title: Tissue engineering

text: There are a few versatile synthetic materials used for many different scaffold applications. One of these commonly used materials is polylactic acid (PLA), a synthetic polymer. PLA – polylactic acid. This is a polyester which degrades within the human body to form lactic acid, a naturally occurring chemical which is easily removed from the body. Similar materials are polyglycolic acid (PGA) and polycaprolactone (PCL): their degradation mechanism is similar to that of PLA,  but PCL degrades slower and PGA degrades faster. PLA is commonly combined with PGA to create poly-lactic-co-glycolic acid (PLGA). This is especially useful because the degradation of PLGA can be tailored by altering the weight percentages of PLA and PGA: More PLA – slower degradation, more PGA – faster degradation. This tunability, along with its biocompatibility, makes it an extremely useful material for scaffold creation.


title: Tissue engineering

text: Scaffolds may also be constructed from natural materials: in particular different derivatives of the extracellular matrix have been studied to evaluate their ability to support cell growth. Protein based materials – such as collagen, or fibrin, and polysaccharidic materials- like chitosan or glycosaminoglycans (GAGs), have all proved suitable in terms of cell compatibility. Among GAGs, hyaluronic acid, possibly in combination with cross linking agents (e.g. glutaraldehyde, water-soluble carbodiimide, etc.), is one of the possible choices as scaffold material. Additionally, a fragment of an extracellular matrix protein, such as the RGD peptide, can be coupled to a non-bioactive material to promote cell attachment. Another form of scaffold is decellularized tissue. This is a process where chemicals are used to extracts cells from tissues, leaving just the extracellular matrix. This has the benefit of a fully formed matrix specific to the desired tissue type. However, the decellurised scaffold may present immune problems with future introduced cells.


title: Tissue engineering

text: A number of different methods have been described in the literature for preparing porous structures to be employed as tissue engineering scaffolds. Each of these techniques presents its own advantages, but none are free of drawbacks.


title: Tissue engineering

text: Molecular self-assembly is one of the few methods for creating biomaterials with properties similar in scale and chemistry to that of the natural "in vivo" extracellular matrix (ECM), a crucial step toward tissue engineering of complex tissues. Moreover, these hydrogel scaffolds have shown superiority in in vivo toxicology and biocompatibility compared to traditional macro-scaffolds and animal-derived materials.


title: Tissue engineering

text: These techniques include all the approaches that have been successfully employed for the preparation of non-woven meshes of different polymers. In particular, non-woven polyglycolide structures have been tested for tissue engineering applications: such fibrous structures have been found useful to grow different types of cells. The principal drawbacks are related to the difficulties in obtaining high porosity and regular pore size.


title: Tissue engineering

text: Solvent casting and particulate leaching (SCPL) allows for the preparation of structures with regular porosity, but with limited thickness. First, the polymer is dissolved into a suitable organic solvent (e.g. polylactic acid could be dissolved into dichloromethane), then the solution is cast into a mold filled with porogen particles. Such porogen can be an inorganic salt like sodium chloride, crystals of saccharose, gelatin spheres or paraffin spheres. The size of the porogen particles will affect the size of the scaffold pores, while the polymer to porogen ratio is directly correlated to the amount of porosity of the final structure. After the polymer solution has been cast the solvent is allowed to fully evaporate, then the composite structure in the mold is immersed in a bath of a liquid suitable for dissolving the porogen: water in the case of sodium chloride, saccharose and gelatin or an aliphatic solvent like hexane for use with paraffin. Once the porogen has been fully dissolved, a porous structure is obtained. Other than the small thickness range that can be obtained, another drawback of SCPL lies in its use of organic solvents which must be fully removed to avoid any possible damage to the cells seeded on the scaffold.


title: Tissue engineering

text: To overcome the need to use organic solvents and solid porogens, a technique using gas as a porogen has been developed. First, disc-shaped structures made of the desired polymer are prepared by means of compression molding using a heated mold. The discs are then placed in a chamber where they are exposed to high pressure CO for several days. The pressure inside the chamber is gradually restored to atmospheric levels. During this procedure the pores are formed by the carbon dioxide molecules that abandon the polymer, resulting in a sponge-like structure. The main problems resulting from such a technique are caused by the excessive heat used during compression molding (which prohibits the incorporation of any temperature labile material into the polymer matrix) and by the fact that the pores do not form an interconnected structure.


title: Tissue engineering

text: This technique does not require the use of a solid porogen like SCPL. First, a synthetic polymer is dissolved into a suitable solvent (e.g. polylactic acid in dichloromethane) then water is added to the polymeric solution and the two liquids are mixed in order to obtain an emulsion. Before the two phases can separate, the emulsion is cast into a mold and quickly frozen by means of immersion into liquid nitrogen. The frozen emulsion is subsequently freeze-dried to remove the dispersed water and the solvent, thus leaving a solidified, porous polymeric structure. While emulsification and freeze-drying allow for a faster preparation when compared to SCPL (since it does not require a time-consuming leaching step), it still requires the use of solvents. Moreover, pore size is relatively small and porosity is often irregular. Freeze-drying by itself is also a commonly employed technique for the fabrication of scaffolds. In particular, it is used to prepare collagen sponges: collagen is dissolved into acidic solutions of acetic acid or hydrochloric acid that are cast into a mold, frozen with liquid nitrogen and then lyophilized.


title: Tissue engineering

text: Similar to the previous technique, the TIPS phase separation procedure requires the use of a solvent with a low melting point that is easy to sublime. For example, dioxane could be used to dissolve polylactic acid, then phase separation is induced through the addition of a small quantity of water: a polymer-rich and a polymer-poor phase are formed. Following cooling below the solvent melting point and some days of vacuum-drying to sublime the solvent, a porous scaffold is obtained. Liquid-liquid phase separation presents the same drawbacks of emulsification/freeze-drying.


title: Tissue engineering

text: Electrospinning is a highly versatile technique that can be used to produce continuous fibers ranging in diameter from a few microns to a few nanometers. In a typical electrospinning set-up, the desired scaffold material is dissolved within a solvent and placed within a syringe. This solution is fed through a needle and a high voltage is applied to the tip and to a conductive collection surface. The buildup of electrostatic forces within the solution causes it to eject a thin fibrous stream towards the oppositely charged or grounded collection surface. During this process the solvent evaporates, leaving solid fibers leaving a highly porous network. This technique is highly tunable, with variation to solvent, voltage, working distance (distance from the needle to collection surface), flow rate of solution, solute concentration, and collection surface. This allows for precise control of fiber morphology.


title: Tissue engineering

text: On a commercial level however, due to scalability reasons, there are 40 or sometimes 96 needles involved operating at once. The bottle-necks in such set-ups are: 1) Maintaining the aforementioned variables uniformly for all of the needles and 2) formation of "beads" in single fibers that we as engineers, want to be of a uniform diameter. By modifying variables such as the distance to collector, magnitude of applied voltage, or solution flow rateresearchers can dramatically change the overall scaffold architecture.


title: Tissue engineering

text: Historically, research on electrospun fibrous scaffolds dates back to at least the late 1980s when Simon showed that electrospinning could be used to produced nano- and submicron-scale fibrous scaffolds from polymer solutions specifically intended for use as "in vitro" cell and tissue substrates. This early use of electrospun lattices for cell culture and tissue engineering showed that various cell types would adhere to and proliferate upon polycarbonate fibers. It was noted that as opposed to the flattened morphology typically seen in 2D culture, cells grown on the electrospun fibers exhibited a more rounded 3-dimensional morphology generally observed of tissues "in vivo".


title: Tissue engineering

text: Because most of the above techniques are limited when it comes to the control of porosity and pore size, computer assisted design and manufacturing techniques have been introduced to tissue engineering. First, a three-dimensional structure is designed using CAD software. The porosity can be tailored using algorithms within the software. The scaffold is then realized by using ink-jet printing of polymer powders or through Fused Deposition Modeling of a polymer melt.


