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Advanced Drug Delivery Reviews (v.63, #4-5)

Editorial Board (pp. ii).

From tissue engineering to regenerative medicine—the potential and the pitfalls by Katja Schenke-Layland (Theme Editor) (pp. 193-194).

In vitro human tissue models — moving towards personalized regenerative medicine by Katja Schenke-Layland; Robert M. Nerem (pp. 195-196).

The field of tissue engineering is a rapidly growing interdisciplinary field within regenerative medicine involving biology, chemistry, physics, engineering and medical sciences, which focuses on the fabrication of replacement tissues and organs. Another major focus of tissue engineering is the creation of ex vivo-manufactured multi-organ test systems, in order to explore fundamental questions of cell, matrix and developmental biology. These ex-vivo manufactured systems can also be used to study drug delivery dynamics.

Keywords: Organ culture; Pharmaceutical tests; Disease-in-a-dish; Stem cells; Induced-pluripotent stem cells

RNA interference therapy via functionalized scaffolds by Michael Monaghan; Abhay Pandit (pp. 197-208).

Tissue engineering aims to provide structural and biomolecular cues to compromised tissues through scaffolds. An emerging biomolecular cue is that of RNA interference by which the expression of genes can be silenced through a potent endogenous pathway. Recombinant viral-based approaches in RNAi delivery exist; however non-viral strategies offer many opportunities to exploit this mechanism of regulation in a safer way. Current RNAi therapies in clinical trials are without a vector (naked) or have slightly modified structures. Modification of these molecules with efficient backbone moieties for improved stability and potency, protecting and buffering them with delivery vehicles, and using scaffolds as reservoirs of delivery is at the frontier of current research. However, to enable an efficient sustained therapeutic effect scaffolds have a potentially significant role to play. This review presents non-viral delivery of RNAi that have been attempted via tissue engineered scaffolds. For RNAi to have a clinical impact, it is imperative to evaluate optimal delivery systems to ensure that the efficacy of this promising technology can be maximized.Display Omitted

Keywords: RNAi; Matrix; Scaffold; Reservoir; Delivery; Non-viral; siRNA; shRNA; MicroRNA; AntimiR

Electrospun cellular microenvironments: Understanding controlled release and scaffold structure by Andreas Szentivanyi; Tanmay Chakradeo; Holger Zernetsch; Birgit Glasmacher (pp. 209-220).

Electrospinning is a versatile technique in tissue engineering for the production of scaffolds. To guide tissue development, scaffolds must provide specific biochemical, structural and mechanical cues to cells and deliver them in a controlled fashion over time. Electrospun scaffold design thus includes aspects of both controlled release and structural cues. Controlled multicomponent and multiphasic drug delivery can be achieved by the careful application and combination of novel electrospinning techniques, i.e., emulsion and co-axial electrospinning. Drug distribution and polymer properties influence the resulting release kinetics. Pore size is far more relevant as a structural parameter than previously recognized. It enables cell proliferation and ingrowth, whereas fiber diameter predominantly influences cell fate. Both parameters can be exploited by combining multiple fiber types in the form of multifiber and multilayer scaffolds. Such scaffolds are required to reproduce more complex tissue structures.Display Omitted

Keywords: Electrospinning; Tissue engineering; Protein delivery; Release kinetics; Porosity; Pore size; Fiber diameter; Cell proliferation; Cell ingrowth

Substrates for cardiovascular tissue engineering by C.V.C. Bouten; P.Y.W. Dankers; A. Driessen-Mol; S. Pedron; A.M.A. Brizard; F.P.T. Baaijens (pp. 221-241).

