissue formation, neovascularization, and remodelling. Re-epithelialization describes the resurfacing of a wound with new epithelium. The cellular and molecular processes involved in the initiation, maintenance, and completion of epithelialization are essential for successful wound closure. A variety of modulators are involved, including growth factors, cytokines, matrix metalloproteinases, cellular receptors, and extracellular matrix components. Here, we focus on cellular mechanisms underlying keratinocyte migration and proliferation during epidermal closure. Inability to re-epithelialize is a clear indicator of chronic non-healing wounds, which fail to proceed through the normal phases of wound healing in an orderly and timely manner. This review summarizes the current knowledge regarding the management and treatment of acute and chronic wounds, with a focus on re-epithelialization, offering some insights into novel future therapies.Graphical Unlabelled Image
       
  • Bioresponsive drug delivery systems in intestinal inflammation:
           State-of-the-art and future perspectives
    • Abstract: Publication date: Available online 5 July 2018Source: Advanced Drug Delivery ReviewsAuthor(s): Niranjan G. Kotla, Shubhasmin Rana, Gandhi Sivaraman, Omprakash Sunnapu, Praveen K. Vemula, Abhay Pandit, Yury Rochev Oral colon-specific delivery systems emerged as the main therapeutic cargos by making a significant impact in the field of modern medicine for local drug delivery in intestinal inflammation. The site-specific delivery of therapeutics (aminosalicylates, glucocorticoids, biologics) to the ulcerative mucus tissue can provide prominent advantages in mucosal healing (MH). Attaining gut mucosal healing and anti-fibrosis are main treatment outcomes in inflammatory bowel disease (IBD). The pharmaceutical strategies that are commonly used to achieve a colon-specific drug delivery system include time, pH-dependent polymer coating, prodrug, colonic microbiota-activated delivery systems and a combination of these approaches. Amongst the different approaches reported, the use of biodegradable polysaccharide coated systems holds great promise in delivering drugs to the ulcerative regions. The present review focuses on major physiological gastro-intestinal tract challenges involved in altering the pharmacokinetics of delivery systems, pathophysiology of MH and fibrosis, reported drug-polysaccharide cargos and focusing on conventional to advanced disease responsive delivery strategies, highlighting their limitations and future perspectives in intestinal inflammation therapy.Graphical abstractUnlabelled Image
       
  • SEDDS: A game changing approach for the oral administration of hydrophilic
           macromolecular drugs
    • Abstract: Publication date: Available online 4 July 2018Source: Advanced Drug Delivery ReviewsAuthor(s): Arshad Mahmood, Andreas Bernkop-Schnürch Since the development of self-emulsifying drug delivery systems (SEDDS) in 1980's, they attract the attention of researchers in order to confront the challenge of poor water-solubility of orally given drugs. Within recent years, SEDDS were also discovered for oral administration of hydrophilic macromolecular drugs such as peptides, proteins, polysaccharides and pDNA. Due to hydrophobic ion pairing (HIP) with oppositely charged lipophilic auxiliary agents the resulting complexes can be incorporated in the lipophilic phase of SEDDS. Depending on the solubility of the complex in the SEDDS pre-concentrate and in the release medium drug release can be adjusted on purpose by choosing more or less lipophilic auxiliary agents in appropriate quantities for HIP. Within the oily droplets formed in the GI-tract drugs are protected towards degradation by proteases and nucleases and thiol-disulfide exchange reactions with dietary proteins. The oily droplets can be made mucoadhesive or highly mucus permeating depending on their target site. Furthermore, even their cellular uptake properties can be tuned by adjusting their zeta potential or decorating them with cell penetrating peptides. The potential of SEDDS for oral administration of hydrophilic macromolecular drugs could meanwhile be demonstrated via various in vivo studies showing a bioavailability at least in the single digit percentage range. Owing to these properties advanced SEDDS turned out to be a game changing approach for the oral administration of hydrophilic macromolecular drugs.Graphical abstractUnlabelled Image
       
  • Unintended effects of drug carriers: Big issues of small particles
    • Abstract: Publication date: Available online 3 July 2018Source: Advanced Drug Delivery ReviewsAuthor(s): Hamideh Parhiz, Makan Khoshnejad, Jacob W. Myerson, Elizabeth Hood, Priyal N. Patel, Jacob S. Brenner, Vladimir R. Muzykantov Humoral and cellular host defense mechanisms including diverse phagocytes, leukocytes, and immune cells have evolved over millions of years to protect the body from microbes and other external and internal threats. These policing forces recognize engineered sub-micron drug delivery systems (DDS) as such a threat, and react accordingly. This leads to impediment of the therapeutic action, extensively studied and discussed in the literature. Here, we focus on side effects of DDS interactions with host defenses. We argue that for nanomedicine to reach its clinical potential, the field must redouble its efforts in understanding the interaction between drug delivery systems and the host defenses, so that we can engineer safer interventions with the greatest potential for clinical success.Graphical abstractUnlabelled Image
       
  • Use of phage therapy to treat long-standing, persistent, or chronic
           bacterial infections
    • Abstract: Publication date: Available online 3 July 2018Source: Advanced Drug Delivery ReviewsAuthor(s): Stephen T. Abedon Viruses of bacteria – known as bacteriophages or phages – have been used clinically as antibacterial agents for nearly 100 years. Often this phage therapy is of long-standing, persistent, or chronic bacterial infections, and this can be particularly so given prior but insufficiently effective infection treatment using standard antibiotics. Such infections, in turn, often have a biofilm component. Phages in modern medicine thus are envisaged to serve especially as anti-biofilm/anti-persistent infection agents. Here I review the English-language literature concerning in vivo experimental and clinical phage treatment of longer-lived bacterial infections. Overall, published data appears to be supportive of a relatively high potential for phages to cure infections which are long standing and which otherwise have resisted treatment with antibieiotics.Graphical abstractUnlabelled Image
       
  • Molecular imaging of β-cells: diabetes and beyond
    • Abstract: Publication date: Available online 3 July 2018Source: Advanced Drug Delivery ReviewsAuthor(s): Weijun Wei, Emily B. Ehlerding, Xiaoli Lan, Quan-Yong Luo, Weibo Cai Since diabetes is becoming a global epidemic, there is a great need to develop early β-cell specific diagnostic techniques for this disorder. There are two types of diabetes (i.e., type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM)). In T1DM, the destruction of pancreatic β-cells leads to reduced insulin production or even absolute insulin deficiency, which consequently results in hyperglycemia. Actually, a central issue in the pathophysiology of all types of diabetes is the relative reduction of β-cell mass (BCM) and/or impairment of the function of individual β-cells. In the past two decades, scientists have been trying to develop imaging techniques for noninvasive measurement of the viability and mass of pancreatic β-cells. Despite intense scientific efforts, only two tracers for positron emission tomography (PET) and one contrast agent for magnetic resonance (MR) imaging are currently under clinical evaluation. β-cell specific imaging probes may also allow us to precisely and specifically visualize transplanted β-cells and to improve transplantation outcomes, as transplantation of pancreatic islets has shown promise in treating T1DM. In addition, some of these probes can be applied to the preoperative detection of hidden insulinomas as well. In the present review, we primarily summarize potential tracers under development for imaging β-cells with a focus on tracers for PET, SPECT, MRI, and optical imaging. We will discuss the advantages and limitations of the various imaging probes and extend an outlook on future developments in the field.Graphical abstractUnlabelled Image
       
  • Zero-dimensional, one-dimensional, two-dimensional and three-dimensional
           biomaterials for cell fate regulation
    • Abstract: Publication date: Available online 30 June 2018Source: Advanced Drug Delivery ReviewsAuthor(s): Can Zhang, Bei Xie, Yujian Zou, Dan Zhu, Lei Lei, Dapeng Zhao, Hemin Nie The interaction of biological cells with artificial biomaterials is one of the most important issues in tissue engineering and regenerative medicine. The interaction is strongly governed by physical and chemical properties of the materials and displayed with differentiated cellular behaviors, including cell self-renewal, differentiation, reprogramming, dedifferentiation, or transdifferentiation as a result. A number of engineered biomaterials with micro- or nano-structures have been developed to mimic structural components of cell niche and specific function of extra cellular matrix (ECM) over past two decades. In this review article, we briefly introduce the fabrication of biomaterials and their classification into zero-dimensional (0D), one-dimensional (1D), two-dimensional (2D) and three-dimensional (3D) ones. More importantly, the influence of different biomaterials on inducing cell self-renewal, differentiation, reprogramming, dedifferentiation, and transdifferentiation was discussed based on the progress at 0D, 1D, 2D and 3D levels, following which the current research limitations and research perspectives were provided.Graphical abstractUnlabelled Image
       
  • Regulatory challenges of nanomedicines and their follow-on versions: A
           generic or similar approach'
    • Abstract: Publication date: Available online 30 June 2018Source: Advanced Drug Delivery ReviewsAuthor(s): Stefan Mühlebach Nanomedicines and follow-on versions (also called nanosimilars in the EU) have been on the market partially for decades although without recognition of their nano properties in the beginning; a substantial number is in clinical development. Nanomedicines are typically synthetic and belong to the non-biological complex drugs. They show a high variability in form, structure, and size. Additionally large molecule biologics show nano-characteristics meaning nano-dimension in size (1–100 nm) or specific properties related to these dimensions. The high complexity of nanomedicines with their heterogeneous structures do not allow a full physicochemical quality characterization, challenging the regulatory evaluation especially for follow-on versions upon comparison with the reference product. The generic paradigm with the sameness approach for quality and bioequivalence in blood plasma is not appropriate for nanomedicines where a similar approach is needed. After experiencing non-equivalence of authorized parenteral colloidal iron follow-on versions, EMA and FDA issued reflection papers and draft guidances for industry to present their current thinking on the evaluation of such complex products. A stepwise approach to evaluate the extent of similarity, from quality, including critical quality attributes (CQA) and assessment of nano properties, to a non-clinical biodistribution assay, required in the the EU but not in the US, and to clinical evaluation makes sense. The cumulated totality of evidence for the authorization of nanomedicine follow-on versions goes case-by-case. Interchangeability, or substitutability, is a challenge. However, a defined or even harmonized approval pathway for these follow-versions is still missing and causes potential differences in approval. To progress, a science-based discussion platform among stakeholders and experts in the field is necessary. An agenda has been agreed [5], namely CQA assessment, publication of scientific and clinical findings, consensus on nomenclature and labelling, and regulatory actions on substandard complex drug products. Consensus created in a public private approach will support progress towards a defined and harmonized regulatory pathway for nanomedicines and their follow-on versions. This will provide drug innovation but also larger access to follow-on versions of nanomedicines, both a benefit for the patient.
       