title: Tissue engineering

text: A 2011 study by El-Ayoubi et al. investigated "3D-plotting technique to produce (biocompatible and biodegradable) poly-L-Lactide macroporous scaffolds with two different pore sizes" via solid free-form fabrication (SSF) with computer-aided-design (CAD), to explore therapeutic articular cartilage replacement as an "alternative to conventional tissue repair". The study found the smaller the pore size paired with mechanical stress in a bioreactor (to induce in vivo-like conditions), the higher the cell viability in potential therapeutic functionality via decreasing recovery time and increasing transplant effectiveness.


title: Tissue engineering

text: In a 2012 study, Koch et al. focused on whether Laser-assisted BioPrinting (LaBP) can be used to build multicellular 3D patterns in natural matrix, and whether the generated constructs are functioning and forming tissue. LaBP arranges small volumes of living cell suspensions in set high-resolution patterns. The investigation was successful, the researchers foresee that "generated tissue constructs might be used for in vivo testing by implanting them into animal models" (14). As of this study, only human skin tissue has been synthesized, though researchers project that "by integrating further cell types (e.g. melanocytes, Schwann cells, hair follicle cells) into the printed cell construct, the behavior of these cells in a 3D in vitro microenvironment similar to their natural one can be analyzed", which is useful for drug discovery and toxicology studies.


title: Tissue engineering

text: Gustafsson et al. demonstrated free‐standing, bioactive membranes of cm-sized area, but only 250 nm thin, that were formed by self‐assembly of spider silk at the interface of an aqueous solution. The membranes uniquely combine nanoscale thickness, biodegradability, ultrahigh strain and strength, permeability to proteins and promote rapid cell adherence and proliferation. They demonstrated growing a coherent layer of keratinocytes. These spider silk nanomembranes have also been used to create a static "in-vitro" model of a blood vessel.


title: Tissue engineering

text: A persistent problem within tissue engineering is mass transport limitations. Engineered tissues generally lack an initial blood supply, thus making it difficult for any implanted cells to obtain sufficient oxygen and nutrients to survive, or function properly.


title: Tissue engineering

text: Self-assembly methods have been shown to be promising methods for tissue engineering. Self-assembly methods have the advantage of allowing tissues to develop their own extracellular matrix, resulting in tissue that better recapitulates biochemical and biomechanical properties of native tissue. Self-assembling engineered articular cartilage was introduced by Jerry Hu and Kyriacos A. Athanasiou in 2006 and applications of the process have resulted in engineered cartilage approaching the strength of native tissue. Self-assembly is a prime technology to get cells grown in a lab to assemble into three-dimensional shapes. To break down tissues into cells, researchers first have to dissolve the extracellular matrix that normally binds them together. Once cells are isolated, they must form the complex structures that make up our natural tissues.


title: Tissue engineering

text: The air-liquid surface established by Faraday waves is explored as a template to assemble biological entities for bottom-up tissue engineering. This liquid-based template can be dynamically reconfigured in a few seconds, and the assembly on the template can be achieved in a scalable and parallel manner. Assembly of microscale hydrogels, cells, neuron-seeded micro-carrier beads, cell spheroids into various symmetrical and periodic structures was demonstrated with good cell viability. Formation of 3-D neural network was achieved after 14-day tissue culture.


title: Tissue engineering

text: It might be possible to print organs, or possibly entire organisms using additive manufacturing techniques. A recent innovative method of construction uses an ink-jet mechanism to print precise layers of cells in a matrix of thermo-reversible gel. Endothelial cells, the cells that line blood vessels, have been printed in a set of stacked rings. When incubated, these fused into a tube. This technique has been referred to as "bioprinting" within the field as it involves the printing of biological components in a structure resembling the organ of focus.


title: Tissue engineering

text: The field of three-dimensional and highly accurate models of biological systems is pioneered by multiple projects and technologies including a rapid method for creating tissues and even whole organs involve a 3-D printer that can bio-print the scaffolding and cells layer by layer into a working tissue sample or organ. The device is presented in a TED talk by Dr. Anthony Atala, M.D. the Director of the Wake Forest Institute for Regenerative Medicine, and the W.H. Boyce Professor and Chair of the Department of Urology at Wake Forest University, in which a kidney is printed on stage during the seminar and then presented to the crowd. It is anticipated that this technology will enable the production of livers in the future for transplantation and theoretically for toxicology and other biological studies as well.


title: Tissue engineering

text: Recently Multi-Photon Processing (MPP) was employed for in vivo experiments by engineering artificial cartilage constructs. An ex vivo histological examination showed that certain pore geometry and the pre-growing of chondrocytes (Cho) prior to implantation significantly improves the performance of the created 3-D scaffolds. The achieved biocompatibility was comparable to the commercially available collagen membranes. The successful outcome of this study supports the idea that hexagonal-pore-shaped hybrid organic-inorganic micro-structured scaffolds in combination with Cho seeding may be successfully implemented for cartilage tissue engineering.


title: Tissue engineering

text: In 2013, using a 3-D scaffolding of Matrigel in various configurations, substantial pancreatic organoids was produced in vitro. Clusters of small numbers of cells proliferated into 40,000 cells within one week. The clusters transform into cells that make either digestive enzymes or hormones like insulin, self-organizing into branched pancreatic organoids that resemble the pancreas.


title: Tissue engineering

text: The cells are sensitive to the environment, such as gel stiffness and contact with other cells. Individual cells do not thrive; a minimum of four proximate cells was required for subsequent organoid development. Modifications to the medium composition produced either hollow spheres mainly composed of pancreatic progenitors, or complex organoids that spontaneously undergo pancreatic morphogenesis and differentiation. Maintenance and expansion of pancreatic progenitors require active Notch and FGF signaling, recapitulating in vivo niche signaling interactions.


title: Tissue engineering

text: The organoids were seen as potentially offering mini-organs for drug testing and for spare insulin-producing cells.


title: Tissue engineering

text: Aside from Matrigel 3-D scaffolds, other collagen gel systems have been developed. Collagen/hyaluronic acid scaffolds have been used for modeling the mammary gland In Vitro while co-coculturing epithelial and adipocyte cells. The HyStem kit is another 3-D platform containing ECM components and hyaluronic acid that has been used for cancer research. Additionally, hydrogel constituents can be chemically modified to assist in crosslinking and enhance their mechanical properties.


title: Tissue engineering

text: In many cases, creation of functional tissues and biological structures "in vitro" requires extensive culturing to promote survival, growth and inducement of functionality. In general, the basic requirements of cells must be maintained in culture, which include oxygen, pH, humidity, temperature, nutrients and osmotic pressure maintenance.


title: Tissue engineering

text: Tissue engineered cultures also present additional problems in maintaining culture conditions. In standard cell culture, diffusion is often the sole means of nutrient and metabolite transport. However, as a culture becomes larger and more complex, such as the case with engineered organs and whole tissues, other mechanisms must be employed to maintain the culture, such as the creation of capillary networks within the tissue.


title: Tissue engineering

text: Another issue with tissue culture is introducing the proper factors or stimuli required to induce functionality. In many cases, simple maintenance culture is not sufficient. Growth factors, hormones, specific metabolites or nutrients, chemical and physical stimuli are sometimes required. For example, certain cells respond to changes in oxygen tension as part of their normal development, such as chondrocytes, which must adapt to low oxygen conditions or hypoxia during skeletal development. Others, such as endothelial cells, respond to shear stress from fluid flow, which is encountered in blood vessels. Mechanical stimuli, such as pressure pulses seem to be beneficial to all kind of cardiovascular tissue such as heart valves, blood vessels or pericardium.


title: Tissue engineering

text: In tissue engineering, a bioreactor is a device that attempts to simulate a physiological environment in order to promote cell or tissue growth in vitro. A physiological environment can consist of many different parameters such as temperature, pressure, oxygen or carbon dioxide concentration, or osmolality of fluid environment, and it can extend to all kinds of biological, chemical or mechanical stimuli. Therefore, there are systems that may include the application of forces such as electromagnetic forces, mechanical pressures, or fluid pressures to the tissue. These systems can be two- or three-dimensional setups. Bioreactors can be used in both academic and industry applications. General-use and application-specific bioreactors are also commercially available, which may provide static chemical stimulation or a combination of chemical and mechanical stimulation.