Cardiovascular tissue engineering aims to find solutions for the suboptimal regeneration of heart valves, arteries and myocardium by creating ‘living’ tissue replacements outside (in vitro) or inside (in situ) the human body. A combination of cells, biomaterials and environmental cues of tissue development is employed to obtain tissues with targeted structure and functional properties that can survive and develop within the harsh hemodynamic environment of the cardiovascular system. This paper reviews the up-to-date status of cardiovascular tissue engineering with special emphasis on the development and use of biomaterial substrates. Key requirements and properties of these substrates, as well as methods and readout parameters to test their efficacy in the human body, are described in detail and discussed in the light of current trends toward designing biologically inspired microenviroments for in situ tissue engineering purposes.Display Omitted

Keywords: Abbreviations; bFGF; basic fibroblast growth factor; DLLA; D,L; -lactide; ECM; extracellular matrix; Fmoc; fluorenylmethoxycarbonyl; HUVEC; human umbilical vein endothelial cell; IKVAV; Ile-Lys-Val-Ala-Val peptide sequence; LRKKLGKA; Leu-Arg-Lys-Lys-Leu-Gly-Lys-Ala peptide sequence; MMP; matrix metalloproteinases; PA; peptide amphiphile; PCL; poly(ε-caprolactone); PEG; poly(ethylene glycol); PET; poly(ethylene terephthalate); PGA; poly(glycolic acid); PGG; pentagalloyl glucose; PHA; poly(hydroxyl alkanoate); PHSRN; Pro-His-Ser-Arg-Asn peptide sequence; PLA; poly(lactic acid); PLGA; poly(lactic-; co; -glycolic acid); PTFE; poly(tetrafluoro ethylene); PTMC; poly (1,3-trimethylene carbonate); RYVVLPR; Arg-Tyr-Val-Val-Leu-Pro-Arg peptide sequence; RADA16; (Arg-Ala-Asp-Ala)4; RGD; Arg-Gly-Asp peptide sequence; REDV; Arg-Glu-Asp-Val peptide sequence; SIS; small intestine submucosa; TAGSCLRKFSTM; Thr-Ala-Gly-Ser-Cys-Leu-Arg-Lys-Phe-Ser-Thr-Met peptide sequence; TGF-β1; transforming growth factor β1; UPy; ureido-pyrimidinone; VAPG; Val-Ala-Pro-Gly peptide sequence; VEGF; vascular endothelial growth factor; VIC; valvular interstitial cell; YIGSR; Tyr-Ile-Gly-Ser-Arg peptide sequenceScaffolds; Bioactive materials; Heart valves; Artery; Myocardium; Extracellular matrix; Cellular microenvironment; Substrate testing; Computational modeling; Imageable materials

Aortic valve disease and treatment: The need for naturally engineered solutions by Jonathan T. Butcher; Gretchen J. Mahler; Laura A. Hockaday (pp. 242-268).

The aortic valve regulates unidirectional flow of oxygenated blood to the myocardium and arterial system. The natural anatomical geometry and microstructural complexity ensures biomechanically and hemodynamically efficient function. The compliant cusps are populated with unique cell phenotypes that continually remodel tissue for long-term durability within an extremely demanding mechanical environment. Alteration from normal valve homeostasis arises from genetic and microenvironmental (mechanical) sources, which lead to congenital and/or premature structural degeneration. Aortic valve stenosis pathobiology shares some features of atherosclerosis, but its final calcification endpoint is distinct. Despite its broad and significant clinical significance, very little is known about the mechanisms of normal valve mechanobiology and mechanisms of disease. This is reflected in the paucity of predictive diagnostic tools, early stage interventional strategies, and stagnation in regenerative medicine innovation. Tissue engineering has unique potential for aortic valve disease therapy, but overcoming current design pitfalls will require even more multidisciplinary effort. This review summarizes the latest advancements in aortic valve research and highlights important future directions.Display Omitted