  • Current state of in vivo panning technologies: Designing specificity and
           affinity into the future of drug targeting
    • Abstract: Publication date: Available online 28 June 2018Source: Advanced Drug Delivery ReviewsAuthor(s): Heather H. Gustafson, Audrey Olshefsky, Meilyn Sylvestre, Drew L. Sellers, Suzie H. Pun Targeting ligands are used in drug delivery to improve drug distribution to desired cells or tissues and to facilitate cellular entry. In vivo biopanning, whereby billions of potential ligand sequences are screened in biologically-relevant and complex conditions, is a powerful method for identification of novel target ligands. This tool has impacted drug delivery technologies and expanded our arsenal of therapeutics and diagnostics. Within this review we will discuss current in vivo panning technologies and ways that these technologies can be improved to advance next-generation drug delivery strategies.Graphical abstractUnlabelled Image
       
  • Strategic design of extracellular vesicle drug delivery systems
    • Abstract: Publication date: Available online 28 June 2018Source: Advanced Drug Delivery ReviewsAuthor(s): James P.K. Armstrong, Molly M. Stevens Extracellular vesicles (EVs), nanoscale vectors used in intercellular communication, have demonstrated great promise as natural drug delivery systems. Recent reports have detailed impressive in vivo results from the administration of EVs pre-loaded with therapeutic cargo, including small molecules, nanoparticles, proteins and oligonucleotides. These results have sparked intensive research interest across a huge range of disease models. There are, however, enduring limitations that have restricted widespread clinical and pharmaceutical adoption. In this perspective, we discuss these practical and biological concerns, critically compare the relative merit of EVs and synthetic drug delivery systems, and highlight the need for a more comprehensive understanding of in vivo transport and delivery. Within this framework, we seek to establish key areas in which EVs can gain a competitive advantage in order to provide the tangible added value required for widespread translation.Graphical abstractUnlabelled Image
       
  • The emerging role of physiologically based pharmacokinetic modelling in
           solid drug nanoparticle translation
    • Abstract: Publication date: Available online 27 June 2018Source: Advanced Drug Delivery ReviewsAuthor(s): Marco Siccardi, Steve Rannard, Andrew Owen The use of solid drug nanoparticles (SDN) has become an established approach to improve drug delivery, supporting enhancement of oral absorption and long-acting administration strategies. A broad range of SDNs have been successfully utilised for multiple products and several development programmes are currently underway across different therapeutic areas. With some approaches, a large range of material space is available with diversity in physical characteristics, excipient choice and pharmacological behaviour. The selection of SDN lead candidates is a complex process including a broad range of in vitro and in vivo data, and a better understanding of how physical characteristics relate to performance is required. Physiologically-based pharmacokinetic (PBPK) modelling is based upon a comprehensive integration of experimental data into a mathematical description of drug distribution, allowing simulation of SDN pharmacokinetics that can be qualified in vivo prior to human prediction. This review aims to provide a description of how PBPK can find application into the development of SDN. Integration of predictive PBPK modelling into SDN development allows a better understanding of the SDN dose-response relationship, supporting a framework for rational optimisation while reducing the risk of failure in developing safe and effective nanomedicines.Graphical abstractUnlabelled Image
       
  • Use of nano engineered approaches to overcome the stromal barrier in
           pancreatic cancer
    • Abstract: Publication date: Available online 26 June 2018Source: Advanced Drug Delivery ReviewsAuthor(s): Huan Meng, Andre E. Nel While chemotherapy is the only approved non-surgical option for the majority of pancreatic cancer patients, it rarely results in a cure. The failure to respond to chemotherapy is due to the presence of an abundant dysplastic stroma that interferes in drug delivery and as a result of drug resistance. It is appropriate, therefore, to consider the stromal contribution to the resistance to chemotherapy and sidestepping this barrier with nanocarriers that improve survival outcome. In this paper, we provide a short overview of the role of the stroma in chemotherapy resistance, including the use of nanocarriers to negate this barrier. We provide a perspective and guidance towards the implementation of nanotherapeutic approaches to improve therapeutic delivery and efficacy of PDAC management.Graphical abstractUnlabelled Image
       
  • Advanced in vitro models of vascular biology: Human induced pluripotent
           stem cells and organ-on-chip technology
    • Abstract: Publication date: Available online 23 June 2018Source: Advanced Drug Delivery ReviewsAuthor(s): Amy Cochrane, Hugo J. Albers, Robert Passier, Christine L. Mummery, Albert van den Berg, Valeria V. Orlova, Andries D. van der Meer The vascular system is one of the first to develop during embryogenesis and is essential for all organs and tissues in our body to develop and function. It has many essential roles including controlling the absorption, distribution and excretion of compounds and therefore determines the pharmacokinetics of drugs and therapeutics. Vascular homeostasis is under tight physiological control which is essential for maintaining tissues in a healthy state. Consequently, disruption of vascular homeostasis plays an integral role in many disease processes, making cells of the vessel wall attractive targets for therapeutic intervention. Experimental models of blood vessels can therefore contribute significantly to drug development and aid in predicting the biological effects of new drug entities. The increasing availability of human induced pluripotent stem cells (hiPSC) derived from healthy individuals and patients have accelerated advances in developing experimental in vitro models of the vasculature: human endothelial cells (ECs), pericytes and vascular smooth muscle cells (VSMCs), can now be generated with high efficiency from hiPSC and used in ‘microfluidic chips’ (also known as ‘organ-on-chip’ technology) as a basis for in vitro models of blood vessels. These near physiological scaffolds allow the controlled integration of fluid flow and three-dimensional (3D) co-cultures with perivascular cells to mimic tissue- or organ-level physiology and dysfunction in vitro. Here, we review recent multidisciplinary developments in these advanced experimental models of blood vessels that combine hiPSC with microfluidic organ-on-chip technology. We provide examples of their utility in various research areas and discuss steps necessary for further integration in biomedical applications so that they can be contribute effectively to the evaluation and development of new drugs and other therapeutics as well as personalized (patient-specific) treatments.Graphical abstractUnlabelled Image
       
  • Bioengineered cellular and cell membrane-derived vehicles for actively
           targeted drug delivery: So near and yet so far
    • Abstract: Publication date: Available online 21 June 2018Source: Advanced Drug Delivery ReviewsAuthor(s): Thanuja M.Y., Anupama C., Sudhir H. Ranganath Cellular carriers for drug delivery are attractive alternatives to synthetic nanoparticles owing to their innate homing/targeting abilities. Here, we review molecular interactions involved in the homing of Mesenchymal stem cells (MSCs) and other cell types to understand the process of designing and engineering highly efficient, actively targeting cellular vehicles. In addition, we comprehensively discuss various genetic and non-genetic strategies and propose futuristic approaches of engineering MSC homing using micro/nanotechnology and high throughput small molecule screening. Most of the targeting abilities of a cell come from its plasma membrane, thus, efforts to harness cell membranes as drug delivery vehicles are gaining importance and are highlighted here. We also recognize and report the lack of detailed characterization of cell membranes in terms of safety, structural integrity, targeting functionality, and drug transport. Finally, we provide insights on future development of bioengineered cellular and cell membrane-derived vesicles for successful clinical translation.Graphical abstractUnlabelled Image
       
  • 3D bioprinting of functional tissue models for personalized drug screening
           and in vitro disease modeling
    • Abstract: Publication date: Available online 21 June 2018Source: Advanced Drug Delivery ReviewsAuthor(s): Xuanyi Ma, Justin Liu, Wei Zhu, Min Tang, Natalie Lawrence, Claire Yu, Maling Gou, Shaochen Chen 3D bioprinting is emerging as a promising technology for fabricating complex tissue constructs with tailored biological components and mechanical properties. Recent advances have enabled scientists to precisely position materials and cells to build functional tissue models for in vitro drug screening and disease modeling. This review presents state-of-the-art 3D bioprinting techniques and discusses the choice of cell source and biomaterials for building functional tissue models that can be used for personalized drug screening and disease modeling. In particular, we focus on 3D-bioprinted liver models, cardiac tissues, vascularized constructs, and cancer models for their promising applications in medical research, drug discovery, toxicology, and other pre-clinical studies.Graphical abstractSchematic diagram showing the use of 3D bioprinting to build in vitro constructs that can be used for drug testing and disease modeling.Unlabelled Image
       
  • Intracellular delivery of colloids: Past and future contributions from
           microinjection
    • Abstract: Publication date: Available online 20 June 2018Source: Advanced Drug Delivery ReviewsAuthor(s): Peter Tiefenboeck, Jong Ah Kim, Jean-Christophe Leroux The manipulation of single cells and whole tissues has been possible since the early 70’s, when semi-automatic injectors were developed. Since then, microinjection has been used to introduce an ever-expanding range of colloids of up to 1000 nm in size into living cells. Besides injecting nucleic acids to study transfection mechanisms, numerous cellular pathways have been unraveled through the introduction of recombinant proteins and blocking antibodies. The injection of nanoparticles has also become popular in recent years to investigate toxicity mechanisms and intracellular transport, and to conceive semi-synthetic cells containing artificial organelles. This article reviews colloidal systems such as proteins, nucleic acids and nanoparticles that have been injected into cells for different research aims, and discusses the scientific advances achieved through them. The colloids' intracellular processing and ultimate fate are also examined from a drug delivery perspective with an emphasis on the differences observed for endocytosed versus microinjected material.Graphical abstractUnlabelled Image
       
  • Practical guidelines for the characterization and quality control of pure
           drug nanoparticles and nano-cocrystals in the pharmaceutical industry
    • Abstract: Publication date: Available online 18 June 2018Source: Advanced Drug Delivery ReviewsAuthor(s): Leena Peltonen The number of poorly soluble drug candidates is increasing, and this is also seen in the research interest towards drug nanoparticles and (nano-)cocrystals; improved solubility is the most important application of these nanosystems. In order to confirm the functionality of these nanoparticles throughout their lifecycle, repeatability of the formulation processes, functional performance of the formed systems in pre-determined way and system stability, a thorough physicochemical understanding with the aid of necessary analytical techniques is needed. Even very minor deviations in for example particle size or size deviation in nanoscale can alter the product bioavailability, and the effect is even more dramatic with the smallest particle size fractions. Also, small particle size sets special requirements for the analytical techniques. In this review most important physicochemical properties of drug nanocrystals and nano-cocrystals are presented, suitable analytical techniques, their pros and cons, are described with the extra input on practical point of view.Graphical abstractUnlabelled Image
       
  • Local delivery of adenosine receptor agonists to promote bone regeneration
           and defect healing
    • Abstract: Publication date: Available online 18 June 2018Source: Advanced Drug Delivery ReviewsAuthor(s): Christopher D. Lopez, Jonathan M. Bekisz, Carmen Corciulo, Aranzazu Mediero, Paulo G. Coelho, Lukasz Witek, Roberto L. Flores, Bruce N. Cronstein Adenosine receptor activation has been investigated as a potential therapeutic approach to heal bone. Bone has enhanced regenerative potential when influenced by either direct or indirect adenosine receptor agonism. As investigators continue to elucidate how adenosine influences bone cell homeostasis at the cellular and molecular levels, a small but growing body of literature has reported successful in vivo applications of adenosine delivery. This review summarizes the role adenosine receptor ligation plays in osteoblast and osteoclast biology and remodeling/regeneration. It also reports on all the modalities described in the literature at this point for delivery of adenosine through in vivo models for bone healing and regeneration.Graphical abstractUnlabelled Image
       
  • Microphysiological systems meet hiPSC technology – New tools for disease
           modeling of liver infections in basic research and drug development
    • Abstract: Publication date: Available online 15 June 2018Source: Advanced Drug Delivery ReviewsAuthor(s): Martin Raasch, Enrico Fritsche, Andreas Kurtz, Michael Bauer, Alexander S. Mosig Complex cell culture models such as microphysiological models (MPS) mimicking human liver functionality in vitro are in the spotlight as alternative to conventional cell culture and animal models. Promising techniques like microfluidic cell culture or micropatterning by 3D bioprinting are gaining increasing importance for the development of MPS to address the needs for more predictivity and cost efficiency. In this context, human induced pluripotent stem cells (hiPSCs) offer new perspectives for the development of advanced liver-on-chip systems by recreating an in vivo like microenvironment that supports the reliable differentiation of hiPSCs to hepatocyte-like cells (HLC). In this review we will summarize current protocols of HLC generation and highlight recently established MPS suitable to resemble physiological hepatocyte function in vitro. In addition, we are discussing potential applications of liver MPS for disease modeling related to systemic or direct liver infections and the use of MPS in testing of new drug candidates.Graphical abstractUnlabelled Image
       
