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Progress in gene therapy has produced promising results that translate experimental research into clinical treatment. Gene modification has been extensively employed in cell transplantation. The main barrier is an effective gene delivery system. Several viral vectors were utilized in end-stage differentiated cells. Recently, successful applications were described with adenovirus-associated vectors. As an alternative, embryonic stem cell- and stem cell-like systems were established for generation of tissue-specified gene-modified cells. Owing to the feasibility for genetic manipulations and the self-renewing potency of these cells they can be used in a way enabling large-scale in vitro production. This approach offers the establishment of in vitro cell culture systems that will deliver sufficient amounts of highly purified, immunoautologous cells suitable for application in regenerative medicine. In this review, the current technology of gene delivery systems to cells is recapitulated and the latest developments for cell transplantation are discussed.
Yi Laia Irina Drobinskayab Eugen Kolossovc Chunguang Chend Thomas LinndEmail:Thomas.linn@innere.med.uni-giessen.de
[a]Department of Molecular Microbiology & Immunology, University of Missouri-Columbia, USA;[b]Institute for Neurophysiology, University of Cologne, Germany;[c]Axiogenesis AG, Cologne, Germany;[d]Medical Clinic and Policlinic 3, Justus Liebig University, Rodthohl 6, 35392 Giessen, Germany
Protection of transplanted cells from the host immune system using immunoisolation technology will be important in realizing the full potential of cell-based therapeutics. Microencapsulation of cells and cell aggregates has been the most widely explored immunoisolation strategy, but widespread clinical application of this technology has been limited, in part, by inadequate transport of nutrients, deleterious innate inflammatory responses, and immune recognition of encapsulated cells via indirect antigen presentation pathways. To reduce mass transport limitations and decrease void volume, recent efforts have focused on developing conformal coatings of micron and submicron scale on individual cells or cell aggregates. Additionally, anti-inflammatory and immunomodulatory capabilities are being integrated into immunoisolation devices to generate bioactive barriers that locally modulate host responses to encapsulated cells. Continued exploration of emerging paradigms governed by the inherent challenges associated with immunoisolation will be critical to actualizing the clinical potential of cell-based therapeutics.
John T. Wilsona Elliot L. ChaikofaEmail:echaiko@emory.edu
[a]Departments of Surgery and Biomedical Engineering, Emory University School of Medicine and the Georgia Institute of Technology, Atlanta, GA 30332, USA
Beta-cell replacement is considered the optimal treatment for type 1 diabetes, however, it is hindered by a shortage of human organ donors. Given the difficulty of expanding adult beta cells in vitro, stem/progenitor cells, which can be expanded in tissue culture and induced to differentiate into multiple cell types, represent an attractive source for generation of cells with beta-cell properties. In the absence of well-characterized human pancreas progenitor cells, investigators are exploring the use of embryonic stem cells and stem/progenitor cells from other tissues. Once abundant surrogate beta cells are available, the challenge will be to protect them from recurring autoimmunity.
Shimon EfrataEmail:sefrat@post.tau.ac.il
[a]Department of Human Molecular Genetics and Biochemistry, Sackler School of Medicine, Tel Aviv University, Ramat Aviv, Tel Aviv, 69978
In recent years, considerable attention has been given to immune tolerance and its potential clinical applications for the treatment of cancers and autoimmune diseases, and the prevention of allo-graft rejection and graft-versus-host diseases. Advances in our understanding of the underlying mechanisms of establishment and maintenance of immune tolerance in various experimental settings and animal models, and in our ability to manipulate the development of various immune tolerogenic cells in vitro and in vivo, have generated significant momentum for the field of cell-based tolerogenic therapy. This review briefly summarizes the major tolerogenic cell populations and their mechanisms of action, while focusing mainly on potential exploitation of their tolerogenic mechanisms for clinical applications.
Ping-Ying PanaEmail:ping-ying.pan@mssm.edu Junko Ozaoa Zuping Zhoua Shu-Hsia ChenaEmail:shu-hsia.chen@mssm.edu
[a]Department of Gene and Cell Medicine, Box 1946, Mount Sinai School of Medicine, One Gustave L. Levy Place, New York, NY, 10029, USA
In order to improve the dissolution properties of poorly water-soluble drugs, some drugs were subjected to micronization or prepared as composite particles using supercritical fluid (SCF) technology with carbon dioxide (CO2). Solubility in CO2 is the key when using this method. Solubility affects the supersaturation of the materials in the solvent as well as the mass transfer of that solvent, which are both critical to the micronization of the materials and the formation of the composite particles. Some useful techniques that can be used to avoid the problems posed by the characteristics of the drug itself are combining SC-CO2 with other technologies, such as the formation of coacervates or emulsions, and other equipment types, such as milling or ultrasound fields. Another advantage of SCF technology is that it is considered to be green chemistry. SC-CO2 can improve the solubility of poorly water-soluble drug substances using few or no organic solvents and with little or no heating.