title: Tissue engineering

text: Cell proliferation and differentiation are largely influenced by mechanical and biochemical cues in the surrounding extracellular matrix environment. Bioreactors are typically developed to replicate the specific physiological environment of the tissue being grown (e.g., flex and fluid shearing for heart tissue growth). This can allow specialized cell lines to thrive in cultures replicating their native environments, but it also makes bioreactors attractive tools for culturing stem cells. A successful stem-cell-based bioreactor is effective at expanding stem cells with uniform properties and/or promoting controlled, reproducible differentiation into selected mature cell types.


title: Tissue engineering

text: There are a variety of bioreactors designed for 3D cell cultures. There are small plastic cylindrical chambers, as well as glass chambers, with regulated internal humidity and moisture specifically engineered for the purpose of growing cells in three dimensions. The bioreactor uses bioactive synthetic materials such as polyethylene terephthalate membranes to surround the spheroid cells in an environment that maintains high levels of nutrients. They are easy to open and close, so that cell spheroids can be removed for testing, yet the chamber is able to maintain 100% humidity throughout. This humidity is important to achieve maximum cell growth and function. The bioreactor chamber is part of a larger device that rotates to ensure equal cell growth in each direction across three dimensions.


title: Tissue engineering

text: QuinXell Technologies now under Quintech Life Sciences from Singapore has developed a bioreactor known as the TisXell Biaxial Bioreactor which is specially designed for the purpose of tissue engineering. It is the first bioreactor in the world to have a spherical glass chamber with biaxial rotation; specifically to mimic the rotation of the fetus in the womb; which provides a conducive environment for the growth of tissues.


title: Tissue engineering

text: Multiple forms of mechanical stimulation have also been combined into a single bioreactor. Using gene expression analysis, one academic study found that applying a combination of cyclic strain and ultrasound stimulation to pre-osteoblast cells in a bioreactor accelerated matrix maturation and differentiation. The technology of this combined stimulation bioreactor could be used to grow bone cells more quickly and effectively in future clinical stem cell therapies.


title: Tissue engineering

text: MC2 Biotek has also developed a bioreactor known as ProtoTissue that uses gas exchange to maintain high oxygen levels within the cell chamber; improving upon previous bioreactors, since the higher oxygen levels help the cell grow and undergo normal cell respiration.


title: Tissue engineering

text: Active areas of research on bioreactors includes increasing production scale and refining the physiological environment, both of which could improve the efficiency and efficacy of bioreactors in research or clinical use. Bioreactors are currently used to study, among other things, cell and tissue level therapies, cell and tissue response to specific physiological environment changes, and development of disease and injury.


title: Tissue engineering

text: In 2013, a group from the University of Tokyo developed cell laden fibers up to a meter in length and on the order of 100 µm in size. These fibers were created using a microfluidic device that forms a double coaxial laminar flow. Each 'layer' of the microfluidic device (cells seeded in ECM, a hydrogel sheath, and finally a calcium chloride solution). The seeded cells culture within the hydrogel sheath for several days, and then the sheath is removed with viable cell fibers. Various cell types were inserted into the ECM core, including myocytes, endothelial cells, nerve cell fibers, and epithelial cell fibers. This group then showed that these fibers can be woven together to fabricate tissues or organs in a mechanism similar to textile weaving. Fibrous morphologies are advantageous in that they provide an alternative to traditional scaffold design, and many organs (such as muscle) are composed of fibrous cells.


title: Tissue engineering

text: An artificial organ is an engineered device that can be extra corporeal or implanted to support impaired or failing organ systems. Bioartificial organs are typically created with the intent to restore critical biological functions like in the replacement of diseased hearts and lungs, or provide drastic quality of life improvements like in the use of engineered skin on burn victims. While some examples of bioartificial organs are still in the research stage of development due to the limitations involved with creating functional organs, others are currently being used in clinical settings experimentally and commercially.


title: Tissue engineering

text: Extracorporeal membrane oxygenation (ECMO) machines, otherwise known as heart and lung machines, are an adaptation of cardiopulmonary bypass techniques that provide heart and lung support. It is used primarily to support the lungs for a prolonged but still temporary timeframe (1–30 days) and allow for recovery from reversible diseases. Robert Bartlett is known as the father of ECMO and performed the first treatment of a newborn using an EMCO machine in 1975.


title: Tissue engineering

text: Tissue-engineered skin is a type of bioartificial organ that is often used to treat burns, diabetic foot ulcers, or other large wounds that cannot heal well on their own. Artificial skin can be made from autografts, allografts, and xenografts. Autografted skin comes from a patient's own skin, which allows the dermis to have a faster healing rate, and the donor site can be re-harvested a few times. Allograft skin often comes from cadaver skin and is mostly used to treat burn victims. Lastly, xenografted skin comes from animals and provides a temporary healing structure for the skin. They assist in dermal regeneration, but cannot become part of the host skin. Tissue-engineered skin is now available in commercial products. Integra, originally used to only treat burns, consists of a collagen matrix and chondroitin sulfate that can be used as a skin replacement. The chondroitin sulfate functions as a component of proteoglycans, which helps to form the extracellular matrix. Integra can be repopulated and revascularized while maintaining its dermal collagen architecture, making it a bioartificial organ Dermagraft, another commercial-made tissue-engineered skin product, is made out of living fibroblasts. These fibroblasts proliferate and produce growth factors, collagen, and ECM proteins, that help build granulation tissue.


title: Tissue engineering

text: Since the number of patients awaiting a heart transplant is continuously increasing over time, and the number of patients on the waiting list surpasses the organ availability, artificial organs used as replacement therapy for terminal heart failure would help alleviate this difficulty. Artificial hearts are usually used to bridge the heart transplantation or can be applied as replacement therapy for terminal heart malfunction. The total artificial heart (TAH), first introduced by Dr. Vladimir P. Demikhov in 1937, emerged as an ideal alternative. Since then it has been developed and improved as a mechanical pump that provides long-term circulatory support and replaces diseased or damaged heart ventricles that cannot properly pump the blood, restoring thus the pulmonary and systemic flow. Some of the current TAHs include AbioCor, an FDA-approved device that comprises two artificial ventricles and their valves, and does not require subcutaneous connections, and is indicated for patients with biventricular heart failure. In 2010 SynCardia released the portable freedom driver that allows patients to have a portable device without being confined to the hospital.


title: Tissue engineering

text: While kidney transplants are possible, renal failure is more often treated using an artificial kidney. The first artificial kidneys and the majority of those currently in use are extracorporeal, such as with hemodialysis, which filters blood directly, or peritoneal dialysis, which filters via a fluid in the abdomen. In order to contribute to the biological functions of a kidney such as producing metabolic factors or hormones, some artificial kidneys incorporate renal cells. There has been progress in the way of making these devices smaller and more transportable, or even implantable . One challenge still to be faced in these smaller devices is countering the limited volume and therefore limited filtering capabilities.


title: Tissue engineering

text: Bioscaffolds have also been introduced to provide a framework upon which normal kidney tissue can be regenerated. These scaffolds encompass natural scaffolds (e.g., decellularized kidneys, collagen hydrogel, or silk fibroin), synthetic scaffolds (e.g., poly[lactic-co-glycolic acid] or other polymers), or a combination of two or more natural and synthetic scaffolds. These scaffolds can be implanted into the body either without cell treatment or after a period of stem cell seeding and incubation. In vitro and In vivo studies are being conducted to compare and optimize the type of scaffold and to assess whether cell seeding prior to implantation adds to the viability, regeneration and effective function of the kidneys. A recent systematic review and meta-analysis compared the results of published animal studies and identified that improved outcomes are reported with the use of hybrid (mixed) scaffolds and cell seeding; however, the meta-analysis of these results were not in agreeement with the evaluation of descriptive results from the review. Therefore, further studies involving larger animals and novel scaffolds, and more transparent reproduction of previous studies are advisable.