  • Repurposing drugs as inhaled therapies in asthma
    • Abstract: Publication date: Available online 12 June 2018Source: Advanced Drug Delivery ReviewsAuthor(s): Sandra D. Anderson For the first 40 years of the 20th century treatment for asthma occurred in response to an asthma attack. The treatments were given by injection or orally and included the adrenergic agonists adrenalin/epinephrine and ephedrine and a phosphodiesterase inhibitor theophylline. Epinephrine became available as an aerosol in 1930. After 1945, isoprenaline, a non-selective beta agonist, became available for oral use but it was most widely used by inhalation. Isoprenaline was short-acting with unwanted cardiac effects. More selective beta agonists, with a longer duration of action and fewer side-effects became available, including orciprenaline in 1967, salbutamol in 1969 and terbutaline in 1970. The inhaled steroid beclomethasone was available by 1972 and budesonide by 1982. Spirometry alone and in response to exercise was used to assess efficacy and duration of action of these drugs for the acute benefits of beta2 agonists and the chronic benefits of corticosteroids. Early studies comparing oral and aerosol beta2 agonists found equivalence in bronchodilator effect but the aerosol treatment was superior in preventing exercise-induced bronchoconstriction. Inhaled drugs are now widely used including the long-acting beta2 agonists, salmeterol and formoterol, and the corticosteroids, fluticasone, ciclesonide, mometasone and triamcinolone, that act locally and have low systemic bio-availability. Repurposing drugs as inhaled therapies permitted direct delivery of low doses of drug to the site of action reducing the incidence of unwanted side-effects and permitting the prophylactic treatment of asthma.Graphical abstractUnwanted side-effects are greatest when beta2 agonists and steroids are given by tablet or injection and least when they are given by inhalation.Unlabelled Image
       
  • Inhalation of repurposed drugs to treat pulmonary hypertension
    • Abstract: Publication date: Available online 8 June 2018Source: Advanced Drug Delivery ReviewsAuthor(s): Tobias Gessler Pulmonary arterial hypertension (PAH) is a rare, but severe and life-threatening disease characterized by vasoconstriction and remodeling of the pulmonary arterioles, leading to progressive increase in pulmonary vascular resistance and ultimately to right-heart failure. In the last two decades, significant progress in treatment of PAH has been made, with currently 12 drugs approved for targeted therapy. Among these, the stable prostacyclin analogues iloprost and treprostinil have been repurposed for inhalation. The paper highlights the development of the two drugs emphasizing the rationale and advantages of the inhalative approach.Despite substantial advances in the specific, mainly vasodilatory PAH therapy, disease progression is mostly inevitable and mortality remains unacceptably high. Thus, introduction of new drugs targeting the cancer-like remodeling of the diseased pulmonary arteries is urgently needed. Inhalation offers pulmonary selectivity and will hopefully pioneer the repurposing of novel highly potent drugs for effective aerosol therapy of PAH.Graphical abstractUnlabelled Image
       
  • Repurposing of statins via inhalation to treat lung inflammatory
           conditions
    • Abstract: Publication date: Available online 8 June 2018Source: Advanced Drug Delivery ReviewsAuthor(s): Peta Bradbury, Daniela Traini, Alaina J. Ammit, Paul M. Young, Hui Xin Ong Despite many therapeutic advancements over the past decade, the continued rise in chronic inflammatory lung diseases incidence has driven the need to identify and develop new therapeutic strategies, with superior efficacy to treat these diseases. Statins are one class of drug that could potentially be repurposed as an alternative treatment for chronic lung diseases. They are currently used to treat hypercholesterolemia by inhibiting the 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, that catalyses the rate limiting step in the mevalonate biosynthesis pathway, a key intermediate in cholesterol metabolism. Recent research has identified statins to have other protective pleiotropic properties including anti-inflammatory, anti-oxidant, muco-inhibitory effects that may be beneficial for the treatment of chronic inflammatory lung diseases. However, clinical studies have yielded conflicting results. This review will summarise some of the current evidences for statins pleiotropic effects that could be applied for the treatment of chronic inflammatory lung diseases, their mechanisms of actions, and the potential to repurpose statins as an inhaled therapy, including a detailed discussion on their different physical-chemical properties and how these characteristics could ultimately affect treatment efficacies. The repurposing of statins from conventional anti-cholesterol oral therapy to inhaled anti-inflammatory formulation is promising, as it provides direct delivery to the airways, reduced risk of side effects, increased bioavailability and tailored physical-chemical properties for enhanced efficacy.Graphical abstractUnlabelled Image
       
  • Repurposing of gamma interferon via inhalation delivery
    • Abstract: Publication date: Available online 7 June 2018Source: Advanced Drug Delivery ReviewsAuthor(s): Gerald C. Smaldone Pulmonary diseases frequently involve imbalances in immunity. The inability to control bacteria in tuberculosis is a failed response to a pathogen. Idiopathic pulmonary fibrosis (IPF), a progressive fibrotic lung disease, can lead to respiratory failure and death within 3 years of diagnosis. Chronic obstructive pulmonary disease (COPD) progresses until death and in recent years has been labeled an autoimmune disease. Proposed mechanistic pathways of pathophysiology involve uncontrolled healing governed by pro-fibrotic cytokines that are unresponsive to the standard anti-inflammatory agents (e.g., corticosteroids). Interferon-γ (IFN-γ), currently delivered as a subcutaneous injection for chronic granulomatous disease and osteopetrosis, is a cytokine that can stimulate macrophage function and inhibit fibrotic pathways. In recent studies, our group has repurposed IFN-γ as an inhaled aerosol, targeted directly to the lung to treat a host of diseases affected by dysregulated immunity. At present, we have studied its potential in treating tuberculosis and IPF. In a controlled clinical trial in tuberculosis, inhaled IFN-γ was effective while parenteral IFN-γ was not, indicating that macrophages can be effectively immune-stimulated by aerosol therapy. A similar approach has been taken in IPF. In a two-year safety study treating patients with IPF, the drug was safe and the pretreatment decline in pulmonary function was reversed. Furthermore, the same fibrotic pathways active in the lung parenchyma in IPF may be at fault in the airways of COPD patients. These experiences warrant the continued evaluation of inhaled IFN-γ in human clinical trials.Graphical abstractUnlabelled Image
       
  • Progress, obstacles, and limitations in the use of stem cells in
           organ-on-a-chip models
    • Abstract: Publication date: Available online 6 June 2018Source: Advanced Drug Delivery ReviewsAuthor(s): Alexa Wnorowski, Huaxiao Yang, Joseph C. Wu In recent years, drug development costs have soared, primarily due to the failure of preclinical animal and cell culture models, which do not directly translate to human physiology. Organ-on-a-chip (OOC) is a burgeoning technology with the potential to revolutionize disease modeling, drug discovery, and toxicology research by strengthening the relevance of culture-based models while reducing costly animal studies. Although OOC models can incorporate a variety of tissue sources, the most robust and relevant OOC models going forward will include stem cells. In this review, we will highlight the benefits of stem cells as a tissue source while considering current limitations to their complete and effective implementation into OOC models.Graphical abstractUnlabelled Image
       
  • Engineered delivery strategies for enhanced control of growth factor
           activities in wound healing
    • Abstract: Publication date: Available online 5 June 2018Source: Advanced Drug Delivery ReviewsAuthor(s): Yiming Niu, Qiu Li, Ya Ding, Lei Dong, Chunming Wang Growth factors (GFs) are versatile signalling molecules that orchestrate the dynamic, multi-stage process of wound healing. Delivery of exogenous GFs to the wound milieu to mediate healing in an active, physiologically-relevant manner has shown great promise in laboratories; however, the inherent instability of GFs, accompanied with numerous safety, efficacy and cost concerns, has hindered the clinical success of GF delivery. In this article, we highlight that the key to overcoming these challenges is to enhance the control of the activities of GFs throughout the delivering process. We summarise the recent strategies based on biomaterials matrices and molecular engineering, which aim to improve the conditions of GFs for delivery (at the ‘supply’ end of the delivery), increase the stability and functions of GFs in extracellular matrix (in transportation to target cells), as well as enhance the GFs/receptor interaction on the cell membrane (at the ‘destination’ end of the delivery). Many of these investigations have led to encouraging outcomes in various in vitro and in vivo regenerative models with considerable translational potential.Graphical abstractUnlabelled Image
       
  • Reduction-sensitive polymeric nanomedicines: An emerging multifunctional
           platform for targeted cancer therapy
    • Abstract: Publication date: Available online 24 May 2018Source: Advanced Drug Delivery ReviewsAuthor(s): Huanli Sun, Yifan Zhang, Zhiyuan Zhong The development of smart delivery systems that are robust in circulation and quickly release drugs following selective internalization into target cancer cells is a key to precision cancer therapy. Interestingly, reduction-sensitive polymeric nanomedicines showing high plasma stability and triggered cytoplasmic drug release behavior have recently emerged as one of the most exciting platforms for targeted delivery of various anticancer drugs including small chemical drugs, proteins, and nucleic acids. In vivo studies in varying tumor models reveal that these reduction-sensitive multifunctional nanomedicines outperform the currently used clinical formulations and reduction-insensitive counterparts, bringing about not only significantly enhanced tumor selectivity, accumulation and inhibition efficacy but also markedly reduced systemic toxicity and improved therapeutic index. In this review, we will highlight the cutting-edge advancement with a focus on in vivo performances as well as future perspectives on reduction-sensitive polymeric nanomedicines for targeted cancer therapy.Graphical abstractUnlabelled Image
       
  • Perspectives on the past, present, and future of cancer nanomedicine
    • Abstract: Publication date: Available online 18 May 2018Source: Advanced Drug Delivery ReviewsAuthor(s): Yu Seok Youn, You Han Bae The justification of cancer nanomedicine relies on enhanced permeation (EP) and retention (R) effect and the capability of intracellular targeting due primarily to size after internalization (endocytosis) into the individual target cells. The EPR effect implies improved efficacy. Affinity targeting for solid tumors only occur after delivery to individual cells, which help internalization and/or retention. The design principles have been supported by animal results in numerous publications, but hardly translated. The natures of EP and R, such as frequency of large openings in tumor vasculature and their dynamics, are not understood, in particular, in clinical settings. Although various attempts to address the issues related to EP and delivery, by modifying design factors and manipulating tumor microenvironment, are being reported, they are still verified in artificial rodent tumors which do not mimic the nature of human tumor physiology/pathology in terms of transport and delivery. The clinical trials of experimental nanomedicine have experienced unexpected adverse effects with modest improvement in efficacy when compared to current frontline therapy. Future nanomedicine may require new design principles without consideration of EP and affinity targeting. A possible direction is to set new approaches to intentionally minimize adverse effects, rather than aiming at better efficacy, which can widen the therapeutic window of an anticancer drug of interest. Broadening indications and administration routes of developed therapeutic nanotechnology would benefit patients.Graphical abstractUnlabelled Image
       
  • Stem cell-based retina models
    • Abstract: Publication date: Available online 17 May 2018Source: Advanced Drug Delivery ReviewsAuthor(s): Kevin Achberger, Jasmin C. Haderspeck, Alexander Kleger, Stefan Liebau From the early days of cell biological research, the eye—especially the retina—has evoked broad interest among scientists. The retina has since been thoroughly investigated and numerous models have been exploited to shed light on its development, morphology, and function. Apart from various animal models and human clinical and anatomical research, stem cell-based models of animal and human cells of origin have entered the field, especially during the last decade. Despite the observation that the retina of different species comprises endogenous stem cells, most stem cell-related research in the human retina is now based on pluripotent stem cell models. Herein, systems of two-dimensional (2D) cultures and co-cultures of distinctly differentiated retinal subtypes revealed a variety of cellular aspects but have in many aspects been replaced by three-dimensional (3D) structures—the so-called retinal organoids. These organoids not only contain all major retinal cell subtypes compared to the physiological situation, but also show a distinct layering in close proximity to the in vivo morphology. Nevertheless, all these models have inherent advantages and disadvantages, which are expounded and summarized in this review. Finally, we discuss current application aspects of stem cell-based retina models and the specific promises they hold for the future.Graphical abstractUnlabelled Image
       