Takehiko Yasujia Hirofumi TakeuchibEmail:takeuchi@gifu-pu.ac.jp Yoshiaki Kawashimac
[a]Pharmaceutical Research and Technology Labs, Astellas Pharma Inc., 180 Ozumi, Yaizu, Shizuoka 425-0072, Japan;[b]Pharmaceutical Engineering, Department of Manufacturing Pharmacy, Gifu Pharmaceutical University, 5-6-1, Mitahora-higashi, Gifu, Gifu 502-8585, Japan;[c]Pharmaceutical Engineering, School of Pharmaceutical science, Aichi Gukuin University, 1-100 Kusumoto, Chikusaku, Nagoya, Aichi 464-8650, Japan
The application of supercritical carbon dioxide to particle design has recently emerged as a promising way to produce powders of macromolecules such as proteins and genes. Recently, an insulin powder for inhalation was approved by authorities in Europe and the USA. Other macromolecules for inhalation therapy will follow. In the 1990s proteins were precipitated with supercritical CO2 from solutions in an organic solvent such as dimethylsulfoxide, which caused significant unfolding of protein. Since 2000, aqueous solutions of proteins and genes have generally been used with a cosolvent such as ethanol to precipitate in CO2. Operating conditions such as temperature, pressure, flow rates, and concentration of ingredients affect the particle size and integrity of proteins or genes. By optimizing these conditions, the precipitation of proteins and genes with supercritical CO2 is a promising way to produce protein and gene particles for inhalation.
Hirokazu OkamotoaEmail:okamotoh@ccmfs.meijo-u.ac.jp Kazumi Danjoa
[a]Faculty of Pharmacy, Meijo University, 150 Yagotoyama, Tempaku-ku, Nagoya 468-8503, Japan
Supercritical CO2 has the potential to be an excellent environment within which controlled release polymers and dry composites may be formed. The low temperature and dry conditions within the fluid offer obvious advantages in the processing of water, solvent or heat labile molecules. The low viscosity and high diffusivity of scCO2 offer the possibility of novel processing routes for polymer drug composites, but there are still technical challenges to overcome. Moreover, the low solubility of most drug molecules in scCO2 presents both challenges and advantages. This review explores the current methods that use high pressure and scCO2 for the production of drug delivery systems and the more specialized application of the fluid in the formation of highly porous tissue engineering scaffolds.
Owen R. Daviesa Andrew L. Lewisa Martin J. Whitakera Hongyun Taib Kevin M. Shakesheffb Steven M. HowdleaEmail:steve.howdle@nottingham.ac.uk
[a]Critical Pharmaceuticals Ltd BioCity Pennyfoot St., Nottingham, NG1 1GF, United Kingdom;[b]School of Pharmacy, University of Nottingham, University Park, Nottingham, NG7 2RD, United Kingdom;[c]School of Chemistry, University of Nottingham, University Park, Nottingham, NG7 2RD, United Kingdom
Supercritical fluids have been applied for many years for the separation of solutes from solids or solute mixtures in both exploratory and industrial applications. In the pharmaceutical industry the generation of pure solid states without impurities is important as the presence of impurities can result in a change in chemical properties or lead to physical instability. The literature on the separation and purification of solutes from solid matrices and solute mixtures using supercritical fluids, with the main emphasis on pharmaceutically important molecules, is reviewed in this article. Also discussed is the application of supercritical fluids in the control of process impurities such as chemical intermediates and residual solvent and in polymorphic control and chiral resolution.As the generation of organic molecules of pharmaceutical interest with high purity is important in pharmaceuticals this review additionally provides a brief overview of highly selective chemical reactions in supercritical fluids.
L.S. DaintreeaEmail:L.Daintree@leeds.ac.uk A. Kordikowskib P. Yorkc
[a]ParticlesCIC, University of Leeds, Houldsworth Building, Leeds LS2 9JT, United Kingdom;[b]Activery Biotech SL, Edificio MATGAS, Campus de la Universitat Autónoma de Barcelona, 08193 Cerdanyola del Vallès, Barcelona, Spain;[c]Institute of Pharmaceutical Innovation, University of Bradford, Bradford BD7 1DP, United Kingdom
Supercritical fluid techniques for materials precipitation have been proposed as an alternative to conventional precipitation processes as they allow to improve the performance of these processes in terms of reduction of particle size and control of morphology and particle size distribution, without degradation or contamination of the product. These techniques have received much attention during the last years, and their feasibility and performance have been experimentally demonstrated for many substances. One of the main pending tasks is the development of a systematic procedure for the design and scale-up of these processes. This requires not only empirical knowledge, but also information about the fundamentals of the process. This work aims to review the published literature dealing with a fundamental investigation or modeling of supercritical fluid precipitation processes.
A. Martína M.J. CoceroaEmail:mjcocero@iq.uva.es
[a]Departamento de Ingeniería Química y Tecnología del Medio Ambiente, Facultad de Ciencias, Universidad de Valladolid, 47011 Valladolid, Spain
Supercritical fluid technique have been exploited in extraction, separation and crystallization processes. In the field of pharmaceutics, supercritical carbon dioxide (scCO2) has been used for the purpose of micronization, polymorphic control, and preparation of solid dispersion and complexes. Particle design of active pharmaceutical ingredients is important to make the solid dosage forms with suitable physicochemical properties. Control of the characteristic properties of particles, such as size, shape, crystal structure and morphology is required to optimize the formulation. For solubility enhancement of poorly water-soluble drugs, preparation of the solid dispersion or the complexation with proper drugs or excipients should be a promising approach. This review focuses on aspects of polymorphic control and complexation behavior of active pharmaceutical ingredients by scCO2 processing.
Kunikazu Moribea Yuichi Tozukab Keiji YamamotoaEmail:yamamotk@p.chiba-u.ac.jp
[a]Graduate School of Pharmaceutical Sciences, Chiba University, 1-33 Yayoi-cho, Inage-ku, Chiba 263-8522, Japan;[b]Department of Pharmaceutical Engineering, Gifu Pharmaceutical University, 5-6-1 Mitahora-Higashi, Gifu 502-8585, Japan