title: Tissue engineering

text: Biomimetics is a field that aims to produce materials and systems that replicate those present in nature. In the context of tissue engineering, this is a common approach used by engineers to create materials for these applications that are comparable to native tissues in terms of their structure, properties, and biocompatibility. Material properties are largely dependent on physical, structural, and chemical characteristics of that material. Subsequently, a biomimetic approach to system design will become significant in material integration, and a sufficient understanding of biological processes and interactions will be necessary. Replication of biological systems and processes may also be used in the synthesis of bio-inspired materials to achieve conditions that produce the desired biological material. Therefore, if a material is synthesized having the same characteristics of biological tissues both structurally and chemically, then ideally the synthesized material will have similar properties. This technique has an extensive history originating from the idea of using natural phenomenon as design inspiration for solutions to human problems. Many modern advancements in technology have been inspired by nature and natural systems, including aircraft, automobiles, architecture, and even industrial systems. Advancements in nanotechnology initiated the application of this technique to micro- and nano-scale problems, including tissue engineering. This technique has been used to develop synthetic bone tissues, vascular technologies, scaffolding materials and integration techniques, and functionalized nanoparticles.


title: Tissue engineering

text: In 2018, scientists at Brandeis University reported their research on soft material embedded with chemical networks which can mimic the smooth and coordinated behavior of neural tissue. This research was funded by the U.S. Army Research Laboratory. The researchers presented an experimental system of neural networks, theoretically modeled as reaction-diffusion systems. Within the networks was an array of patterned reactors, each performing the Belousov-Zhabotinsky (BZ) reaction. These reactors could function on a nanoliter scale.


title: Tissue engineering

text: The researchers state that the inspiration for their project was the movement of the blue ribbon eel. The eel's movements are controlled by electrical impulses determined by a class of neural networks called the central pattern generator.  Central Pattern Generators function within the autonomic nervous system to control bodily functions such as respiration, movement, and peristalsis.


title: Tissue engineering

text: Qualities of the reactor that were designed were the network topology, boundary conditions, initial conditions, reactor volume, coupling strength, and the synaptic polarity of the reactor (whether its behavior is inhibitory or excitatory). A BZ emulsion system with a solid elastomer polydimethylsiloxane (PDMS) was designed. Both light and bromine permeable PDMS have been reported as viable methods to create a pacemaker for neural networks.


title: Tissue engineering

text: The history of the tissue engineering market can be divided into three major parts. The time before the crash of the biotech market in the early 2000s, the crash and the time afterward.


title: Tissue engineering

text: Most early progress in tissue engineering research was done in the US. This is due to less strict regulations regarding stem cell research and more available funding than in other countries. This leads to the creation of academic startups many of them coming from Harvard or MIT. Examples are BioHybrid Technologies whose founder, Bill Chick, went to Harvard Medical School and focused on the creation of artificial pancreas. Another example would be Organogenesis Inc. whose founder went to MIT and worked on skin engineering products. Other companies with links to the MIT are TEI Biosciences, Therics and Guilford Pharmaceuticals. The renewed interest in biotechnologies in the 1980s leads to many private investors investing in these new technologies even though the business models of these early startups were often not very clear and did not present a path to long term profitability. Government sponsors were more restrained in their funding as tissue engineering was considered a high-risk investment.


title: Tissue engineering

text: In the UK the market got off to a slower start even though the regulations on stem cell research were not strict as well. This is mainly due to more investors being less willing to invest in these new technologies which were considered to be high-risk investments. Another problem faced by British companies was getting the NHS to pay for their products. This especially because the NHS runs a cost-effectiveness analysis on all supported products. Novel technologies often do not do well in this respect.


title: Tissue engineering

text: In Japan, the regulatory situation was quite different. First cell cultivation was only allowed in a hospital setting and second academic scientists employed by state-owned universities were not allowed outside employment until 1998. Moreover, the Japanese authorities took longer to approve new drugs and treatments than there US and European counterparts.


title: Tissue engineering

text: For these reasons in the early days of the Japanese market, the focus was mainly on getting products that were already approved elsewhere in Japan and selling them. Contrary to the US market the early actors in Japan were mainly big firms or sub-companies of such big firms, such as J-TEC, Menicon and Terumo, and not small startups. After regulatory changes in 2014, which allowed cell cultivation outside of a hospital setting, the speed of research in Japan increased and Japanese companies also started to develop their own products.


title: Tissue engineering

text: Japanese companies, such as REPROCELL and iPS Academia Japan, are currently working on iPS cell-related products.


title: Tissue engineering

text: Soon after the big boom, the first problems started to appear. There were problems getting products approved by the FDA and if they got approved there were often difficulties in getting insurance providers to pay for the products and getting it accepted by health care providers.


title: Tissue engineering

text: For example, organogenesis ran into problems marketing its product and integrating its product in the health system. This partially due to the difficulties of handling living cells and the increased difficulties faced by physicians in using these products over conventional methods.


title: Tissue engineering

text: Another example would be Advanced Tissue Sciences Dermagraft skin product which could not create a high enough demand without reimbursements from insurance providers. Reasons for this were $4000 price-tag and the circumstance that Additionally Advanced Tissue Sciences struggled to get their product known by physicians.


title: Tissue engineering

text: The above examples demonstrate how companies struggled to make profit. This, in turn, lead investors to lose patience and stopping further funding. In consequence, several Tissue Engineering companies such as Organogenesis and Advanced Tissue Sciences filed for bankruptcy in the early 2000s. At this time, these were the only ones having commercial skin products on the market.


title: Tissue engineering

text: The technologies of the bankrupt or struggling companies were often bought by other companies which continued the development under more conservative business models. Examples of companies who sold their products after folding were Curis and Intercytex.


title: Tissue engineering

text: Many of the companies abandoned their long-term goals of developing fully functional organs in favor of products and technologies that could turn a profit in the short run. Examples of these kinds of products are products in the cosmetic and testing industry.


title: Tissue engineering

text: In the 2010s the regulatory framework also started to facilitate faster time to market especially in the US as new centres and pathways were created by the FDA specifically aimed at products coming from living cells such as the Center for Biologics Evaluation and Research.


title: Tissue engineering

text: In Europe, regulation is currently split into three areas of regulation: medical devices, medicinal products, and biologics. Tissue engineering products are often of hybrid nature, as they are often composed of cells and a supporting structure. While some products can be approved as medicinal products, others need to gain approval as medical devices. Derksen explains in her thesis that tissue engineering researchers are sometimes confronted with regulation that does not fit the characteristics of tissue engineering.


title: Tissue engineering

text: New regulatory regimes have been observed in Europe that tackle these issues. An explanation for the difficulties in finding regulatory consensus in this matter is given by a survey conducted in the UK. The authors attribute these problems to the close relatedness and overlap with other technologies such as xenotransplantation. It can therefore not be handled separately by regulatory bodies. Regulation is further complicated by the ethical controversies associated with this and related fields of research (e.g. stem cells controversy, ethics of organ transplantation). The same survey as mentioned above shows on the example of autologous cartilage transplantation that a specific technology can be regarded as 'pure' or 'polluted' by the same social actor.


title: Tissue engineering

text: Two regulatory movements are most relevant to tissue engineering in the European Union. These are the Directive on standards of quality and safety for the sourcing and processing of human tissues which was adopted by the European Parliament in 2004 and a proposed cells and the Human Tissue- Engineered Products regulation. The latter was developed under the abscise of the European Commission DG Enterprise and presented in Brussels in 2004.


title: Xunantunich

text: Xunantunich () is an Ancient Maya archaeological site in western Belize, about 70 miles (110 km) west of Belize City, in the Cayo District. Xunantunich is located atop a ridge above the Mopan River, well within sight of the Guatemala border – which is to the west. It served as a Maya civic ceremonial centre to the Belize Valley region in the Late and Terminal Classic periods. At that time, when the region was at its peak, nearly 200,000 people lived in the Belize Valley.