  • Production of pure drug nanocrystals and Nano Co-crystals by
           confinement methods
    • Abstract: Publication date: Available online 5 May 2018Source: Advanced Drug Delivery ReviewsAuthor(s): Flavia Fontana, Patricia Figueiredo, Pei Zhang, Jouni T. Hirvonen, Dongfei Liu, Helder A. Santos The use of drug nanocrystals in the drug formulation is increasing due to the large number of poorly water-soluble drug compounds synthetized and due to the advantages brought by the nanonization process. The downsizing processes are done using a top-down approach (milling and homogenization currently employed at the industrial level), while the crystallization process is performed by bottom-up techniques (e.g., antisolvent precipitation to the use of supercritical fluids or spray and freeze drying). In addition, the production of nanocrystals in confined environment can be achieved within microfluidics channels. This review analyzes the processes for the preparation of nanocrystals and co-crystals, divided by top-down and bottom-up approaches, together with their combinations. The combination of both strategies merges the favorable features of each process and avoids the disadvantages of single processes. Overall, the applicability of drug nanocrystals is highlighted by the widespread research on the production processes at the engineering, pharmaceutical, and nanotechnology level.Graphical abstractUnlabelled Image
       
  • Electrospinning: An enabling nanotechnology platform for drug delivery and
           regenerative medicine
    • Abstract: Publication date: Available online 2 May 2018Source: Advanced Drug Delivery ReviewsAuthor(s): Shixuan Chen, Ruiquan Li, Xiaoran Li, Jingwei Xie Electrospinning provides an enabling nanotechnology platform for generating a rich variety of novel structured materials in many biomedical applications including drug delivery, biosensing, tissue engineering, and regenerative medicine. In this review article, we begin with a thorough discussion on the method of producing 1D, 2D, and 3D electrospun nanofiber materials. In particular, we emphasize on how the 3D printing technology can contribute to the improvement of traditional electrospinning technology for the fabrication of 3D electrospun nanofiber materials as drug delivery devices/implants, scaffolds or living tissue constructs. We then highlight several notable examples of electrospun nanofiber materials in specific biomedical applications including cancer therapy, guiding cellular responses, engineering in vitro 3D tissue models, and tissue regeneration. Finally, we finish with conclusions and future perspectives of electrospun nanofiber materials for drug delivery and regenerative medicine.Graphical abstractThis review summarizes the methods for producing 1D electrospun fragment, 1D nanofiber bundles, 2D nanofiber membranes, and 3D nanofiber scaffolds. Next, the combination of electrospinning with 3D printing, flexible electrode, and microfluidcs are discussed. And the review highlights the biomedical applications of nanofiber scaffolds, including drug delivery, controlling cellular behaviors, engineering in vitro 3D tissue/tumor models, and regenerative medicine.Unlabelled Image
       
  • Cell encapsulation: Overcoming barriers in cell transplantation in
           diabetes and beyond
    • Abstract: Publication date: Available online 30 April 2018Source: Advanced Drug Delivery ReviewsAuthor(s): Marco Farina, Jenolyn F. Alexander, Usha Thekkedath, Mauro Ferrari, Alessandro Grattoni Cell-based therapy is emerging as a promising strategy for treating a wide range of human diseases, such as diabetes, blood disorders, acute liver failure, spinal cord injury, and several types of cancer. Pancreatic islets, blood cells, hepatocytes, and stem cells are among the many cell types currently used for this strategy. The encapsulation of these “therapeutic” cells is under intense investigation to not only prevent immune rejection but also provide a controlled and supportive environment so they can function effectively. Some of the advanced encapsulation systems provide active agents to the cells and enable a complete retrieval of the graft in the case of an adverse body reaction. Here, we review various encapsulation strategies developed in academic and industrial settings, including the state-of-the-art technologies in advanced preclinical phases as well as those undergoing clinical trials, and assess their advantages and challenges. We also emphasize the importance of stimulus-responsive encapsulated cell systems that provide a “smart and live” therapeutic delivery to overcome barriers in cell transplantation as well as their use in patients.Graphical abstractUnlabelled Image
       
  • Fibrillin microfibrils and proteases, key integrators of fibrotic pathways
    • Abstract: Publication date: Available online 27 April 2018Source: Advanced Drug Delivery ReviewsAuthor(s): Paola Zigrino, Gerhard Sengle Supramolecular networks composed of multi-domain ECM proteins represent intricate cellular microenvironments which are required to balance tissue homeostasis and direct remodeling. Structural deficiency in ECM proteins results in imbalances in ECM-cell communication resulting often times in fibrotic reactions. To understand how individual components of the ECM integrate communication with the cell surface by presenting growth factors or providing fine-tuned biomechanical properties is mandatory for gaining a better understanding of disease mechanisms in the quest for new therapeutic approaches. Here we provide an overview about what we can learn from inherited connective tissue disorders caused primarily by mutations in fibrillin-1 and binding partners as well as by altered ECM processing leading to defined structural changes and similar functional knock-in mouse models. We will utilize this knowledge to propose new molecular hypotheses which should be tested in future studies.Graphical abstractUnlabelled Image
       
  • Intervertebral disc regeneration: From cell therapy to the development of
           novel bioinspired endogenous repair strategies
    • Abstract: Publication date: Available online 26 April 2018Source: Advanced Drug Delivery ReviewsAuthor(s): Johann Clouet, Marion Fusellier, Anne Camus, Catherine Le Visage, Jérôme Guicheux Low back pain (LBP), frequently associated with intervertebral disc (IVD) degeneration, is a major public health concern. LBP is currently managed by pharmacological treatments and, if unsuccessful, by invasive surgical procedures, which do not counteract the degenerative process.Considering that IVD cell depletion is critical in the degenerative process, the supplementation of IVD with reparative cells, associated or not with biomaterials, has been contemplated. Recently, the discovery of reparative stem/progenitor cells in the IVD has led to increased interest in the potential of endogenous repair strategies. Recruitment of these cells by specific signals might constitute an alternative strategy to cell transplantation. Here, we review the status of cell-based therapies for treating IVD degeneration and emphasize the current concept of endogenous repair as well as future perspectives. This review also highlights the challenges of the mobilization/differentiation of reparative progenitor cells through the delivery of biologics factors to stimulate IVD regeneration.Graphical abstractUnlabelled Image
       
  • Sphingolipids as targets for inhalation treatment of cystic fibrosis
    • Abstract: Publication date: Available online 24 April 2018Source: Advanced Drug Delivery ReviewsAuthor(s): Katrin Anne Becker, Joachim Riethmüller, Aaron P. Seitz, Aaron Gardner, Ryan Boudreau, Markus Kamler, Burkhard Kleuser, Edward Schuchman, Charles C. Caldwell, Michael J. Edwards, Heike Grassmé, Malcolm Brodlie, Erich Gulbins Studies over the past several years have demonstrated the important role of sphingolipids in cystic fibrosis (CF), chronic obstructive pulmonary disease and acute lung injury. Ceramide is increased in airway epithelial cells and alveolar macrophages of CF mice and humans, while sphingosine is dramatically decreased. This increase in ceramide results in chronic inflammation, increased death of epithelial cells, release of DNA into the bronchial lumen and thereby an impairment of mucociliary clearance; while the lack of sphingosine in airway epithelial cells causes high infection susceptibility in CF mice and possibly patients. The increase in ceramide mediates an ectopic expression of β1-integrins in the luminal membrane of CF epithelial cells, which results, via an unknown mechanism, in a down-regulation of acid ceramidase. It is predominantly this down-regulation of acid ceramidase that results in the imbalance of ceramide and sphingosine in CF cells. Correction of ceramide and sphingosine levels can be achieved by inhalation of functional acid sphingomyelinase inhibitors, recombinant acid ceramidase or by normalization of β1-integrin expression and subsequent re-expression of endogenous acid ceramidase. These treatments correct pulmonary inflammation and prevent or treat, respectively, acute and chronic pulmonary infections in CF mice with Staphylococcus aureus and mucoid or non-mucoid Pseudomonas aeruginosa. Inhalation of sphingosine corrects sphingosine levels only and seems to mainly act against the infection. Many antidepressants are functional inhibitors of the acid sphingomyelinase and were designed for systemic treatment of major depression. These drugs could be repurposed to treat CF by inhalation.Graphical abstractMechanisms of ceramide and sphingosine alterations in cystic fibrosis (CF) epithelial cells and potential treatmentsCFTR deficiency results in increased ceramide levels that mediate surface clustering of β1-integrins. The luminal clustering of β1-integrins mediates a down-regulation of the expression of acid ceramidase (AC) in CF airway epithelial cells. This results in a vicious cycle with a further increase of ceramide concentrations and a decrease of sphingosine levels. Ceramide also induces cell death and a release of DNA into the airways. The low sphingosine concentrations in CF upper airways allow pathogens to reach the lung in which the viscous mucus containing dead cells and DNA promotes their adherence, growth and chronic infection. Treatments that directly reduce ceramide, for instance by blocking the acid sphingomyelinase (ASM), and/or normalize expression of β1-integrins and thereby correct expression levels of acid ceramidase and ceramide will reduce infection and inflammation, in CF lungs. Inhalation of sphingosine may predominantly mediate direct killing of pathogens. Sm: Sphingomyelin; C: ceramide; Sg: Sphingosine; ®: ®1-integrin, L: Ligands of ®1-integrin; FIASMA: Functional inhibitors of the acid sphingomyelinase.Unlabelled Image
       
  • Regulatory pitfalls and opportunities when repurposing for inhalation
           therapy
    • Abstract: Publication date: Available online 19 April 2018Source: Advanced Drug Delivery ReviewsAuthor(s): Svetlana Lyapustina This article reviews regulatory considerations for companies wishing to develop drugs for delivery via the respiratory tract (e.g., by oral inhalation or intranasally) using molecules previously approved for a different therapeutic indication and/or a different delivery route. Conceptually, such repurposing has many medical and business advantages, but turning promising ideas into real products requires overcoming a number of practical challenges. Obtaining regulatory approval to market a candidate product comes at the end of a product development, but being aware of the regulatory requirements is necessary before the development even starts. Understanding the scope and type of data that regulatory agencies would like to see may have a decisive influence on the design of the development program itself. For example, even for repurposed drugs, safety, efficacy, quality, and usability must be demonstrated, either from prior knowledge or through newly generated data. Furthermore, products for respiratory delivery have unique regulatory challenges due to the nature of these drug-device combinations.Graphical abstractUnlabelled Image
       
  • Impact of aging, Alzheimer's disease and Parkinson's disease on the
           blood-brain barrier transport of therapeutics
    • Abstract: Publication date: Available online 14 April 2018Source: Advanced Drug Delivery ReviewsAuthor(s): Yijun Pan, Joseph A. Nicolazzo Older people are at a greater risk of medicine-induced toxicity resulting from either increased drug sensitivity or age-related pharmacokinetic changes. The scenario is further complicated with the two most prevalent age-related neurodegenerative diseases, Alzheimer's disease (AD) and Parkinson's disease (PD). With aging, AD and PD, there is growing evidence of altered structure and function of the blood-brain barrier (BBB), including modifications to tight junctions and efflux transporters, such as P-glycoprotein. The subsequent impact on CNS drug exposure and risk of neurotoxicity from systemically-acting medicines is less well characterized. The purpose of this review, therefore, is to provide an overview of the multiple changes that occur to the BBB as a result of aging, AD and PD, and the impact that such changes have on CNS exposure of drugs, based on studies conducted in aged rodents or rodent models of disease, and in elderly people with and without AD or PD.Graphical abstractUnlabelled Image
       
  • Dosage form modification and oral drug delivery in older people
    • Abstract: Publication date: Available online 13 April 2018Source: Advanced Drug Delivery ReviewsAuthor(s): Esther T.L. Lau, Kathryn J. Steadman, Julie A.Y. Cichero, Lisa M. Nissen Many people cannot swallow whole tablets and capsules. The cause ranges from difficulties overriding the natural instinct to chew solids/foodstuff before swallowing, to a complex disorder of swallowing function affecting the ability to manage all food and fluid intake. Older people can experience swallowing difficulties because of co-morbidities, age-related physiological changes, and polypharmacy. To make medicines easier to swallow, many people will modify the medication dosage form e.g. split or crush tablets, and open capsules. Some of the challenges associated with administering medicines to older people, and issues with dosage form modification will be reviewed. Novel dosage forms in development are promising and may help overcome some of the issues. However, until these are more readily available, effective interdisciplinary teams, and improving patient health literacy will help reduce the risk of medication misadventures in older people.Graphical abstractUnlabelled Image
       
