Check out our New Publishers' Select for Free Articles

Advanced Drug Delivery Reviews (v.60, #2)

Editorial Board (pp. ii).

Emerging trends in cell-based therapies by Zhaoyang Ye (Theme Editor); Ram I. Mahato Theme editor (pp. 89-90).

Advancements in immune tolerance by Ping-Ying Pan; Junko Ozao; Zuping Zhou; Shu-Hsia Chen (pp. 91-105).

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.

Keywords: Immune tolerance; Cancer immune therapy; Autoimmune; Treg; MDSC; Dendritic cells; GVHD

Induction of immune tolerance to facilitate β cell regeneration in type 1 diabetes by Lorenzo Pasquali; Nick Giannoukakis; Massimo Trucco (pp. 106-113).

A definitive cure for type 1 diabetes is currently being pursued with enormous effort by the scientific community. Different strategies are followed to restore physiologic production of insulin in diabetic patients. Restoration of self-tolerance remains the milestone that must be reached in order to move a step further and recover a cell source capable of independent and functional insulin production. Multiple strategies aimed at modulation of both central and peripheral immunity must be considered. Promising results now show that the immune system can be modulated in a way that acquisition of a “diabetes-suppressive” phenotype is possible. Once self-tolerance is achieved, reversal of the disease may be obtained by simply allowing physiologic rescue and/or regeneration of the β cells to take place. Given that these outcomes have already been confirmed in humans, refinement of existing protocols along with novel methods adapted to T1DM reversal will allow translation into clinical trials.

Keywords: Abbreviations; APC; antigen-presenting cells; AS-ODN; antisense oligodeoxyribonucleotides; BM; bone marrow; DC; dendritic cell; DP-BB; diabetes-prone BioBreeding rat; HLA; human leukocyte antigen; MHC; major histocompatibility complex; NOD; non-obese diabetic; TCR; T-cell receptor; T1D; type 1 diabetes; VNTR; variable number of tandem repeats.Diabetes; Dendritic cells; Histocompatibility; Gene therapy; Regeneration

Beta-cell replacement for insulin-dependent diabetes mellitus by Shimon Efrat (pp. 114-123).

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.

Keywords: Beta-cell transcription factors; Cell encapsulation; Cell transplantation; Insulin production and secretion; Islet regeneration; Stem cells

Challenges and emerging technologies in the immunoisolation of cells and tissues by John T. Wilson; Elliot L. Chaikof (pp. 124-145).

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.

Keywords: Immunoisolation; Cell encapsulation; Cell transplantation; Conformal coating; Cell surface modification; Pancreatic islet; Immunomodulation; Anti-inflammatory

Genetic modification of cells for transplantation by Yi Lai; Irina Drobinskaya; Eugen Kolossov; Chunguang Chen; Thomas Linn (pp. 146-159).

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.

Keywords: Virus technology; Non-viral transgenes; Pancreatic islet cells; Transgenic embryonic stem cells

Genetic modification of stem cells for transplantation by M. Ian Phillips; Yao Liang Tang (pp. 160-172).

Gene modification of cells prior to their transplantation, especially stem cells, enhances their survival and increases their function in cell therapy. Like the Trojan horse, the gene-modified cell has to gain entrance inside the host's walls and survive and deliver its transgene products Using cellular, molecular and gene manipulation techniques the transplanted cell can be protected in a hostile environment from immune rejection, inflammation, hypoxia and apoptosis. Genetic engineering to modify cells involves constructing modules of functional gene sequences. They can be simple reporter genes or complex cassettes with gene switches, cell specific promoters and multiple transgenes. We discuss methods to deliver and construct gene cassettes with viral and non-viral delivery, siRNA, and conditional Cre/Lox P. We review the current uses of gene-modified stem cells in cardiovascular disease, diabetes, neurological diseases, (including Parkinson's, Alzheimer's and spinal cord injury repair), bone defects, hemophilia, and cancer.