Keywords: Abbreviations; 2D; two-dimensional; 3D; three-dimensional; 5-HT; serotonin; 5-HTT; serotonin transporter; αSMA; Alpha smooth muscle actin; ACE; angiotensin converting enzymes; ADHD; attention-deficit hyperactivity disorder; ANF; atrial natriuretic factor; ANGII; angiotensin II; APOE; Apolipoprotein E; ARB; angiotensin receptor blocker; AT1; angiotensin II Type 1; AVD; Aortic valve disorders; B1 and B2; bradykinin receptors; BAV; bicuspid aortic valve; BK; bradykinin; BMP; bone morphogenic protein; BMSC; bone marrow derived mesenchymal stem cells; BPV; bioprosthetic valve; CAD; computer aided design; CAVD; calcific aortic valve disease; CHD; congenital heart defect; CVD; cardiovascular disease; COL; collagen; CX40; connexin 40; DGEA; collagen-derived peptide motif; EC; endothelial cells; ECM; extracellular matrix; EDMP; Endocardial derived mesenchymal progenitors; EDS; Ehlers–Danlos syndrome; EDTA; Ethylenediaminetetraacetic acid; ELN; elastin; EMT; endothelial to mesenchymal transformation; eNOS; endothelial nitric oxide synthase; FBN1; fibrillin; FDA; Federal Drug Administration; FZD; frizzled receptors; GAG; glycosaminoglycans; HMG-CoA; 3-hydroxy-3-methylglutaryl-coenzyme A; HVD; heart valve disease; KKS; kallikrein-kinin system; LDL; low density lipoprotein; LDLr; low density lipoprotein receptor; LPS; lipopolysaccharide; MDA; N; -demethylated metabolite 3,4-methylenedioxyamphetamine; MDMA; 3,4-methylenedioxymetham-phetamine; MGP; matrix gla protein; MMP; matrix metalloproteases; MPV; mechanical prosthetic valves; NADPH; nicotinamide adenine dinucleotide phosphate-oxidase; NFκB; nuclear factor kappa B; OPG; osteoprotegerin; OPN; osteopontin; P4HB; poly-4-hydroxybutyrate; PEG-DA; poly (ethylene glycol) diacrylate; PGA; polyglycolic acid; PHO; polyhydroxyalkanoate; PLGA; poly (lactic-co-glycolic acid); PLLA; poly; (; l; -; lactic acid); RANK; receptor activator of nuclear factor kappa B; RANKL; receptor activator of nuclear factor kappa B ligand; RAS; renin-angiotensin system; RGDS; fibronectin-derived peptide motif; ROS; reactive oxygen species; RVD; rheumatic valve disease; SDS; sodium dodecyl sulfate; SMM; smooth muscle myosin; SPARC; secreted protein acidic and rich in cysteine; TEHV; tissue engineered aortic heart valves; TGFβ; transforming growth factor beta; TIMP; tissue inhibitor of metalloproteinases; TNX; tenascin-x; TLR; toll-like receptors; VEC; valve endothelial cells; VEGF; vascular endothelial growth factor; VIC; valve interstitial cells; YIGSR; laminin-derived peptide motifAtherosclerosis; Stenosis; Calcification; Risk factors; Heterogeneous; Biomarkers; Congenital heart defects; Genetic mutations; Animal models; Tissue engineering; Biomechanics; Endothelial; Interstitial; Clinical trials; Drug discovery

Lessons from (patho)physiological tissue stiffness and their implications for drug screening, drug delivery and regenerative medicine by Wen Li Kelly Chen; Craig A. Simmons (pp. 269-276).

Diseased tissues are noted for their compromised mechanical properties, which contribute to organ failure; regeneration entails restoration of tissue structure and thereby functions. Thus, the physical signature of a tissue is closely associated with its biological function. In this review, we consider a mechanics-centric view of disease and regeneration by drawing parallels between in vivo tissue-level observations and corroborative cellular evidence in vitro to demonstrate the importance of the mechanical stiffness of the extracellular matrix in these processes. This is not intended to devalue the importance of biochemical signaling; in fact, as we discuss, many mechanical stiffness-driven processes not only require cooperation with biochemical cues, but they ultimately converge at common signaling cascades to influence cell and tissue function in an integrative manner. The study of how physical and biochemical signals collectively modulate cell function not only brings forth a more holistic understanding of cell (patho)biology, but it also creates opportunities to control material properties to improve culture platforms for research and drug screening and aid in the rationale design of biomaterials for molecular therapy and tissue engineering applications.Display Omitted

Keywords: Abbreviations; PA; polyacrylamide; EGF; epidermal growth factor; ERK; extracellular signal-regulated kinase; FAK; focal adhesion kinase; hBMMSC; human bone marrow mesenchymal stem cell; HCC; hepatocellular carcinoma; kPa; kilopascal; MEC; mammary epithelial cell; MuSC; muscle stem cell; LOX; lysyl oxidase; RGD; arginine–glycine–aspartic acid; ROCK; Rho kinase; SCP; single cell population; TGF-β1; transforming growth factor-β1Substrate stiffness; Elasticity; Biomechanics; Stem cells; Cancer biology; Mechanobiology; Biomaterials

Applying macromolecular crowding to enhance extracellular matrix deposition and its remodeling in vitro for tissue engineering and cell-based therapies by Clarice Chen; Felicia Loe; Anna Blocki; Yanxian Peng; Michael Raghunath (pp. 277-290).