  • Scarless wound healing: From development to senescence
    • Abstract: Publication date: Available online 12 April 2018Source: Advanced Drug Delivery ReviewsAuthor(s): Harris Pratsinis, Eleni Mavrogonatou, Dimitris Kletsas An essential element of tissue homeostasis is the response to injuries, cutaneous wound healing being the most studied example. In the adults, wound healing aims at quickly restoring the barrier function of the skin, leading however to scar, a dysfunctional fibrotic tissue. On the other hand, in fetuses a scarless tissue regeneration takes place. During ageing, the wound healing capacity declines; however, in the absence of comorbidities a higher quality in tissue repair is observed. Senescent cells have been found to accumulate in chronic unhealed wounds, but more recent reports indicate that their transient presence may be beneficial for tissue repair. In this review data on skin wound healing and scarring are presented, covering the whole spectrum from early embryonic development to adulthood, and furthermore until ageing of the organism.Graphical abstractUnlabelled Image
       
  • Delivering drugs to the lungs: The history of repurposing in the treatment
           of respiratory diseases
    • Abstract: Publication date: Available online 11 April 2018Source: Advanced Drug Delivery ReviewsAuthor(s): Stephen P. Newman The repurposing of drug delivery by the pulmonary route has been applied to treatment and prophylaxis of an increasingly wide range of respiratory diseases. Repurposing has been most successful for the delivery of inhaled bronchodilators and corticosteroids in patients with asthma and chronic obstructive pulmonary disease (COPD). Repurposing utilizes the advantages that the pulmonary route offers in terms of more targeted delivery to the site of action, the use of smaller doses, and a lower incidence of side-effects. Success has been more variable for other drugs and treatment indications. Pulmonary delivery is now well established for delivery of inhaled antibiotics in cystic fibrosis (CF), and in the treatment of pulmonary arterial hypertension (PAH). Other inhaled treatments such as those for idiopathic pulmonary fibrosis (IPF), lung transplant rejection or tuberculosis may also become routine. Repurposing has progressed in parallel with the development of new drugs, inhaler devices and formulations.Graphical abstractUnlabelled Image
       
  • Nucleic acids delivering nucleic acids
    • Abstract: Publication date: Available online 6 April 2018Source: Advanced Drug Delivery ReviewsAuthor(s): Silvia Catuogno, Carla Lucia Esposito, Gerolama Condorelli, Vittorio de Franciscis Nucleic acid therapeutics, including siRNAs, miRNAs/antimiRs, gRNAs and ASO, represent innovative and highly promising molecules for the safe treatment of a wide range of pathologies. The efficiency of systemic treatments is impeded by 1) the need to overcome physical and functional barriers in the organism, and 2) to accumulate in the intracellular active site at therapeutic concentrations. Although oligonucleotides either as modified naked molecules or complexed with delivery carriers have revealed to be effectively delivered to the affected target cells, this is restricted to topic treatments or to a few highly vascularized tissues. Therefore, the development of effective strategies for therapeutic nucleic acid selective delivery to target tissues is of primary importance in order to reduce the occurrence of undesired effects on non-target healthy tissues and to permit their translation to clinic. Due to their high affinity for specific ligands, high tissue penetration and chemical flexibility, short single-stranded nucleic acid aptamers are emerging as very attractive carriers for various therapeutic oligonucleotides. Yet, different aptamer-based bioconjugates, able to provide accumulation into target tissues, as well as efficient processing of therapeutic oligonucleotides, have been developed. In this respect, nucleic acid aptamer-mediated delivery strategies represent a powerful approach able to increase the therapeutic efficacy also highly reducing the overall toxicity. In this review, we will summarize recent progress in the field and discuss achieved objectives and optimization of aptamers as delivery carriers of short oligonucleotides.Graphical abstractUnlabelled Image
       
  • Aptamers as targeting ligands and therapeutic molecules for overcoming
           drug resistance in cancers
    • Abstract: Publication date: Available online 6 April 2018Source: Advanced Drug Delivery ReviewsAuthor(s): Gang Zhou, Olivier Latchoumanin, Lionel Hebbard, Wei Duan, Christopher Liddle, Jacob George, Liang Qiao Traditional anticancer therapies are often unable to completely eradicate the tumor bulk due to multi-drug resistance (MDR) of cancers. A number of mechanisms such as micro-environmental stress and overexpression of drug efflux pumps are involved in the MDR process. Hence, therapeutic strategies for overcoming MDR are urgently needed to improve cancer treatment efficacy. Aptamers are short single-stranded oligonucleotides or peptides exhibiting unique three-dimensional structures and possess several unique advantages over conventional antibodies such as low immunogenicity and stronger tissue-penetration capacity. Aptamers targeting cancer-associated receptors have been explored to selectively deliver a therapeutic cargo (anticancer drugs, siRNAs, miRNAs and drug-carriers) to the intratumoral compartment where they can exert better tumor-killing effects. In this review, we summarize current knowledge of the multiple regulatory mechanisms of MDR, with a particular emphasis on aptamer-mediated novel therapeutic agents and strategies that seek to reversing MDR. The challenges associated with aptamer-based agents and approaches are also discussed.Graphical abstractUnlabelled Image
       
  • Repurposing excipients as active inhalation agents: The mannitol story
    • Abstract: Publication date: Available online 5 April 2018Source: Advanced Drug Delivery ReviewsAuthor(s): Sandra D. Anderson, Evangelia Daviskas, John D. Brannan, Hak Kim Chan The story of how we came to use inhaled mannitol to diagnose asthma and to treat cystic fibrosis began when we were looking for a surrogate for exercise as a stimulus to identify asthma. We had proposed that exercise-induced asthma was caused by an increase in osmolarity of the periciliary fluid. We found hypertonic saline to be a surrogate for exercise but an ultrasonic nebuliser was required. We produced a dry powder of sodium chloride but it proved unstable. We developed a spray dried preparation of mannitol and found that bronchial responsiveness to inhaling mannitol identified people with currently active asthma. We reasoned that mannitol had potential to replace the ‘osmotic’ benefits of exercise and could be used as a treatment to enhance mucociliary clearance in patients with cystic fibrosis. These discoveries were the start of a journey to develop several registered products that are in clinical use globally today.Graphical abstractUnlabelled Image
       
  • Aptamer chemistry
    • Abstract: Publication date: Available online 4 April 2018Source: Advanced Drug Delivery ReviewsAuthor(s): Pascal Röthlisberger, Marcel Hollenstein Aptamers are single-stranded DNA or RNA molecules capable of tightly binding to specific targets. These functional nucleic acids are obtained by an in vitro Darwinian evolution method coined SELEX (Systematic Evolution of Ligands by EXponential enrichment). Compared to their proteinaceous counterparts, aptamers offer a number of advantages including a low immunogenicity, a relative ease of large-scale synthesis at affordable costs with little or no batch-to-batch variation, physical stability, and facile chemical modification. These alluring properties have propelled aptamers into the forefront of numerous practical applications such as the development of therapeutic and diagnostic agents as well as the construction of biosensing platforms. However, commercial success of aptamers still proceeds at a weak pace. The main factors responsible for this delay are the susceptibility of aptamers to degradation by nucleases, their rapid renal filtration, suboptimal thermal stability, and the lack of functional group diversity. Here, we describe the different chemical methods available to mitigate these shortcomings. Particularly, we describe the chemical post-SELEX processing of aptamers to include functional groups as well as the inclusion of modified nucleoside triphosphates into the SELEX protocol. These methods will be illustrated with successful examples of chemically modified aptamers used as drug delivery systems, in therapeutic applications, and as biosensing devices.Graphical abstractUnlabelled Image
       
  • Engineered cell and tissue models of pulmonary fibrosis
    • Abstract: Publication date: April 2018Source: Advanced Drug Delivery Reviews, Volume 129Author(s): Aswin Sundarakrishnan, Ying Chen, Lauren D. Black, Bree B. Aldridge, David L. Kaplan Pulmonary fibrosis includes several lung disorders characterized by scar formation and Idiopathic Pulmonary Fibrosis (IPF) is a particularly severe form of pulmonary fibrosis of unknown etiology with a mean life expectancy of 3 years' post-diagnosis. Treatments for IPF are limited to two FDA approved drugs, pirfenidone and nintedanib. Most lead candidate drugs that are identified in pre-clinical animal studies fail in human clinical trials. Thus, there is a need for advanced humanized in vitro models of the lung to improve candidate treatments prior to moving to human clinical trials. The development of 3D tissue models has created systems capable of emulating human lung structure, function, and cell and matrix interactions. The specific models accomplish these features and preliminary studies conducted using some of these systems have shown potential for in vitro anti-fibrotic drug testing. Further characterization and improvements will enable these tissue models to extend their utility for in vitro drug testing, to help identify signaling pathways and mechanisms for new drug targets, and potentially reduce animal models as standard pre-clinical models of study. In the current review, we contrast different in vitro models based on increasing dimensionality (2D, 2.5D and 3D), with added focus on contemporary 3D pulmonary models of fibrosis.Graphical abstractImage 1
       
  • Tackling muscle fibrosis: From molecular mechanisms to next generation
           engineered models to predict drug delivery
    • Abstract: Publication date: April 2018Source: Advanced Drug Delivery Reviews, Volume 129Author(s): S. Bersini, M. Gilardi, M. Mora, S. Krol, C. Arrigoni, C. Candrian, S. Zanotti, M. Moretti Muscle fibrosis represents the end stage consequence of different diseases, among which muscular dystrophies, leading to severe impairment of muscle functions. Muscle fibrosis involves the production of several growth factors, cytokines and proteolytic enzymes and is strictly associated to inflammatory processes. Moreover, fibrosis causes profound changes in tissue properties, including increased stiffness and density, lower pH and oxygenation. Up to now, there is no therapeutic approach able to counteract the fibrotic process and treatments directed against muscle pathologies are severely impaired by the harsh conditions of the fibrotic environment. The design of new therapeutics thus need innovative tools mimicking the obstacles posed by the fibrotic environment to their delivery. This review will critically discuss the role of in vivo and 3D in vitro models in this context and the characteristics that an ideal model should possess to help the translation from bench to bedside of new candidate anti-fibrotic agents.Graphical abstractUnlabelled Image
       
  • MicroRNAs in the pathogenesis and treatment of progressive liver injury in
           NAFLD and liver fibrosis
    • Abstract: Publication date: April 2018Source: Advanced Drug Delivery Reviews, Volume 129Author(s): Qiaozhu Su, Virender Kumar, Neetu Sud, Ram I. Mahato Non-alcoholic fatty liver disease (NAFLD) increases the risk of various liver injuries, ranging from simple steatosis to non-alcoholic steatohepatitis (NASH), fibrosis and cirrhosis, and ultimately hepatocellular carcinoma (HCC). Ample evidence has suggested that aberrant expression of microRNAs (miRNAs) is functionally involved in the activation of cellular stress, inflammation and fibrogenesis in hepatic cells, including hepatocytes, Kupffer and hepatic stellate cells (HSCs), at different pathological stages of NAFLD and liver fibrosis. Here, we overview recent findings on the potential role of miRNAs in the pathogenesis of NAFLD, including lipotoxicity, oxidative stress, metabolic inflammation and fibrogenesis. We critically assess the literatures on both human subjects and animal models of NAFLD and liver fibrosis with miRNA dysregulation and their mechanisms of actions in liver damage. We further highlight the potential use of miRNA mimics or antimiRNAs as therapeutic approaches for the prevention and treatment of NAFLD and liver fibrosis.Graphical abstractUnlabelled Image
       