Keywords: Vigilant Vector; Stem cells; MicroRNA; Cre/Lox P; Heart failure; Cancer; Diabetes; Neurological diseases

Immunotherapy with dendritic cells for cancer by Alberto Ballestrero; Davide Boy; Eva Moran; Gabriella Cirmena; Peter Brossart; Alessio Nencioni (pp. 173-183).

Dendritic cells are professional antigen-presenting cells with a key role in both immunity induction and tolerance maintenance. Dendritic cells are highly specialized in antigen capture, processing and presentation, and express co-stimulation signals which activate T lymphocytes and NK cells. Dendritic cells generated in culture and loaded with an antigen efficiently induce antigen-specific immunity after injection. More recently, methods have been developed that target antigens to dendritic cells in vivo, bypassing the need for ex vivo cell manipulations. Numerous ongoing studies aim to evaluate the effectiveness of dendritic cell vaccines in preventing tumor relapses and extending patients' survival. Further implementation of this form of immunotherapy is expected following the identification of the mechanisms controlling dendritic cell immunogenicity, and from a better understanding of the cell dynamics whereby immune responses are orchestrated. Here, we discuss these new insights together with an overview of the dendritic cell-based clinical studies carried out to date.

Keywords: Dendritic cells; Immunotherapy; Tumor antigens; Tolerance; Toll-like receptors; Cytokines

Biomimetic materials for tissue engineering by Peter X. Ma (pp. 184-198).

Tissue engineering and regenerative medicine is an exciting research area that aims at regenerative alternatives to harvested tissues for transplantation. Biomaterials play a pivotal role as scaffolds to provide three-dimensional templates and synthetic extracellular matrix environments for tissue regeneration. It is often beneficial for the scaffolds to mimic certain advantageous characteristics of the natural extracellular matrix, or developmental or wound healing programs. This article reviews current biomimetic materials approaches in tissue engineering. These include synthesis to achieve certain compositions or properties similar to those of the extracellular matrix, novel processing technologies to achieve structural features mimicking the extracellular matrix on various levels, approaches to emulate cell–extracellular matrix interactions, and biologic delivery strategies to recapitulate a signaling cascade or developmental/wound healing program. The article also provides examples of enhanced cellular/tissue functions and regenerative outcomes, demonstrating the excitement and significance of the biomimetic materials for tissue engineering and regeneration.

Keywords: Biomimetic; Tissue engineering; Regeneration; Polymer scaffold; Matrix; Biomaterial; Nano; Controlled release

Controlled differentiation of stem cells by Nathaniel S. Hwang; Shyni Varghese; Jennifer Elisseeff (pp. 199-214).

The extracellular microenvironment plays a significant role in controlling cellular behavior. Identification of appropriate biomaterials that support cellular attachment, proliferation and, most importantly in the case of human embryonic stem cells, lineage-specific differentiation is critical for tissue engineering and cellular therapy. In addition to growth factors and morphogenetic factors known to induce lineage commitment of stem cells, a number of scaffolding materials, including synthetic and naturally-derived biomaterials, have been utilized in tissue engineering approaches to direct differentiation. This review focuses on recent emerging findings and well-characterized differentiation models of human embryonic stem cells. Additionally, we also discuss about various strategies that have been used in stem cell expansion.

Keywords: Embryonic stem cells; Biomaterials; Microenvironment; Differentiation; Self-renewal; Biomimetic

Biomaterials for stem cell differentiation by Eileen Dawson; Gazell Mapili; Kathryn Erickson; Sabia Taqvi; Krishnendu Roy (pp. 215-228).

The promise of cellular therapy lies in the repair of damaged organs and tissues in vivo as well as generating tissue constructs in vitro for subsequent transplantation. Unfortunately, the lack of available donor cell sources limits its ultimate clinical applicability. Stem cells are a natural choice for cell therapy due to their pluripotent nature and self-renewal capacity. Creating reserves of undifferentiated stem cells and subsequently driving their differentiation to a lineage of choice in an efficient and scalable manner is critical for the ultimate clinical success of cellular therapeutics. In recent years, a variety of biomaterials have been incorporated in stem cell cultures, primarily to provide a conducive microenvironment for their growth and differentiation and to ultimately mimic the stem cell niche. In this review, we examine applications of natural and synthetic materials, their modifications as well as various culture conditions for maintenance and lineage-specific differentiation of embryonic and adult stem cells.