With the advent of multicellular organisms, the exterior of the cells evolved dramatically from highly aqueous surroundings into an extracellular matrix and space crowded with macromolecules. Cell-based therapies require removal of cells from their crowded physiological context and propagating them in dilute culture medium to attain therapeutically relevant numbers whilst preserving their phenotype. However, bereft of their microenvironment, cells under perform and lose functionality. Major efforts currently aim to modify cell culture surfaces and build three dimensional scaffolds to improve this situation. We discuss here alternative strategies that enable cells to re-create their own microenvironment in vitro, using carbohydrate-based macromolecules as culture media additives that create an excluded volume effect at defined fraction volume occupancies. This biophysical approach dramatically enhances extracellular matrix deposition by differentiated cells and stem cells, and boosts progenitor cell differentiation and proliferation. We begin to understand how well cells really can perform ex vivo if given the chance.Display Omitted

Keywords: Microenvironment; Excluded volume effect; Stem cells; Differentiated cells; Matrix maturation; Collagen assembly

Co-culture systems for vascularization — Learning from nature by C. James Kirkpatrick; Sabine Fuchs; Ronald E. Unger (pp. 291-299).

The endothelial cell (EC) is practically ubiquitous in the human body and forms the inner cellular lining of the entire cardiovascular system. Following tissue injury, the microcirculation becomes the stage for both the inflammatory response and the subsequent healing reaction to restore physiological function to the damaged tissue. The advent of the multidisciplinary field of Regenerative Medicine (RegMed), of which Tissue Engineering (TE) and drug delivery using modern stimuli-responsive or interactive biomaterials are important components, has opened up new approaches to the acceleration of the healing response. A central and rate-limiting role in the latter is played by the process of vascularization or neovascularization, so that it is not surprising that in RegMed concepts have been developed for the drug- and gene-delivery of potent stimuli such as vascular-endothelial growth factor (VEGF) to promote neovessel development. However, not all of these novel materials can be tested in vivo, and in vitro co-culture model systems using human primary cells are being developed to pre-evaluate and determine which of the RegMed concepts exhibit the most promising potential for success after implantation. This review describes some of the growing number of in vitro co-cultures model systems that are being used to study cell–cell and cell–material interactions at the cellular and molecular levels to determine which materials are best suited to integrate into the host, promote a rapid vascularization and fit into the regenerative process without disturbing or slowing the normal healing steps.Display Omitted

Keywords: Vascularization; Co-culture; Endothelial; Osteoblast; Tissue engineering; Regeneration

Vascularization is the key challenge in tissue engineering by Esther C. Novosel; Claudia Kleinhans; Petra J. Kluger (pp. 300-311).

The main limitation in engineering in vitro tissues is the lack of a sufficient blood vessel system — the vascularization. In vivo almost all tissues are supplied by these endothelial cell coated tubular networks. Current strategies to create vascularized tissues are discussed in this review. The first strategy is based on the endothelial cells and their ability to form new vessels known as neoangiogenesis. Herein prevascularization techniques are compared to approaches in which biomolecules, such as growth factors, cytokines, peptides and proteins as well as cells are applied to generate new vessels. The second strategy is focused on scaffold-based techniques. Naturally-derived scaffolds, which contain vessels, are distinguished from synthetically manufactured matrices. Advantages and pitfalls of the approaches to create vascularized tissues in vitro are outlined and feasible future strategies are discussed.Display Omitted

Keywords: Neovascularization; Angiogenesis; Scaffolds; Endothelial cells; Growth factors; Rapid prototyping; Nutrient supply; Regenerative medicine

Vascular tissue engineering: Towards the next generation vascular grafts by Yuji Naito; Toshiharu Shinoka; Daniel Duncan; Narutoshi Hibino; Daniel Solomon; Muriel Cleary; Animesh Rathore; Corey Fein; Spencer Church; Christopher Breuer (pp. 312-323).