  • Integrins in wound healing, fibrosis and tumor stroma: High potential
           targets for therapeutics and drug delivery
    • Abstract: Publication date: April 2018Source: Advanced Drug Delivery Reviews, Volume 129Author(s): Jonas Schnittert, Ruchi Bansal, Gert Storm, Jai Prakash Wound healing is a complex process, which ultimately leads to fibrosis if not repaired well. Pathologically very similar to fibrosis is the tumor stroma, found in several solid tumors which are regarded as wounds that do not heal. Integrins are heterodimeric surface receptors which control various physiological cellular functions. Additionally, integrins also sense ECM-induced extracellular changes during pathological events, leading to cellular responses, which influence ECM remodeling. The purpose and scope of this review is to introduce integrins as key targets for therapeutics and drug delivery within the scope of wound healing, fibrosis and the tumor stroma. This review provides a general introduction to the biology of integrins including their types, ligands, means of signaling and interaction with growth factor receptors. Furthermore, we highlight integrins as key targets for therapeutics and drug delivery, based on their biological role, expression pattern within human tissues and at cellular level. Next, therapeutic approaches targeting integrins, with a focus on clinical studies, and targeted drug delivery strategies based on ligands are described.Graphical abstractExisting integrin drug targeting ligands, applied for the modification of drug molecules, drug carriers and CAR-T cells (CAR-T), in the context of wound healing, fibrosis or tumor stroma and their respective integrin targets. Dashed lines show potential integrin targets for existing ligands (PHSCNK, PR_b, RGD, RKK12, quinolonic, echistatin) that have not yet been used for targeting the respective cell line. In addition to already targeted integrins, integrins that have not yet been targeted but play a role in the pathology of wound healing, fibrosis or tumor stroma are presented.Unlabelled Image
       
  • Insights into the key roles of epigenetics in matrix
           macromolecules-associated wound healing
    • Abstract: Publication date: April 2018Source: Advanced Drug Delivery Reviews, Volume 129Author(s): Zoi Piperigkou, Martin Götte, Achilleas D. Theocharis, Nikos K. Karamanos Extracellular matrix (ECM) is a dynamic network of macromolecules, playing a regulatory role in cell functions, tissue regeneration and remodeling. Wound healing is a tissue repair process necessary for the maintenance of the functionality of tissues and organs. This highly orchestrated process is divided into four temporally overlapping phases, including hemostasis, inflammation, proliferation and tissue remodeling. The dynamic interplay between ECM and resident cells exerts its critical role in many aspects of wound healing, including cell proliferation, migration, differentiation, survival, matrix degradation and biosynthesis. Several epigenetic regulatory factors, such as the endogenous non-coding microRNAs (miRNAs), are the drivers of the wound healing response. microRNAs have pivotal roles in regulating ECM composition during wound healing and dermal regeneration. Their expression is associated with the distinct phases of wound healing and they serve as target biomarkers and targets for systematic regulation of wound repair. In this article we critically present the importance of epigenetics with particular emphasis on miRNAs regulating ECM components (i.e. glycoproteins, proteoglycans and matrix proteases) that are key players in wound healing. The clinical relevance of miRNA targeting as well as the delivery strategies designed for clinical applications are also presented and discussed.
       
  • The apparent competitive action of ECM proteases and cross-linking enzymes
           during fibrosis: Applications to drug discovery
    • Abstract: Publication date: April 2018Source: Advanced Drug Delivery Reviews, Volume 129Author(s): Nikolaos A. Afratis, Mordehay Klepfish, Nikos K. Karamanos, Irit Sagi Progressive loss of organ function in most organs is associated with fibrosis, a tissue state associated with abnormal matrix buildup. If highly progressive, the fibrotic process eventually leads to organ failure and death. Fibrosis is a basic connective tissue lesion defined by the increase in the amount of fibrillar extracellular matrix (ECM) components in a tissue or organ. In addition, intrinsic changes in important structural cells can induce the fibrotic response by regulating the differentiation, recruitment, proliferation and activation of extracellular matrix-producing myofibroblasts. ECM enzymes belonging to the family of matrix metalloproteinases (MMPs) and lysyl oxidases (LOXs) play a crucial role in ECM remodeling and regeneration. MMPs have a catalytic role in degradation of ECM, whereas LOX/LOXLs mediate ECM, especially collagen, cross-linking and stiffening. Importantly, enzymes from both families are elevated during the fibrotic response to tissue injury and its resolution. Yet, the apparent molecular competition or antagonistic activities of these enzyme families during the various stages of fibrosis is often overlooked. In this review, we discuss the diverse roles of MMPs and LOX/LOXL2 in chronic organ fibrosis. Finally, we review contemporary therapeutic strategies for fibrosis treatment, based on neutralization of MMP and LOX activity, as well as the development of novel drug delivery approaches.Graphical abstractUnlabelled Image
       
  • Wound healing and scar wars
    • Abstract: Publication date: April 2018Source: Advanced Drug Delivery Reviews, Volume 129Author(s): Eugenia Pugliese, João Q. Coentro, Michael Raghunath, Dimitrios I. Zeugolis
       
  • Scarring vs. functional healing: Matrix-based strategies to regulate
           tissue repair
    • Abstract: Publication date: April 2018Source: Advanced Drug Delivery Reviews, Volume 129Author(s): Timothy J. Keane, Christine-Maria Horejs, Molly M. Stevens All vertebrates possess mechanisms to restore damaged tissues with outcomes ranging from regeneration to scarring. Unfortunately, the mammalian response to tissue injury most often culminates in scar formation. Accounting for nearly 45% of deaths in the developed world, fibrosis is a process that stands diametrically opposed to functional tissue regeneration. Strategies to improve wound healing outcomes therefore require methods to limit fibrosis. Wound healing is guided by precise spatiotemporal deposition and remodelling of the extracellular matrix (ECM). The ECM, comprising the non-cellular component of tissues, is a signalling depot that is differentially regulated in scarring and regenerative healing. This Review focuses on the importance of the native matrix components during mammalian wound healing alongside a comparison to scar-free healing and then presents an overview of matrix-based strategies that attempt to exploit the role of the ECM to improve wound healing outcomes.Graphical abstractUnlabelled Image
       
  • Blood derivatives awaken in regenerative medicine strategies to modulate
           wound healing
    • Abstract: Publication date: April 2018Source: Advanced Drug Delivery Reviews, Volume 129Author(s): Bárbara B. Mendes, Manuel Gómez-Florit, Pedro S. Babo, Rui M. Domingues, Rui L. Reis, Manuela E. Gomes Blood components play key roles in the modulation of the wound healing process and, together with the provisional fibrin matrix ability to selectively bind bioactive molecules and control its spatial-temporal presentation, define the complex microenvironment that characterize this biological process. As a biomimetic approach, the use of blood derivatives in regenerative strategies has awakened as a source of multiple therapeutic biomolecules. Nevertheless, and despite their clinical relevance, blood derivatives have been showing inconsistent therapeutic results due to several factors, including proper control over their delivery mechanisms. Herein, we highlight recent trends on the use biomaterials to protect, sequester and deliver these pools of biomolecules in tissue engineering and regenerative medicine approaches. Particular emphasis is given to strategies that enable to control their spatiotemporal delivery and improve the selectivity of presentation profiles of the biomolecules derived from blood derivatives rich in platelets. Finally, we discussed possible directions for biomaterials design to potentiate the aimed regenerative effects of blood derivatives and achieve efficient therapies.Graphical abstractImage 1
       
  • Rescue plan for Achilles: Therapeutics steering the fate and functions of
           stem cells in tendon wound healing
    • Abstract: Publication date: April 2018Source: Advanced Drug Delivery Reviews, Volume 129Author(s): Magdalena Schneider, Peter Angele, Tero A.H. Järvinen, Denitsa Docheva Due to the increasing age of our society and a rise in engagement of young people in extreme and/or competitive sports, both tendinopathies and tendon ruptures present a clinical and financial challenge. Tendon has limited natural healing capacity and often responds poorly to treatments, hence it requires prolonged rehabilitation in most cases. Till today, none of the therapeutic options has provided successful long-term solutions, meaning that repaired tendons do not recover their complete strength and functionality. Our understanding of tendon biology and healing increases only slowly and the development of new treatment options is insufficient.In this review, following discussion on tendon structure, healing and the clinical relevance of tendon injury, we aim to elucidate the role of stem cells in tendon healing and discuss new possibilities to enhance stem cell treatment of injured tendon. To date, studies mainly apply stem cells, often in combination with scaffolds or growth factors, to surgically created tendon defects. Deeper understanding of how stem cells and vasculature in the healing tendon react to growth factors, common drugs used to treat injured tendons and promising cellular boosters could help to develop new and more efficient ways to manage tendon injuries.Graphical abstractA schematic drawing of the different phases of tendon healing, including tendon appearance, molecular changes, growth factors involved and the time course. Tendon healing can be subdivided into three different stages: the inflammation phase, the reparation phase and the remodeling phase. Various growth factors are involved in the healing phases in a distinct time-specific pattern. They tightly regulate cell migration, proliferation and ECM production and organization.Image 1
       
  • Lumican as a multivalent effector in wound healing
    • Abstract: Publication date: April 2018Source: Advanced Drug Delivery Reviews, Volume 129Author(s): Konstantina Karamanou, Gwenn Perrot, Francois-Xavier Maquart, Stéphane Brézillon Wound healing, a complex physiological process, is responsible for tissue repair after exposure to destructive stimuli, without resulting in complete functional regeneration. Injuries can be stromal or epithelial, and most cases of wound repair have been studied in the skin and cornea. Lumican, a small leucine-rich proteoglycan, is expressed in the extracellular matrices of several tissues, such as the cornea, cartilage, and skin. This molecule has been shown to regulate collagen fibrillogenesis, keratinocyte phenotypes, and corneal transparency modulation. Lumican is also involved in the extravasation of inflammatory cells and angiogenesis, which are both critical in stromal wound healing. Lumican is the only member of the small leucine-rich proteoglycan family expressed by the epithelia during wound healing.This review summarizes the importance of lumican in wound healing and potential methods of lumican drug delivery to target wound repair are discussed. The involvement of lumican in corneal wound healing is described based on in vitro and in vivo models, with critical emphasis on its underlying mechanisms of action. Similarly, the expression and role of lumican in the healing of other tissues are presented, with emphasis on skin wound healing.Overall, lumican promotes normal wound repair and broadens new therapeutic perspectives for impaired wound healing.Graphical abstractUnlabelled Image
       
  • Functional therapies for cutaneous wound repair in epidermolysis bullosa
    • Abstract: Publication date: April 2018Source: Advanced Drug Delivery Reviews, Volume 129Author(s): Patricia Peking, Ulrich Koller, Eva M. Murauer Chronic wounding as a result of recurrent skin blistering in the painful genetic skin disease epidermolysis bullosa, may lead to life-threatening infections, increased risk of tumor formation, and other serious medical complications. Therefore, epidermolysis bullosa patients have an urgent need for optimal wound care and tissue regeneration. Therapeutic strategies using gene-, protein-, and cell-therapies are being developed to improve clinical symptoms, and some of them have already been investigated in early clinical trials. The most favorable options of functional therapies include gene replacement, gene editing, RNA targeting, and harnessing natural gene therapy. This review describes the current progress of the different approaches targeting autologous skin cells, and will discuss the benefits and challenges of their application.Graphical abstractImage 1
       
  • Drug delivery and tissue engineering to promote wound healing in the
           immunocompromised host: Current challenges and future directions
    • Abstract: Publication date: April 2018Source: Advanced Drug Delivery Reviews, Volume 129Author(s): Alexander M. Tatara, Dimitrios P. Kontoyiannis, Antonios G. Mikos As regenerative medicine matures as a field, more promising technologies are being translated from the benchtop to the clinic. However, many of these strategies are designed with otherwise healthy hosts in mind and validated in animal models without other co-morbidities. In reality, many of the patient populations benefiting from drug delivery and tissue engineering-based devices to enhance wound healing also have significant underlying immunodeficiency. Specifically, patients suffering from diabetes, malignancy, human immunodeficiency virus, post-organ transplantation, and other compromised states have significant pleotropic immune defects that affect wound healing. In this work, we review the role of different immune cells in the regenerative process, highlight the effect of several common immunocompromised states on wound healing, and discuss different drug delivery strategies for overcoming immunodeficiencies.Graphical abstractImage 1
       