Keywords: Embryonic stem cells; Adult stem cells; Polymers; Metals; Ceramics; Bioreactors; Differentiation

Controlled drug delivery in tissue engineering by Marco Biondi; Francesca Ungaro; Fabiana Quaglia; Paolo Antonio Netti (pp. 229-242).

The concept of tissue and cell guidance is rapidly evolving as more information regarding the effect of the microenvironment on cellular function and tissue morphogenesis become available. These disclosures have lead to a tremendous advancement in the design of a new generation of multifunctional biomaterials able to mimic the molecular regulatory characteristics and the three-dimensional architecture of the native extracellular matrix. Micro- and nano-structured scaffolds able to sequester and deliver in a highly specific manner biomolecular moieties have already been proved to be effective in bone repairing, in guiding functional angiogenesis and in controlling stem cell differentiation. Although these platforms represent a first attempt to mimic the complex temporal and spatial microenvironment presented in vivo, an increased symbiosis of material engineering, drug delivery technology and cell and molecular biology may ultimately lead to biomaterials that encode the necessary signals to guide and control developmental process in tissue- and organ-specific differentiation and morphogenesis.

Keywords: Abbreviation list; bFGF; basic fibroblast growth factor; BMP; bone morphogenetic protein; BSA; bovine serum albumin; CASD; computer-aided scaffold design; DS; delivery systems; ECM; extracellular matrix; EGF; epidermal growth factor; EVAc; ethylene-vinyl acetate copolymers; GF; growth factor; HBDS; heparin-based delivery systems; NT-3; neurotrophin-3; PA; peptide amphiphile; PCL; poly(ɛ-caprolactone); PDGF; platelet derived growth factor; PEG; poly(ethylene glycol); PEO; poly(ethylene oxide); PLA; poly(lactide); PLGA; poly(lactide-co-glycolide); POE; poly(ortho esters); PTH; parathyroid hormone; SFF; solid free-form fabrication; TE; tissue engineering; TGF-β1; transforming growth factor-beta1; VEGF; vascular endothelial growth factorTissue engineering; Drug delivery; Biomaterials; Growth factors; Scaffold

Engineering cartilage tissue by Cindy Chung; Jason A. Burdick (pp. 243-262).

Cartilage tissue engineering is emerging as a technique for the regeneration of cartilage tissue damaged due to disease or trauma. Since cartilage lacks regenerative capabilities, it is essential to develop approaches that deliver the appropriate cells, biomaterials, and signaling factors to the defect site. The objective of this review is to discuss the approaches that have been taken in this area, with an emphasis on various cell sources, including chondrocytes, fibroblasts, and stem cells. Additionally, biomaterials and their interaction with cells and the importance of signaling factors on cellular behavior and cartilage formation will be addressed. Ultimately, the goal of investigators working on cartilage regeneration is to develop a system that promotes the production of cartilage tissue that mimics native tissue properties, accelerates restoration of tissue function, and is clinically translatable. Although this is an ambitious goal, significant progress and important advances have been made in recent years.

Keywords: Cartilage; Tissue engineering; Biomaterials; Stem cells; Regeneration

Cell therapy for spinal cord regeneration by Stephanie M. Willerth; Shelly E. Sakiyama-Elbert (pp. 263-276).

This review presents a summary of the various types of cellular therapy used to treat spinal cord injury. The inhibitory environment and loss of axonal connections after spinal cord injury pose many obstacles to regenerating the lost tissue. Cellular therapy provides a means of restoring the cells lost to the injury and could potentially promote functional recovery after such injuries. A wide range of cell types have been investigated for such uses and the advantages and disadvantages of each cell type are discussed along with the research studying each cell type. Additionally, methods of delivering cells to the injury site are evaluated. Based on the current research, suggestions are given for future investigation of cellular therapies for spinal cord regeneration.