The application of tissue engineering technology to cardiovascular surgery holds great promise for improving outcomes in patients with cardiovascular diseases. Currently used synthetic vascular grafts have several limitations including thrombogenicity, increased risk of infection, and lack of growth potential. We have completed the first clinical trial evaluating the feasibility of using tissue engineered vascular grafts (TEVG) created by seeding autologous bone marrow-derived mononuclear cells (BM-MNC) onto biodegradable tubular scaffolds. Despite an excellent safety profile, data from the clinical trial suggest that the primary graft related complication of the TEVG is stenosis, affecting approximately 16% of grafts within the first seven years after implantation. Continued investigation into the cellular and molecular mechanisms underlying vascular neotissue formation will improve our basic understanding and provide insights that will enable the rationale design of second generation TEVG.Display Omitted

Keywords: Abbreviations; BM-MNC; bone marrow-derived mononuclear cells; CT; computed tomography; EB; embryonic bodies; EC; endothelial cells; ELS; electrospinning; ESC; embryonic stem cells; ECM; extracellular matrix; EC-TCPC; extra-cardiac total cavopulmonary connection; ePTFE; expanded polytetrafluoroethylene; FB; fibroblast; FBGC; foreign body giant cells; FN; fibronectin; GFP; green fluorescence protein; iPS cell; induced pluriopotent stem cell; LIF; leukemia inhibitory factor; LN; laminin; miRNA; microRNA; MRI; magnetic resonance imaging; mRNA; messenger RNA; MSC; mesenchymal stem cells; ROIs; reactive oxygen intermediates; SCID; severe combined immune deficiency; TE; tissue engineering; TEVG; tissue engineered vascular graft; SMC; smooth muscle cellsVascular tissue engineering; Stem cells; Bone marrow derived mononuclear cells; Extracellular matrix; Vascular remodeling; Translational research

Induced pluripotent stem cells for regenerative cardiovascular therapies and biomedical discovery by Ali Nsair; W. Robb MacLellan (pp. 324-330).

The discovery of induced pluripotent stem cells (iPSC) has, in the short time since their discovery, revolutionized the field of stem cell biology. This technology allows the generation of a virtually unlimited supply of cells with pluripotent potential similar to that of embryonic stem cells (ESC). However, in contrast to ESC, iPSC are not subject to the same ethical concerns and can be easily generated from living individuals. For the first time, patient-specific iPSC can be generated and offer a supply of genetically identical cells that can be differentiated into all somatic cell types for potential use in regenerative therapies or drug screening and testing. As the techniques for generation of iPSC lines are constantly evolving, new uses for human iPSC are emerging from in-vitro disease modeling to high throughput drug discovery and screening. This technology promises to revolutionize the field of medicine and offers new hope for understanding and treatment of numerous diseases.Display Omitted

Keywords: Abbreviations; ESC; embryonic stem cells; iPSC; induced pluripotent stem cells; CPC; cardiac progenitor cells; SCNT; somatic cell nuclear transfer; CM; cardiac myocytes; SMC; smooth muscle cells; EC; endothelial cellsStem cells; Embryonic stem cells; Induced pluripotent stem cells; Regenerative therapies; Biomedical discovery

The challenges and promises of blood engineered from human pluripotent stem cells by Gautam G. Dravid; Gay M. Crooks (pp. 331-341).

The concept that stem cells can be used to replace and regenerate tissue was founded over half a century ago using hematopoietic stem cells in the clinical field of bone marrow transplantation. The development of human embryonic stem cell lines and patient-specific induced pluripotent stem cells has the potential to overcome the problem presented by shortages of immunologically compatible hematopoietic stem cell donors. This review summarizes the current advances made and limitations to be overcome in order to realize the full potential of engineering blood from pluripotent stem cells for clinical use.Display Omitted

Keywords: Hematopoiesis; Human pluripotent stem cells; Transplantation; Human embryonic stem cells; Induced pluripotent stem cells

Regeneration of cartilage and bone by defined subsets of mesenchymal stromal cells—Potential and pitfalls by Wilhelm K. Aicher; Buhring Hans-Jörg Bühring; Melanie Hart; Bernd Rolauffs; Andreas Badke; Gerd Klein (pp. 342-351).