  • miRNA delivery for skin wound healing
    • Abstract: Publication date: April 2018Source: Advanced Drug Delivery Reviews, Volume 129Author(s): Zhao Meng, Dezhong Zhou, Yongsheng Gao, Ming Zeng, Wenxin Wang The wound healing has remained a worldwide challenge as one of significant public health problems. Pathological scars and chronic wounds caused by injury, aging or diabetes lead to impaired tissue repair and regeneration. Due to the unique biological wound environment, the wound healing is a highly complicated process, efficient and targeted treatments are still lacking. Hence, research-driven to discover more efficient therapeutics is a highly urgent demand. Recently, the research results have revealed that microRNA (miRNA) is a promising tool in therapeutic and diagnostic fields because miRNA is an essential regulator in cellular physiology and pathology. Therefore, new technologies for wound healing based on miRNA have been developed and miRNA delivery has become a significant research topic in the field of gene delivery.Graphical abstractImage 1
       
  • Targeting renal fibrosis: Mechanisms and drug delivery systems
    • Abstract: Publication date: April 2018Source: Advanced Drug Delivery Reviews, Volume 129Author(s): Madalina V. Nastase, Jinyang Zeng-Brouwers, Malgorzata Wygrecka, Liliana Schaefer Renal fibrosis is the common outcome of many chronic kidney diseases (CKD) independent of the underlying etiology. Despite a host of promising experimental data, currently available strategies only ameliorate or delay the progression of CKD but do not reverse fibrosis. One of the major impediments of translating novel antifibrotic strategies from bench to bedside is due to the intricacies of the drug delivery process. In this review, we briefly describe mechanisms of renal fibrosis and methods of drug transfer into the kidney. Various tools used in gene therapy to administer nucleic acids in vivo are discussed. Furthermore, we review the modes of action of protein- or peptide-based drugs with target-specific antibodies and cytokines incorporated in hydrogels. Additionally, we assess an intriguing new method to deliver drugs specifically to tubular epithelial cells via conjugation with ligands binding to the megalin receptor. Finally, plant-derived compounds with antifibrotic properties are also summarized.Graphical abstractImage 1
       
  • Delivery of cellular factors to regulate bone healing
    • Abstract: Publication date: April 2018Source: Advanced Drug Delivery Reviews, Volume 129Author(s): Alexander Haumer, Paul Emile Bourgine, Paola Occhetta, Gordian Born, Roberta Tasso, Ivan Martin Bone tissue has a strong intrinsic regenerative capacity, thanks to a delicate and complex interplay of cellular and molecular processes, which tightly involve the immune system. Pathological settings of anatomical, biomechanical or inflammatory nature may lead to impaired bone healing. Innovative strategies to enhance bone repair, including the delivery of osteoprogenitor cells or of potent cytokines/morphogens, indicate the potential of ‘orthobiologics’, but are not fully satisfactory. Here, we review different approaches based on the delivery of regenerative cues produced by cells but in cell-free, possibly off-the-shelf configurations. Such strategies exploit the paracrine effect of the secretome of mesenchymal stem/stromal cells, presented in soluble form, shuttled through extracellular vesicles, or embedded within the network of extracellular matrix molecules. In addition to osteoinductive molecules, attention is given to factors targeting the resident immune cells, to reshape inflammatory and immunity processes from scarring to regenerative patterns.Graphical abstractUnlabelled Image
       
  • Nanomedicines and gene therapy for the delivery of growth factors to
           improve perfusion and oxygenation in wound healing
    • Abstract: Publication date: April 2018Source: Advanced Drug Delivery Reviews, Volume 129Author(s): Céline M. Desmet, Véronique Préat, Bernard Gallez Oxygen plays a key role in wound healing, and hypoxia is a major cause of wound healing impairment; therefore, treatments to improve hemodynamics and increase wound oxygenation are of particular interest for the treatment of chronic wounds. This article describes the roles of oxygen and angiogenesis in wound healing as well as the tools used to evaluate tissue oxygenation and perfusion and then presents a review of nanomedicines and gene therapies designed to improve perfusion and oxygenation and accelerate wound healing.Graphical abstractUnlabelled Image
       
  • Drug delivery and epimorphic salamander-type mouse regeneration: A full
           parts and labor plan
    • Abstract: Publication date: April 2018Source: Advanced Drug Delivery Reviews, Volume 129Author(s): Ellen Heber-Katz, Phillip Messersmith The capacity to regenerate entire body parts, tissues, and organs had generally been thought to be lost in evolution with very few exceptions (e.g. the liver) surviving in mammals. The discovery of the MRL mouse and the elucidation of the underlying molecular pathway centering around hypoxia inducible factor, HIF-1α, has allowed a drug and materials approach to regeneration in mice and hopefully humans. The HIF-1α pathway is ancient and permitted the transition from unicellular to multicellular organisms. Furthermore, HIF-1α and its regulation by PHDs, important oxygen sensors in the cell, provides a perfect drug target. We review the historical background of regeneration biology, the discovery of the MRL mouse, and its underlying biology, and novel approaches to drugs, targets, and delivery systems (see Fig. 1).Graphical abstractUnlabelled Image
       
  • Wound healing related agents: Ongoing research and perspectives
    • Abstract: Publication date: April 2018Source: Advanced Drug Delivery Reviews, Volume 129Author(s): Konstantina Kaplani, Stamatina Koutsi, Vasileios Armenis, Foteini G. Skondra, Nickolas Karantzelis, Spyridon Champeris Tsaniras, Stavros Taraviras Wound healing response plays a central part in chronic inflammation, affecting millions of people worldwide. It is a dynamic process that can lead to fibrosis, if tissue damage is irreversible and wound resolution is not attained. It is clear that there is a tight interconnection among wound healing, fibrosis and a variety of chronic disease conditions, demonstrating the heterogeneity of this pathology. Based on our further understanding of the cellular and molecular mechanisms underpinning tissue repair, new therapeutic approaches have recently been developed that target different aspects of the wound healing process and fibrosis. Nevertheless, several issues still need to be taken into consideration when designing modern wound healing drug delivery formulations. In this review, we highlight novel pharmacological agents that hold promise for targeting wound repair and fibrosis. We also focus on drug-delivery systems that may enhance current and future therapies.Graphical abstractUnlabelled Image
       
  • Delivery systems of current biologicals for the treatment of chronic
           cutaneous wounds and severe burns
    • Abstract: Publication date: April 2018Source: Advanced Drug Delivery Reviews, Volume 129Author(s): Meilang Xue, Ruilong Zhao, Haiyan Lin, Christopher Jackson While wound therapy remains a clinical challenge in current medical practice, much effort has focused on developing biological therapeutic approaches. This paper presents a comprehensive review of delivery systems for current biologicals for the treatment of chronic wounds and severe burns. The biologicals discussed here include proteins such as growth factors and gene modifying molecules, which may be delivered to wounds free, encapsulated, or released from living systems (cells, skin grafts or skin equivalents) or biomaterials. Advances in biomaterial science and technologies have enabled the synthesis of delivery systems such as scaffolds, hydrogels and nanoparticles, designed to not only allow spatially and temporally controlled release of biologicals, but to also emulate the natural extracellular matrix microenvironment. These technologies represent an attractive field for regenerative wound therapy, by offering more personalised and effective treatments.Graphical abstractTo promote wound repair, strategies consisting of the administration of purified biologicals such as cytokines, growth factors and DNA/RNA; the delivery of biologicals from living systems, such as cells (cultured keratinocytes, stem cells), skin grafts or skin equivalents; or the combined delivery of purified biologicals and biologicals from living systems have been used. Purified biologicals can be applied systemically or locally by topical application or injections, which result in an uncontrolled burst release; they can also be encapsulated into predesigned biomaterial-based delivery systems such as scaffolds or hydrogels that better mimic the native ECM, then delivered to the wound area, which results in a gradient spatial release. In the future, use of biomimetic scaffolds/hydrogels incorporated with critical stem cell populations and growth factors or DNA/RNA released in a programmed spatiotemporal manner, taking into account genetic variability, wound type, and the patient's clinical and metabolic features, will offer more personalised and thus more effective therapies. Perhaps this will ultimately allow us to achieve foetal wound healing properties in adult wound healing, with complete regeneration of hair follicles and sweat glands, without chronicity or scarring.Unlabelled Image
       
  • Nanopharmaceuticals for wound healing – Lost in translation'
    • Abstract: Publication date: April 2018Source: Advanced Drug Delivery Reviews, Volume 129Author(s): Mukul Ashtikar, Matthias G. Wacker Today, many of the newly developed pharmaceuticals and medical devices take advantage of nanotechnology and with a rising incidence of chronic diseases such as diabetes and cardiovascular disease, the number of patients afflicted globally with non-healing wounds is growing. This has created a requirement for improved therapies and wound care. However, converting the strategies applied in early research into new products is still challenging. Many of them fail to comply with the market requirements. This review discusses the legal and scientific challenges in the design of nanomedicines for wound healing. Are they lost in translation or is there a new generation of therapeutics in the pipeline?Graphical abstractUnlabelled Image
       
  • Responsive triggering systems for delivery in chronic wound healing
    • Abstract: Publication date: April 2018Source: Advanced Drug Delivery Reviews, Volume 129Author(s): Mangesh Morey, Abhay Pandit Non-communicable diseases including cancer, cardiovascular disease, diabetes, and neuropathy are chronic in nature. Treatment of these diseases with traditional delivery systems is limited due to lack of site-specificity, non-spatiotemporal release and insufficient doses. Numerous responsive delivery systems which respond to both physiological and external stimuli have been reported in the literature. However, effective strategies incorporating a multifactorial approach are required to control these complex wounds. This can be achieved by fabricating spatiotemporal release systems, multimodal systems or dual/multi-stimuli responsive delivery systems loaded with one or more bioactive components. Critically, these next generation stimuli responsive delivery systems that are at present not feasible are required to treat chronic wounds. This review provides a critical assessment of recent developments in the field of responsive delivery systems, highlighting their limitations and providing a perspective on how these challenges can be overcome.Graphical abstractUnlabelled Image
       
  • Electroactive biomaterials: Vehicles for controlled delivery of
           therapeutic agents for drug delivery and tissue regeneration
    • Abstract: Publication date: April 2018Source: Advanced Drug Delivery Reviews, Volume 129Author(s): Biranche Tandon, Adrián Magaz, Richard Balint, Jonny J. Blaker, Sarah H. Cartmell Electrical stimulation for delivery of biochemical agents such as genes, proteins and RNA molecules amongst others, holds great potential for controlled therapeutic delivery and in promoting tissue regeneration. Electroactive biomaterials have the capability of delivering these agents in a localized, controlled, responsive and efficient manner. These systems have also been combined for the delivery of both physical and biochemical cues and can be programmed to achieve enhanced effects on healing by establishing control over the microenvironment. This review focuses on current state-of-the-art research in electroactive-based materials towards the delivery of drugs and other therapeutic signalling agents for wound care treatment. Future directions and current challenges for developing effective electroactive approach based therapies for wound care are discussed.Graphical abstractImage 1
       
  • Fibrin-based delivery strategies for acute and chronic wound healing
    • Abstract: Publication date: April 2018Source: Advanced Drug Delivery Reviews, Volume 129Author(s): P. Heher, S. Mühleder, R. Mittermayr, H. Redl, P. Slezak Fibrin, a natural hydrogel, is the end product of the physiological blood coagulation cascade and naturally involved in wound healing. Beyond its role in hemostasis, it acts as a local reservoir for growth factors and as a provisional matrix for invading cells that drive the regenerative process. Its unique intrinsic features do not only promote wound healing directly via modulation of cell behavior but it can also be fine-tuned to evolve into a delivery system for sustained release of therapeutic biomolecules, cells and gene vectors. To further augment tissue regeneration potential, current strategies exploit and modify the chemical and physical characteristics of fibrin to employ combined incorporation of several factors and their timed release. In this work we show advanced therapeutic approaches employing fibrin matrices in wound healing and cover the many possibilities fibrin offers to the field of regenerative medicine.Graphical abstractImage 1
       