title: Xunantunich

text: Xunantunich's name means "Maiden of the Rock" in the Maya language (Mopan and Yucatec combination name Xunaan (Noble lady) Tuunich (stone for sculpture)), and, like many names given to Maya archaeological sites, is a modern name; the ancient name is unknown. The "Stone Woman" refers to the ghost of a woman claimed by several people to inhabit the site, beginning in 1892. She is dressed completely in white, and has fire-red glowing eyes. She generally appears in front of "El Castillo", ascends the stone stairs, and disappears into a stone wall.


title: Xunantunich

text: The first modern explorations of the site were conducted by Thomas Gann in the mid-1890s. Gann moved from Britain and served as the district surgeon and district commissioner of Cayo, British Honduras, starting in 1892. He chose this area to settle in because he had an interest in Mayan archaeology, and he wished to be able to explore what were at the time the unknown wonders of the indigenous people. Gann's successor, Sir J. Eric S. Thompson, implemented a more methodical approach, and was able to establish the region's first ceramic chronology. The main recent archaeological teams to work at Xunantunich and the surrounding region are the Xunantunich Archaeological Project (XAP), the Xunantunich Settlement Survey (XSS), and the Belize Valley Archaeological Reconnaissance Project (BVAR).


title: Xunantunich

text: In 1959–60, the Cambridge Expedition to British Honduras arrived in the colony, and its archaeologist member, Euan MacKie, carried out several months of excavation at Xunantunich. He excavated the upper building on Structure A-11 in Group B and a newly discovered residential structure, A-15, just outside the main complex. Using the European method of detailed recording of the stratigraphy of the superficial deposits (the masonry structures themselves were not extensively cut into) he was able to infer that both buildings had been shattered by a sudden disaster which marked the end of the Classic period occupation. An earthquake was tentatively proposed as the cause; it is inferred purely on the basis of the excavated evidence, and also on the very damaged state of the top building of Structure A-6 ('El Castillo'). He was also able to confirm the later part of the pottery sequence constructed by Thompson. The detailed report by MacKie is "Excavations at Xunantunich and Pomona, Belize, in 1959–60". British Archaeological Reports (Int. series), 251, 1985: Oxford.


title: Xunantunich

text: Farmers that fed the people living in Xunantunich typically lived in small villages, divided into kin-based residential groups. The farms were spread out widely over the landscape, though the center of Xunantunich itself is rather small in comparison. These villages were economically self-sufficient, which may be the reason why Xunantunich lasted as long as they did; they were not dependent on the city to provide for them. Settlement density was relative to soil quality, proximity to rivers, and localized political histories. Since the farmers were long established on their plots of land, they would not want to be involved with a polity that was under constant upheaval due to invading forces and more. Other nearby Maya archaeological sites include Chaa Creek and Cahal Pech, Buenavista del Cayo, and Naranjo.


title: Xunantunich

text: There is evidence of Xunantunich being settled as early as the ceramic phase of the Preclassic period. The findings have been too insubstantial to prove that Xunantunich was a site of importance. It was not until the Samal phase in AD 600–670 that Xunantunich began to grow significantly in size. Architectural constructions boomed in Hats’ Chaak phase (AD 670–750) when Xunantunich's connection with the polity Naranjo solidified. Left in a state of abandonment at approximately AD 750 due to an unknown violent event (see Euan MacKie's work in 1959–60, above, which may be relevant here), Xunantunich did not re-establish itself as a strong presence in the region until the Tsak’ phase in AD 780–890.


title: Xunantunich

text: The core of the city Xunantunich occupies about one square mile (2.6 km), consisting of a series of six plazas surrounded by more than 26 temples and palaces. As an entire polity, Xunantunich contains 140 mounds per square km, as discovered in the surveys done by the XSS. One of Xunantunich's better known structures is the pyramid known as "El Castillo" (not to be confused with the El Castillo at Chichen Itza).


title: Xunantunich

text: The site is broken up into four sections – Group A, Group B, Group C, and Group D, with Group A being central and most significant to the people. Prior to the seventh century, the site was mainly occupied by small houses, forming the occasional village. With the architectural boom in the Samal phase, we see the extreme importance of cosmological and political placing of the monuments in relation to the axis mundi (the intersection cardinal axis of the site; the heart of the site).


title: Xunantunich

text: It is the second tallest structure in Belize (after the temple at Caracol), at some 130 feet (40 m) tall. El Castillo is the “axis mundi” of the site, or the intersection of the two cardinal lines. Evidence of construction suggests the temple was built in two stages (the earlier dubbed Structure A-6–2nd, which dates to around 800 AD, and the later Structure A-6–1st). Structure A-6–2nd had three doorways, whereas Structure A-6–1st only had doors on the north and south. The pyramid lies underneath a series of terraces. The fine stucco or "friezes" are located on the final stage. The northern and southern friezes have eroded, and the others were covered during the reconstruction and over time. There is a plaster mold on the Eastern wall frieze. The frieze depicts many things. Each section of the frieze is broken up by framing bands of plaited cloth or twisted cords (which represent celestial phenomena). The frieze depicts the birth of a god associated with the royal family, gods of creation, as well as the tree of life (which extends from the underworld, the earth, and the heavens).


title: Xunantunich

text: Structure A-1 was built in the Late Classic, at around 800 AD. It bisected Plaza A-I, which had until then been the most important plaza in the site. It now lies on top of the original ball court of Xunantunich between Structure A-6 (El Castillo) and A-11. It became a ritual space solely for the rulers and elite, which doubled as an impediment to other public spaces.


title: Xunantunich

text: On July 19, 2016, a team led by Jaime Awe discovered an untouched burial chamber attached to a larger building. It is considered to be one of the largest Mayan burial chambers found within the last 100 years. The chamber contained the corpse of a male, aged between 20 and 30 years. The chamber also contained a number of ceramic vessels, obsidian knives, jade pearls, animal bones and some other artefacts made of stone. Osteologists believe the man was athletic and quite muscular when he died.


title: Xunantunich

text: During a time period when most of Mayan civilizations were crumbling, Xunantunich was managing to expand its city and its power over other areas within the valley. It lasted a century longer than most of the sites within the region. It is known that Xunantunich superseded Buenavista as the hub of sociopolitical administration for the upper valley, in addition to the main location for elite ancestral and funeral rites and ceremonies. One theory is the move was made due to political strife in the lowlands due to neighbors vying for control over Buenavista, and that Xunantunich was a much more easily defensible site (located on top of a hill).


title: Xunantunich

text: There is evidence of trade and communication between other sites in abundance. First, there is the disbursement of pine. Pine naturally grows in the Mountain Pine Ridge, which is accessible via the Macal River. It was imported to Xunantunich, where the disbursement of this valuable commodity could be controlled by elites and rulers. This resource was used in ritualistic and building purposes for the upper class, and would sometimes be given to members of the lower class to strengthen socio-political strategies. Similarities between pottery among different sites is a trait commonly looked for by archaeologists. The difference between qualities of pottery can accentuate gaps between social classes within a location, just as it can show the difference between classes of other polities. In the Terminal Classic period, equality in the distribution of pottery at Xunantunich can be seen as political currency across the Belize Valley. Pottery types became uniform among sites found in the areas in Belize Valley around Xunantunich, further evidence of their strong relationships with the “Stone Woman” site.


title: Xunantunich

text: Due to regional conflicts, Naranjo, a regional polity, began to disintegrate around the 9th century. It transformed from a regional authority to a smaller site, which eventually disappeared into the background. For reasons not yet understood, documentary hieroglyphs rapidly disappeared in AD 820 at Naranjo; which aligns with the earliest stela at Xunantunich, Stela 8. The stela, hieroglyphs and architecture are stylistically similar to Naranjo's in style From here, there was a power shift to Xunantunich, although the influence of Naranjo prior to this is certain. The construction of the core site itself is extremely similar to the layout of Naranjo's Group B layout. The pronounced north–south axis (believed to be a link to royal authority and continuity) is shared between the two, the buildings are placed in similar spots, and the shapes of the buildings resemble one another.