Mesenchymal stromal cells, also referred to as mesenchymal stem cells, can be obtained from various tissues. Today the main source for isolation of mesenchymal stromal cells in mammals is the bone marrow. Mesenchymal stromal cells play an important role in tissue formation and organogenesis during embryonic development. Moreover, they provide the cellular and humoral basis for many processes of tissue regeneration and wound healing in infancy, adolescence and adulthood as well. There is increasing evidence that mesenchymal stromal cells from bone marrow and other sources including term placenta or adipose tissue are not a homogenous cell population. Only a restricted number of appropriate stem cells markers have been explored so far. But routine preparations of mesenchymal stromal cells contain phenotypically and functionally distinct subsets of stromal cells. Knowledge on the phenotypical characteristics and the functional consequences of such subsets will not only extend our understanding of stem cell biology, but might allow to develop improved regimen for regenerative medicine and wound healing and novel protocols for tissue engineering as well. In this review we will discuss novel strategies for regenerative medicine by specific selection or separation of subsets of mesenchymal stromal cells in the context of osteogenesis and bone regeneration. Mesenchymal stromal cells, which express the specific cell adhesion molecule CD146, also known as MCAM or MUC18, are prone for bone repair. Other cell surface proteins may allow the selection of chondrogenic, myogenic, adipogenic or other pre-determined subsets of mesenchymal stromal cells for improved regenerative applications as well.Display Omitted

Keywords: Abbreviations; CD; cluster of differentiation; EPC; endothelial precursor cell; FCS; fetal calf serum; GMP; good medical practice (or procedure); HSC; hematopoietic stem cell; HSPC; hematopoietic stem and progenitor cell; MSC; mesenchymal stem cellMesenchymal stem cell (MSC); Differentiation of MSC; Functional subsets of MSC; MSC niche; Sources for MSC; Osteogenesis; Chondrogenesis

Skin tissue engineering — In vivo and in vitro applications by Florian Groeber; Monika Holeiter; Martina Hampel; Svenja Hinderer; Katja Schenke-Layland (pp. 352-366).

Significant progress has been made over the years in the development of in vitro-engineered substitutes that mimic human skin, either to be used as grafts for the replacement of lost skin or for the establishment of human-based in vitro skin models. This review summarizes these advances in in vivo and in vitro applications of tissue-engineered skin. We further highlight novel efforts in the design of complex disease-in-a-dish models for studies ranging from disease etiology to drug development and screening.Display Omitted

Keywords: Tissue engineering; Extracellular matrix; Skin; In vitro; models; Keratinocytes; Melanocytes

Tracheobronchial bio-engineering: Biotechnology fulfilling unmet medical needs by Thorsten Walles (pp. 367-374).

The development of substitutes for the human trachea or its bronchial tree represents a niche application in the rapidly advancing scientific field of Regenerative Medicine. Despite a comparatively small research foundation in the field of tracheo-bronchial bioengineering, four different approaches have already been translated into clinical settings and applied in patients. This can be attributed to the lack of established treatment options for a small group of patients with extensive major airway disease. In this review, the clinical background and tissue-specific basics of tracheo-bronchial bioengineering will be evaluated. Focusing on the clinical applications of bioengineered tracheal tissues, a “top–down” or “bedside-to-bench” analysis is performed in order to guide future basic and clinical research activities for airway bioengineering.Display Omitted

Keywords: Abbreviations; BioVaSc; biological vascularized scaffold; ECM; extracellular matrix; gal; α-Gal (Galα1,3-Galβ1-4GlcNAc-R) oligosaccharide; GTR; guided tissue regeneration; TE; tissue engineeringClinical application; Guided tissue regeneration; Patient; Regenerative medicine; Review; Tissue engineering; Tracheal replacement; Translation

From tissue engineering to regenerative medicine in urology — The potential and the pitfalls by Gerhard Feil; Lisa Daum; Bastian Amend; Sabine Maurer; Markus Renninger; Martin Vaegler; Jörg Seibold; Arnulf Stenzl; Karl-Dietrich Sievert (pp. 375-378).