  • Bioactive scaffolds based on elastin-like materials for wound healing
    • Abstract: Publication date: April 2018Source: Advanced Drug Delivery Reviews, Volume 129Author(s): J. Carlos Rodríguez-Cabello, I. González de Torre, A. Ibañez-Fonseca, M. Alonso Wound healing is a complex process that, in healthy tissues, starts immediately after the injury. Even though it is a natural well-orchestrated process, large trauma wounds, or injuries caused by acids or other chemicals, usually produce a non-elastic deformed tissue that not only have biological reduced properties but a clear aesthetic effect. One of the main drawbacks of the scaffolds used for wound dressing is the lack of elasticity, driving to non-elastic and contracted tissues. In the last decades, elastin based materials have gained in importance as biomaterials for tissue engineering applications due to their good cyto- and bio-compatibility, their ease handling and design, production and modification. Synthetic elastin or elastin like-peptides (ELPs) are the two main families of biomaterials that try to mimic the outstanding properties of natural elastin, elasticity amongst others; although there are no in vivo studies that clearly support that these two families of elastin based materials improve the elasticity of the artificial scaffolds and of the regenerated skin. Within the next pages a review of the different forms (coacervates, fibres, hydrogels and biofunctionalized surfaces) in which these two families of biomaterials can be processed to be applied in the wound healing field have been done. Here, we explore the mechanical and biological properties of these scaffolds as well as the different in vivo approaches in which these scaffolds have been used.Graphical abstractUnlabelled Image
       
  • Instructive microenvironments in skin wound healing: Biomaterials as
           signal releasing platforms
    • Abstract: Publication date: April 2018Source: Advanced Drug Delivery Reviews, Volume 129Author(s): Oscar Castaño, Soledad Pérez-Amodio, Claudia Navarro-Requena, Miguel Ángel Mateos-Timoneda, Elisabeth Engel Skin wound healing aims to repair and restore tissue through a multistage process that involves different cells and signalling molecules that regulate the cellular response and the dynamic remodelling of the extracellular matrix. Nowadays, several therapies that combine biomolecule signals (growth factors and cytokines) and cells are being proposed. However, a lack of reliable evidence of their efficacy, together with associated issues such as high costs, a lack of standardization, no scalable processes, and storage and regulatory issues, are hampering their application. In situ tissue regeneration appears to be a feasible strategy that uses the body's own capacity for regeneration by mobilizing host endogenous stem cells or tissue-specific progenitor cells to the wound site to promote repair and regeneration. The aim is to engineer instructive systems to regulate the spatio-temporal delivery of proper signalling based on the biological mechanisms of the different events that occur in the host microenvironment. This review describes the current state of the different signal cues used in wound healing and skin regeneration, and their combination with biomaterial supports to create instructive microenvironments for wound healing.Graphical abstractUnlabelled Image
       
  • Extracellular vesicles as modulators of wound healing
    • Abstract: Publication date: April 2018Source: Advanced Drug Delivery Reviews, Volume 129Author(s): Joana Cabral, Aideen E. Ryan, Matthew D. Griffin, Thomas Ritter Impaired healing of cutaneous wounds and ulcers continues to have a major impact on the quality of life of millions of people. In recent years, the capacity for stem and progenitor cells to promote wound repair has been investigated with evidence that secreted factors are responsible for the observed therapeutic benefits. This review addresses current evidence in support of stem/progenitor cell-derived extracellular vesicles (EVs) as a regenerative therapy for acceleration of wound healing. Encouraging results for local or systemic administration of EVs have been reported in a range of clinically-relevant animal models of cutaneous wounds. Furthermore, a number of plausible mechanisms involving EV-mediated transfer of proteins and RNAs that trigger pro-repair pathways in target cells have been demonstrated experimentally. However, for successful clinical translation in the coming years, further emphasis on standardized experimental protocols, detailed methodological reporting and clear definition of EV-based therapeutic products will be required.Graphical abstractUnlabelled Image
       
  • Drug delivery devices for retinal diseases
    • Abstract: Publication date: 15 March 2018Source: Advanced Drug Delivery Reviews, Volume 128Author(s): Hirokazu Kaji, Nobuhiro Nagai, Matsuhiko Nishizawa, Toshiaki Abe Retinal degenerative diseases are a leading cause of irreversible blindness and visual impairment, affecting millions of people worldwide. Although intravitreal injection can directly deliver drugs to the posterior segment of the eye, it is invasive and associated with serious side effects. The design of drug delivery systems targeting the posterior segment of the eye in a less invasive manner has still been challenging because of various anatomical and physiological barriers. In this review, we provide an overview of the current implant device-based approaches used for treating retinal degenerative diseases. We then offer our perspectives on future directions and challenges that remain for developing more effective device-based therapies for retinal diseases.Graphical abstractImage 1
       
  • Recent advances of controlled drug delivery using microfluidic platforms
    • Abstract: Publication date: 15 March 2018Source: Advanced Drug Delivery Reviews, Volume 128Author(s): Sharma T. Sanjay, Wan Zhou, Maowei Dou, Hamed Tavakoli, Lei Ma, Feng Xu, XiuJun Li Conventional systematically-administered drugs distribute evenly throughout the body, get degraded and excreted rapidly while crossing many biological barriers, leaving minimum amounts of the drugs at pathological sites. Controlled drug delivery aims to deliver drugs to the target sites at desired rates and time, thus enhancing the drug efficacy, pharmacokinetics, and bioavailability while maintaining minimal side effects. Due to a number of unique advantages of the recent microfluidic lab-on-a-chip technology, microfluidic lab-on-a-chip has provided unprecedented opportunities for controlled drug delivery. Drugs can be efficiently delivered to the target sites at desired rates in a well-controlled manner by microfluidic platforms via integration, implantation, localization, automation, and precise control of various microdevice parameters. These features accordingly make reproducible, on-demand, and tunable drug delivery become feasible. On-demand self-tuning dynamic drug delivery systems have shown great potential for personalized drug delivery. This review presents an overview of recent advances in controlled drug delivery using microfluidic platforms. The review first briefly introduces microfabrication techniques of microfluidic platforms, followed by detailed descriptions of numerous microfluidic drug delivery systems that have significantly advanced the field of controlled drug delivery. Those microfluidic systems can be separated into four major categories, namely drug carrier-free micro-reservoir-based drug delivery systems, highly integrated carrier-free microfluidic lab-on-a-chip systems, drug carrier-integrated microfluidic systems, and microneedles. Microneedles can be further categorized into five different types, i.e. solid, porous, hollow, coated, and biodegradable microneedles, for controlled transdermal drug delivery. At the end, we discuss current limitations and future prospects of microfluidic platforms for controlled drug delivery.Graphical abstractThis article reviews recent advances of controlled drug delivery using microfluidic platforms which can be implanted in human bodies to control drug release in real time through an on-demand feedback mechanism.Image 1
       
  • Microfluidics in nanoparticle drug delivery; From synthesis to
           pre-clinical screening
    • Abstract: Publication date: 15 March 2018Source: Advanced Drug Delivery Reviews, Volume 128Author(s): Jungho Ahn, Jihoon Ko, Somin Lee, James Yu, YongTae Kim, Noo Li Jeon Microfluidic technologies employ nano and microscale fabrication techniques to develop highly controllable and reproducible fluidic microenvironments. Utilizing microfluidics, lead compounds can be produced with the controlled physicochemical properties, characterized in a high-throughput fashion, and evaluated in in vitro biomimetic models of human organs; organ-on-a-chip. As a step forward from conventional in vitro culture methods, microfluidics shows promise in effective preclinical testing of nanoparticle-based drug delivery. This review presents a curated selection of state-of-the-art microfluidic platforms focusing on the fabrication, characterization, and assessment of nanoparticles for drug delivery applications. We also discuss the current challenges and future prospects of nanoparticle drug delivery development using microfluidics.Graphical abstractUnlabelled Image
       
  • Current developments and applications of microfluidic technology toward
           clinical translation of nanomedicines
    • Abstract: Publication date: 15 March 2018Source: Advanced Drug Delivery Reviews, Volume 128Author(s): Dongfei Liu, Hongbo Zhang, Flavia Fontana, Jouni T. Hirvonen, Hélder A. Santos Nanoparticulate drug delivery systems hold great potential for the therapy of many diseases, especially cancer. However, the translation of nanoparticulate drug delivery systems from academic research to industrial and clinical practice has been slow. This slow translation can be ascribed to the high batch-to-batch variations and insufficient production rate of the conventional preparation methods, and the lack of technologies for rapid screening of nanoparticulate drug delivery systems with high correlation to the in vivo tests. These issues can be addressed by the microfluidic technologies. For example, microfluidics can not only produce nanoparticles in a well-controlled, reproducible, and high-throughput manner, but also create 3D environments with continuous flow to mimic the physiological and/or pathological processes. This review provides an overview of the microfluidic devices developed to prepare nanoparticulate drug delivery systems, including drug nanosuspensions, polymer nanoparticles, polyplexes, structured nanoparticles and theranostic nanoparticles. We also highlight the recent advances of microfluidic systems in fabricating the increasingly realistic models of the in vivo milieu for rapid screening of nanoparticles. Overall, the microfluidic technologies offer a promise approach to accelerate the clinical translation of nanoparticulate drug delivery systems.Graphical abstractImage 1
       
  • Advances in microfluidics for lipid nanoparticles and extracellular
           vesicles and applications in drug delivery systems
    • Abstract: Publication date: 15 March 2018Source: Advanced Drug Delivery Reviews, Volume 128Author(s): Masatoshi Maeki, Niko Kimura, Yusuke Sato, Hideyoshi Harashima, Manabu Tokeshi Lipid-based nanobiomaterials as liposomes and lipid nanoparticles (LNPs) are the most widely used nanocarriers for drug delivery systems (DDSs). Extracellular vesicles (EVs) and exosomes are also expected to be applied as DDS nanocarriers. The performance of nanomedicines relies on their components such as lipids, targeting ligands, encapsulated DNA, encapsulated RNA, and drugs. Recently, the importance of the nanocarrier sizes smaller than 100 nm is attracting attention as a means to improve nanomedicine performance. Microfluidics and lab-on-a chip technologies make it possible to produce size-controlled LNPs by a simple continuous flow process and to separate EVs from blood samples by using a surface marker, ligand, or electric charge or by making a mass or particle size discrimination. Here, we overview recent advances in microfluidic devices and techniques for liposomes, LNPs, and EVs and their applications for DDSs.Graphical abstractUnlabelled Image
       
  • Microfluidics for producing poly (lactic-co-glycolic acid)-based
           pharmaceutical nanoparticles
    • Abstract: Publication date: 15 March 2018Source: Advanced Drug Delivery Reviews, Volume 128Author(s): Xuanyu Li, Xingyu Jiang Microfluidic chips allow the rapid production of a library of nanoparticles (NPs) with distinct properties by changing the precursors and the flow rates, significantly decreasing the time for screening optimal formulation as carriers for drug delivery compared to conventional methods. The batch-to-batch reproducibility which is essential for clinical translation is achieved by precisely controlling the precursors and the flow rate, regardless of operators. Poly (lactic-co-glycolic acid) (PLGA) is the most widely used Food and Drug Administration (FDA)-approved biodegradable polymers. Researchers often combine PLGA with lipids or amphiphilic molecules to assemble into a core/shell structure to exploit the potential of PLGA-based NPs as powerful carriers for cancer-related drug delivery. In this review, we discuss the advantages associated with microfluidic chips for producing PLGA-based functional nanocomplexes for drug delivery. These laboratory-based methods can readily scale up to provide sufficient amount of PLGA-based NPs in microfluidic chips for clinical studies and industrial-scale production.Graphical abstractImage 1
       
 
 
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