title: Nizami Ganjavi

text: Nizami Ganjavi (; c. 1141–1209), Nizami Ganje'i, Nizami, or Nezāmi, whose formal name was "Jamal ad-Dīn Abū Muḥammad Ilyās ibn-Yūsuf ibn-Zakkī", was a 12th-century Persian Sunni Muslim poet. Nezāmi is considered the greatest romantic epic poet in Persian literature, who brought a colloquial and realistic style to the Persian epic. His heritage is widely appreciated and shared by Afghanistan, Republic of Azerbaijan, Iran, the Kurdistan region and Tajikistan.


title: Nizami Ganjavi

text: His personal name was Ilyas and his chosen pen-name was Nezami (also spelled as Nizami and Neẓāmi). He was born of an urban background in Ganja (Seljuq empire, now Republic of Azerbaijan) and is believed to have spent his whole life in South Caucasus. According to De Blois, Ganja was a city which at that time had predominantly an Iranian population. The Armenian historian Kirakos Gandzaketsi (c. 1200 – 1271) mentions that: "This city was densely populated with Iranians and a small number of Christians".


title: Nizami Ganjavi

text: Because Nezami was not a court poet, he does not appear in the annals of the dynasties. Tazkerehs, which are the compilations of literary memoirs that include maxims of the great poets along with biographical information and commentary of styles refer to him briefly. Much of this material in these Tazkerehs are based on legends, anecdotes, and hearsays. Consequently, few facts are known about Nezami's life, the only source being his own work, which does not provide much information on his personal life.


title: Nizami Ganjavi

text: Nezami was orphaned early and was raised by his maternal uncle Khwaja Umar who took responsibility for him and afforded him an excellent education. His mother, named "Ra'isa", was of Kurdish origin. His father, whose name was "Yusuf" is mentioned once by Nezami in his poetry. In the same verse, Nezami mentions his grandfather's name as "Zakki". In part of the same verse, some have taken the word "Mu'ayyad" as a title for Zakki while others have interpreted it as the name of his great-grandfather. Some sources have stated that his father might be possibly from Qom. Nezami is variously mentioned as a Persian and/or Iranian.


title: Nizami Ganjavi

text: Nezami was married three times. His first wife was a Kipchak slave girl which was sent to him by Fakhr al-Din Bahramshah, the ruler of Darband, as part of a larger gift. According to Iraj Bashiri she became Nezami's "most beloved" wife. His only son "Mohammad" was from this wife. She died after "Khosrow and Shirin" was completed. Mohammad was seven at the time. Nezami mentions his son again in Layli and Majnun adding that now this son is 14 years old and "apple of my eyes". In "Haft Peykar" (Seven Beauties), he also mentions and advises his son about taking more responsibility as the father was growing more frail.


title: Nizami Ganjavi

text: Some modern writers in the late 20th century have claimed that this wife was called "Afaq". Vahid Dastgerdi seems to be the first writer to propose this name for Nezami's first wife, but Said Nafisi (at the same time) and a recent source have challenged this interpretation of the corresponding verse in Nezami's work and the assumption that "Afaq" was the real name of his wife and have taken the "Afaq" in that verse to simply mean "horizon" rather than a proper name. Strangely enough, Nezami's two other wives, too, died prematurely – the death of each coinciding with the completion of an epic, prompting the poet to say, "God, why is it that for every mathnavi I must sacrifice a wife!".


title: Nizami Ganjavi

text: Nezami was not a philosopher in the sense of Avicenna or an expositor of theoretical Sufism in the sense of Ibn 'Arabi. However, he is regarded as a philosopher and gnostic who mastered various fields of Islamic thoughts which he synthesized in a way that brings to mind the traditions of later Hakims such as Qutb al-Din Shirazi.


title: Nizami Ganjavi

text: Often referred to by the honorific Hakim ("the Sage"), Nezami is both a learned poet and master of a lyrical and sensuous style. About Nezami's prodigious learning there is no doubt. Poets were expected to be well versed in many subjects; but Nezami seems to have been exceptionally so. His poems show that not only he was fully acquainted with Arabic and Persian literatures and with oral and written popular and local traditions, but was also familiar with such diverse fields as mathematics, astronomy, astrology, alchemy, medicine, botany, Koranic exegesis, Islamic theory and law, Iranian myths and legends, history, ethics, philosophy and esoteric thought, music, and the visual arts. His strong character, social sensibility, and knowledge of oral and written historical records, as well as his rich Persian cultural heritage unite pre-Islamic and Islamic Iran into the creation of a new standard of literary achievement. Being a product of the Iranian culture of the time, he not only created a bridge between pre-Islamic and Islamic Iran, but also between Iran and the whole ancient world.


title: Nizami Ganjavi

text: The recent discovery and publication of the anthology titled "Nozhat al-Majales" contains Persian language quatrains from Nizami and 115 other poets from the northwestern Iran (Arrān, Šarvān, Azerbaijan; including 24 poets from Ganja alone) during the same era. Unlike other parts of Persia, where the poets mostly belonged to higher echelons of society such as scholars, bureaucrats, and secretaries, a good number of poets in the northwestern areas rose from among the common people with working-class backgrounds, and they frequently used colloquial expressions in their poetry. Accordingly, the book demonstrates the social conditions at the time, reflecting the full spread of Persian language and the culture in the region, which is evidenced by the common use of spoken idioms in poems and the professions of many of the poets. The influence of the northwestern Pahlavi language, for example, which had been the spoken dialect of the region, is clearly observed in the poems contained in this anthology. However, at the same time, the Caucasus region was entertaining a unique mixture of ethnic cultures. Khaqani's mother was a Nestorian Christian, Mojir Baylqani's mother was an Armenian, and Nezami's mother was a Kurd. Their works reflect the cultural and linguistic diversity of the region.


title: Nizami Ganjavi

text: By the end of the 10th century, Persian literature became widespread from the eastern Mediterranean to the banks of the Indus. The earliest extant example of Persian poetry from the area is that of Qatran Tabrizi (1009–1072) who served in the courts of the Shaddadid and Rawadid dynasties. Qatran Tabrizi, is credited with what some scholars in the last century have termed as the founder of the "Azerbaijan" or "Trans-Cacausian" school or "Tabriz School" or "Shirvan School" or "Arranian Style" of Persian poetry. This school produced a distinctive style of poetry in Persian, which contrasted with "Khurasani" ("Eastern") style in its rhetorical sophistication, its innovative use of metaphor, its use of technical terminology and Christian imagery, the presence of Persian archaism while borrowing from Arabic vocabulary, as well as new concepts. Other sources including the Encyclopaedia of Islam and traditional Iranian literary sources have used the term "'Iraqi" style for the Persian poetry of Nezami.


title: Nizami Ganjavi

text: The Seljuqs took control of Ganja from the Shaddadids in 1075 and spread Persian literary westwards to their courts. In the middle of the 12th century, the Seljuk Empire's control of the region weakened and their provincial governors, virtually autonomous local princes, further encouraged Persian culture, art and poetry in their courts. Persian culture characteristically flourished in this era, when political power was diffused and Persian remained the primary language, Persian civil servants and merchants were in great demand and rival dynasties continued to vie for the service of Persian poets. This was especially true in Ganjeh, the Caucasian outpost town where Nizami lived. Nezami was patronized by different rulers and dedicated his epics to various rival dynasties, including the Seljuqs, Eldiguzids (who maintained control of Ganja during most of the later 12th century), Shirvanshahs, the ruler of Ahar and Ahmadilis. Although he enjoyed the patronage of various rulers and princes, he avoided the courts and is generally believed to have lived a secluded life. Since he was not a court poet, he does not appear in the annals of the dynasties, which list the names of events of the ruling families.