Keywords: Abbreviations; BBB; Basso, Beattie, and Bresnahan; BMS; Basso mouse scale; BMSCs; Bone marrow stromal cells; BMP; Bone morphogenetic protein; BDNF; Brain derived neurotrophic factor; CNS; Central nervous system; CSF; Cerebrospinal fluid; CSPGs; Chondroitin sulfate proteoglycans; CNTF; Ciliary neurotrophic factor; cAMP; Cyclic adenosine monophosphate; EBs; Embryoid bodies; ESCs; Embryonic stem cells; FGF; Fibroblast growth factor; GDNF; Glial-derived neurotrophic factor; MAG; Myelin associated glycoprotein; NGF; Nerve growth factor; NGCs; Nerve guidance conduits; NPCs; Neural progenitor cells; NSCs; Neural stem cells; NT-3; Neurotrophin-3; OECs; Olfactory ensheathing cells; OMgp; Oligodendrocyte myelin glycoprotein; OPCs; Oligodendrocyte progenitor cells; PNS; Peripheral nervous system; PEG; Poly (ethylene glycol); PLGA; Poly (lactic-co-glycolic) acid; PLLA; Poly (; l; -lactic) acid; SCID; Severe combined immunodeficiency; SCI; Spinal cord injury.Embryonic stem cells; Neural stem cells; Spinal cord injury; Regenerative medicine; Bone marrow stromal cells; Biomaterials

Cell sheet engineering for heart tissue repair by Shinako Masuda; Tatsuya Shimizu; Masayuki Yamato; Teruo Okano (pp. 277-285).

Recently, myocardial tissue engineering has emerged as one of the most promising therapies for patients suffering from severe heart failure. Nevertheless, conventional methods in tissue engineering involving the seeding of cells into biodegradable scaffolds have intrinsic shortcomings, such as inflammatory reactions and fibrous tissue formation caused by scaffold degradation. On the other hand, we have developed cell sheet engineering as scaffoldless tissue engineering, and applied it for myocardial tissue engineering. Using temperature-responsive culture surfaces, cells can be harvested as intact sheets and cell-dense thick tissues are constructed by layering these cell sheets. Myocardial cell sheets non-invasively harvested from temperature-responsive culture surfaces are successfully layered, resulting in electrically communicative 3-dimensional (3-D) cardiac constructs. Transplantation of cell sheets onto damaged hearts improved heart function in several animal models. In this review, we summarize the development of myocardial tissue engineering using cell sheets harvested from temperature-responsive culture surfaces and discuss about future views.

Keywords: Regenerative medicine; Tissue engineering; Temperature-responsive cell culture surface; Myocardial tissue engineering

Cell-based drug delivery by F. Pierigè; S. Serafini; L. Rossi; M. Magnani (pp. 286-295).

Drug delivery has been greatly improved over the years by means of chemical and physical agents that increase bioavailability, improve pharmacokinetic and reduce toxicities. At the same time, cell based delivery systems have also been developed. These possesses a number of advantages including prolonged delivery times, targeting of drugs to specialized cell compartments and biocompatibility. Here we'll focus on erythrocyte-based drug delivery. These systems are especially efficient in releasing drugs in circulations for weeks, have a large capacity, can be easily processed and could accommodate traditional and biologic drugs. These carriers have also been used for delivering antigens and/or contrasting agents. Carrier erythrocytes have been evaluated in thousands of drug administration in humans proving safety and efficacy of the treatments. Erythrocyte-based delivery of new and conventional drugs is thus experiencing increasing interests in drug delivery and in managing complex pathologies especially when side effects could become serious issues.

Keywords: Transduced cells as drug delivery systems; Cell carriers of drugs; Red blood cells as drug delivery systems

Sections

Personal tools

Advanced Drug Delivery Reviews (v.60, #2)

Sections

Personal tools

Local resources

Advanced Drug Delivery Reviews (v.60, #2)