Tissue engineering is a promising technique for the development of biological substitutes that can restore, maintain, or improve tissue function. The creation of human tissue-engineered products, generated of autologous somatic cells or adult stem cells with or without seeding of biocompatible matrices is a vision to resolve the lack of tissues and organs for transplantation and to offer new options for reconstructive surgery. Tissue engineering in urology aims at the reconstruction of the urinary tract by creating anatomically and functionally equal tissue. It is a rapidly evolving field in basic research and the transfer into the clinic has yet to be realized. Necessary steps from bench to bed are the proof of principle in animal models and the proof of concept in clinical trials following good manufacturing practice and ethical and legal requirements for human tissue-engineered products. Up to now, obstacles still occur in the neovascularization of implants and ingrowth of nerves in vivo. Moreover the harvesting of mesenchymal stem cells out of bone marrow as well as the explant of urothelial cells yet demands rather invasive surgery to achieve a successful outcome. Thus, other cell sources and harvesting techniques like placenta and adipose tissue for mesenchymal stem cells and bladder irrigation for urothelial cells require closer investigation.Display Omitted

Keywords: Cell-based therapy; Biomaterial; Bioartificial tissue; Urothelium; Urinary tract; Kidney; Bladder; Urethra; Urethral sphincter; Stem cells

Regenerative medicine of the kidney by Laura Perin; Stefano Da Sacco; Roger E. De Filippo (pp. 379-387).

End stage renal disease is a major health problem in this country and worldwide. Although dialysis and kidney transplantation are currently used to treat this condition, kidney regeneration resulting in complete healing would be a desirable alternative. In this review we focus our attention on current therapeutic approaches used clinically to delay the onset of kidney failure. In addition we describe novel approaches, like Tissue Engineering, Stem cell Applications, Gene Therapy, and Renal Replacement Therapy that may one day be possible alternative therapies for patients with the hope of delaying kidney failure or even stopping the progression of renal disease.Display Omitted

Keywords: Stem cells; Acute kidney injury and chronic kidney disease; Tissue Engineering; Gene Therapy; Renal Replacement Therapy; Renal regeneration

Applications of multiphoton tomographs and femtosecond laser nanoprocessing microscopes in drug delivery research by Konig Karsten König; Anthony P. Raphael; Li Lin; Jeffrey E. Grice; H. Peter Soyer; H. Georg Breunig; Michael S. Roberts; Tarl W. Prow (pp. 388-404).

Multiphoton tomography for in vivo high-resolution multidimensional imaging has been used in clinical investigations and small animal studies. The novel femtosecond laser tomographs have been employed to detect cosmetics and pharmaceutical components in situ as well as to study the interaction of drugs with intratissue cells and the extracellular matrix under physiological conditions. Applications include the intra-tissue accumulation of sunscreen nanoparticles in humans, the monitoring the metabolic status of patients with dermatitis, the biosynthesis of collagen after administration of anti-aging products, and the detection of porphyrins after application of 5-aminolevulinic acid. More than 2000 patients and volunteers in Europe, Australia, and Asia have been investigated with these unique tomographs. In addition, femtosecond laser nanoprocessing microscopes have been employed for targeted delivery and deposition in body organs, optical transfection and optical cleaning of stem cells, as well as for the optical transfer of molecular beacons to track microRNAs. These diverse applications highlight the capacity for multiphoton tomography and femtosecond laser nanoprocessing tools to advance drug delivery research.Display Omitted

Keywords: Femtosecond laser; Two photon imaging; Multiphoton tomography; Cosmetics; Anti-aging; Laser nanoprocessing; Transfection; Collagen; Nanoparticle; Stem cells; Drug delivery; Cornea

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Advanced Drug Delivery Reviews (v.63, #4-5)