title: Nizami Ganjavi

text: According to literary scholar Chelkowski, """it seems that Nezami's favorite pastime was reading Firdawsi's monumental epic Shahnameh (The book of Kings). Nezami mentioned Ferdowsi as the Sage (Hakim) and Knower/Wise (daanaa) and the great master of discourse, "who has decorated words like new bride." Nezami advises the son of the Shirvanshah to read the Shah-nama and to remember the meaningful sayings of the wise. Nezami used the "Shahnameh" as a source in his three epics of "Haft Peykar, Khosrow and Shirin" and "Eskandar-Nameh".


title: Nizami Ganjavi

text: The story of "Vis and Ramin" also had an immense influence on Nezami. Although Nezami takes the bases for most of his plots from Ferdowsi, but the basis for his rhetoric comes from Gorgani. This is especially noticeable in "Khosrow and Shirin", which is of the same meter and imitates some scenes from "Vis and Ramin". Nezami's concern with astrology also has a precedent in an elaborate astrological description of the night sky in "Vis and Ramin". Nezami had a paramount influence on the romantic tradition, and Gorgani can be said to have initiated much of the distinctive rhetoric and poetic atmosphere of this tradition, with the absence of the Sufi influences, which are seen in Nezami's epic poetry.


title: Nizami Ganjavi

text: The first monumental work of Nezami, the "Makhzan al-Asrar" is influenced by Sanai's "Hadikat al-Hakika". Nezami acknowledges this, but considers his work to be superior. The main similarities between Sanai's poem and Nezami's are in its ethico-philosophical genre, although Nezami uses a different metre and organized the whole work in a different fashion. Khaqani Sherwani daring imagery, was to have a momentous influence on Nezami Ganjavi and through the latter on Persian poetry in general.


title: Nizami Ganjavi

text: Nezami lived in an age of both political instability and intense intellectual activity, which his poems reflect; but little is known about his life, his relations with his patrons, or the precise dates of his works, as the many legends built up around the poet color the accounts of his later biographers. He dedicated his poems to various rulers of the region as was custom of that time for great poets, but avoided court life. Nezami was a master of the "Masnavi" style (double-rhymed verses).


title: Nizami Ganjavi

text: Nizami's main poetical work, for which he is best known, is a set of five long narrative poems known as the "Khamsa" (, 'Quintet or Quinary') or "Panj Ganj" (, 'Five Treasures'):


title: Nizami Ganjavi

text: The first of these poems, "Makhzan-ol-Asrâr", was influenced by Sanai's (d. 1131) monumental "Garden of Truth". The four other poems are medieval romances. Khosrow and Shirin, Bahram-e Gur, and Alexander the Great, who all have episodes devoted to them in Ferdowsi's "Shahnameh", appear again here at the center of three of four of Nezami's narrative poems. The adventure of the paired lovers, Layla and Majnun, is the subject of the second of his four romances, and derived from Arabic sources. In all these cases, Nezami reworked the material from his sources in a substantial way.


title: Nizami Ganjavi

text: The "Khamsa" was a popular subject for lavish manuscripts illustrated with painted miniatures at the Persian and Mughal courts in later centuries. Examples include the Khamsa of Nizami (British Library, Or. 12208), created for the Mughal Emperor Akbar in the 1590s.


title: Nizami Ganjavi

text: The ethico-philosophical poems of about 2,250 Persian distichs was dedicated to Fakhr al-Din Bahramshah, the ruler of Erzinjan. The story deals with such esoteric subjects as philosophy and theology. The story contains twenty discourses, each of them portraying an exemplary story on religious and ethical topics. Each chapter concludes with apostrophe to the poet himself containing his pen name. The content of the poems are indicated in the heading to each chapter and are written in a typical Homiletics style. The stories which discuss spiritual and practical concerns enjoin kingly justice, riddance of hypocrisy, warning of vanity of this world and the need to prepare for the after-life. The general message of the discourse is that Nezami preaches the ideal way of life drawing attention to his reader of the supreme rank man among God's creatures and approaching of the end life and the necessity of man becoming aware of his spiritual destination. In a few chapters he address the duties of a king, but as a whole he addresses himself to mankind in general rather than to his royal patrons. In the introduction, the poet provides an account of his solitary vigils, called Khalwat. There is no indication that these were Sufi vigils, but they are used as a literary fantasy on the spiritually-inclined poet he wanted to be. In highly rhetorical style, the aim he pursues is to transcend the limitation of secular literature of the courts. With this work, Nezami joins the destination of Persian poetry, which had started with Sanai and was continued by others, in the first place by Attar.


title: Nizami Ganjavi

text: Not a romantic epic, "The Treasury of Mysteries" was translated into English by Gholam H. Darab in 1945. After this early work, Nezami turned towards narrative poetry.


title: Nizami Ganjavi

text: A story of pre-Islamic Persian origin which is found in the great epico-historical poems of Shahnameh and is based on a true story that was further romanticized by Persian poets. The story chosen by Nezami, was commissioned and dedicated to the Seljuk Sultan Toghril II, the Atabek Muhammad ibn Eldiguz Jahan Pahlavan and his brother Qizil Arslan. It contains about 6,500 distichs in length, the story depicts the love of Sassanian Khosrow II Parviz towards his Armenian princess Shirin. "Khusrow and Shirin" recounts the story of King Khosrow's courtship of Princess Shirin, and the vanquishing of his love-rival, Farhad. The story has a complex structure with several genres exploited simultaneously; and contains many verbal exchanges and letters, all imbued with lyrical intensity. Khosrow endures long journeys, physical and spiritual, before returning to Shirin, his true love. They are eventually married, but finally Khosrow is killed by his son and Shirin commits suicide over the body of her murdered husband. Pure and selfless love is represented here embodied in the figure of Farhad, secretly in love with Shirin, who falls victim to the king's ire and jealousy.


title: Nizami Ganjavi

text: The influence of Vis o Ramin is visible as the poem imitates a major scene (that of the lovers arguing in the snow) from Vis o Rāmin, as well as being in the same meter ("hazaj") as Gorgāni's poem. Nezami's concern with astrology also has a precedent in an elaborate astrological description of the night sky in Vis o Rāmin. In turn, Nezami's great work had a tremendous influence on later authors and many imitations of this work were made. With complete artistic and structural unity, the epic of Khosrow o Shirin turned to be a turning point not only for Nizami but for all of Persian literature.


title: Nizami Ganjavi

text: A story of Arabic origin which was later adapted and embellished by the Persians. The poem of 4,600 distichs was dedicated, in 1192, to Abu al-Muzaffar Shirvanshah, who claimed descent from the Sassanid King, whose exploits are reflected in Nezami's "Seven Beauties" (Haft Paykar). The poem is based on the popular Arab legend of ill-starred lovers: the poet Qays falls in love with his cousin Layla, but is prevented from marrying her by Layla's father. Layla's father forbids contact with Qays, so that Qays becomes obsessed and starts singing of his love for Layla in public. The obsession becomes so severe that he sees and evaluates everything in terms of Layla; hence his sobriquet "the possessed" (Majnun). Realizing that he cannot obtain union, even when other people intercede for him, he leaves society and roams naked in the desert among the beasts. However the image of Layla was so ingrained in him that he cannot eat or sleep. His only activity becomes composing poetry of longing for Layla. Meanwhile, Layla is married against her will, but she guards her virginity by resisting the advances of her husband. In a secret meeting with Majnun, they meet, but have no physical contact. Rather, they recite poetry to each other from a distance. Layla's husband dies eventually, which removes the legal obstacles to a licit union. However Majnun is so focused on the ideal picture of Layla in his mind, that he fled into the desert again. Layla dies out of grief and is buried in her bridal dress. Hearing this news, Majun rushes to her grave, where he instantly dies. They are buried side by side and their grave becomes a site of pilgrimage. Someone dreams that in Paradise they are united and live as a king and queen.


title: Nizami Ganjavi

text: Nezami composed his romance at the request of the Shirvanshah Akhsatan. Initially, he doubted that this simple story about the agony and pain of an Arab boy wandering in rough mountains and burning deserts would be a suitable subject for royal court poetry and his cultured audience. It was his son who persuaded him to undertake the project, saying: "wherever tales of love are read, this will add spice to them". Nezami used many Arabic anecdotes in the story, but also adds a strong Persian flavor to the legend.


title: Nizami Ganjavi

text: An important aspect of Layla and Majun is the poet's highly humanitarian approach. During the war by Nawfal in favor of Majnun, the latter is unhappy wishing the termination of the war. Majun gives away his horse and amours to save a gazelle and a stag.


title: Nizami Ganjavi

text: Nezami gave a Persian character to the poem by adding several techniques borrowed from the Persian epic tradition, such as the portrayal of characters, the relationship between characters, description of time and setting, etc. Further, he adapted the different stories about Majnun to fit a well-crafted Persian romantic epic.


title: Nizami Ganjavi

text: "The Story of Layla and Majnun by Nizami", was edited and translated into English by Swiss scholar of Islamic culture Rudolf Gelpke and published in 1966. A comprehensive analysis in English containing partial translations of Nezami's romance "Layla and Majnun" examining key themes such as chastity, constancy and suffering through an analysis of the main characters was published by Ali Asghar Seyed-Gohrab.


title: Nizami Ganjavi

text: The Romance of Alexander the Great contains 10,500 distichs. There are differences of opinion on whether this or the "Haft Paykar" was Nezami's last epic. The names of its dedicatees are uncertain, but the ruler of Ahar, Nosart al-Din Bishkin b. Mohammad has been mentioned. The story is based on Islamic myths developed about Alexander the Great, which derive from Qur'anic references to the Dhu'l-Qarnayn as well as from the Greek Alexander romance of Pseudo-Callisthenes. It consists of two books, Sharaf-Nama and Iqbal-nameh. The poem narrates the three stages in Alexander's life: first as the conqueror of the world; then as a seeker after knowledge, gaining enough wisdom to acknowledge his own ignorance; and finally as a prophet, traveling once again across the world, from west to east, and south to north to proclaim his monotheistic creed to the world at large. The Sharaf-nama discusses the birth of Alexander, his succession to the throne of Rum (Greece), his wars against Africans who invaded Egypt, his conquest of Persia and his marriage to the daughter of Darius. The episode also discusses Alexander's pilgrimage to Mecca, his stay in the Caucasus and his visit to Queen Nushaba of Barda' and her court of Amazons. Alexander conquers India, China and the land of the Rus. The Sharafnama concludes with Alexander's unsuccessful search for the water of immortal life.


title: Nizami Ganjavi

text: The Iqbal-nameh is a description of Alexander's personal growth into the ideal ruler on a model ultimately derived, through Islamic intermediaries, from Plato's Republic. He has debates with Greek and Indian philosophers (c.f. with Garshaspnama) and a major portion of the text is devoted to the discourses he has with seven Greek sages. The poet then tells of Alexander's end and adds an account of the circumstances of the death of each of the seven sages. Nezami's image of Alexander is that of an Iranian knight.


title: Nizami Ganjavi

text: An English translation of the Sharaf-Nama by Henry Wilberforce-Clarke was published in 1881 under the title "Sikandar Nama e Bara" and is available online.


title: Nizami Ganjavi

text: A pre-Islamic story of Persian origin, it was dedicated to the ruler of Maragha, 'Ala' Al-Din korp Arslan. It is the story of Bahram V, the Sassanid king, who is born to Yazdegerd after twenty years of childlessness and supplication to Ahura Mazda for a child. The Haft Peykar is a romanticized biography of the Sasanian Persian empire ruler Bahram Gur. His adventurous life had already been treated by Ferdowsi in the Shahnama, to which fact Nezami alludes a number of times. In general, his method is to omit those episodes that the earlier poet had treated, or to touch on them only very briefly, and to concentrate on new material. The poet starts by giving an account of the birth of Bahram Gur and his upbringing in the court of the Arab King No'man and his fabled palace Khwarnaq. Bahram whose upbringing is entrusted to No'man becomes a formidable huntsman. While wandering through the fabled palace, he discovers a locked room which contains a depiction of seven princesses; hence the name Haft Peykar (seven beauties). Each of these princesses is from the seven different climes (traditional Zoroastrian-Islamic division of the Earth) and he falls in love with them. His father Yazdegerd I passes away and Bahram returns to Persia to claim his throne from pretenders. After some episodes he is recognized as King and rescues the Persians from a famine. Once the country is stable, the King searches for the seven princesses and wins them as his brides. His architect is ordered to construct seven domes for each of his new brides. The architect tells him that each of the seven climes is ruled by one of the seven planets (classical planetary system of Zoroastrian-Islamic world) and advises him to assure good fortune by adorning each dome with the color that is associated with each clime and planet. Bahram is skeptical but follows the advice of the architect. The princesses take up residence in the splendid pavilions. On each visit, the king visits the princesses on successive days of the week; on Saturday the Indian princess, who is governed by Saturn and so on. The princesses names are Furak (Nurak), the daughter of the Rajah of India, as beautiful as the moon; Yaghma Naz, the daughter of the Khaqan of the Turks; Naz Pari, the daughter of the king of Khwarazm; Nasrin Nush, the daughter of the king of the Slavs; Azarbin (Azareyon), the daughter of the king of Morocco; Humay, the daughter of the Roman Caesar; and Diroste (wholesome), a beautiful Iranian princess from the House of Kay Ka'us. Each princess relates to the king a story matching the mood of her respective color. These seven beautifully constructed, highly sensuous stories occupy about half of the whole poem. While the king is busy with the seven brides, his evil minister seizes power in the realm. Bahram Gur discovers that the affairs of Persia are in disarray, the treasury is empty and the neighboring rulers are posed to invade. He clears his mind first by going hunting. After returning from hunt, he sees a suspended dog from a tree. The owner of the dog, who was shepherd, tells the story of how his faithful watchdog had betrayed his flock to a she-wolf in return for sexual favors. He starts investigating the corrupt minister and from the multitude of complaints, he selects seven who tell him the injustice they have suffered. The minister is subsequently put to death and Bahram Gur restores justice and orders the seven pleasure-domes to be converted to fire temples for the pleasure of God. Bahram then goes hunting for the last time but mysteriously disappears. As a pun on words, while trying to hunt the wild ass ("gūr") he instead finds his tomb ("gūr").


title: Nizami Ganjavi

text: Ritter, in his introduction to the critical edition describes it as: "the best and most beautiful epic in New Persian poetry and at the same time [. . .] one of the most important poetical creations of the whole of oriental Indo-European literature". The Haft Peykar is considered the poet's masterpiece. Overall, Nezami illustrates the harmony of the universe, the affinity of the sacred and the profane, and the concordance of ancient and Islamic Iran.


title: Nizami Ganjavi

text: The story was translated to English in 1924 by Charles Edward Wilson. A newer English rendering based on more complete manuscripts was accomplished by Julie Scott Meysami in 1995.


title: Nizami Ganjavi

text: Only a small corpus of his Persian lyric poetry, mainly qaṣīdahs ("odes") and ghazals ("lyrics") have survived. Ten of his quatrains have also been recorded in the anthology Nozhat al-Majales (which was compiled around 1250) by Jamal Khalil Shirvani along with 23 other poets from Ganja. A famous ghazal of Nezami talks about altruism as the path for reaching the ultimate spiritual goal:


title: Nizami Ganjavi

text: Nizami, whose works are all written in Persian, has a very high reputation in Iran, Afghanistan and Tajikistan, where Persian is the official language. His poetry is especially well known in Iran, and is also very popular in Azerbaijan, where his birthplace and mausoleum are located. He is known in other countries, especially in India and Pakistan .


title: Nizami Ganjavi

text: The influence of Neẓāmi's work on the subsequent development of Persian literature has been enormous and the Khamseh became a pattern that was emulated in later Persian poetry (and also in other Islamic literatures). The legacy of Nezami is widely felt in the Islamic world and his poetry has influenced the development of Persian, Arabic, Turkish, Kurdish and Urdu poetry amongst many other languages.


title: Nizami Ganjavi

text: In the history of Persian miniature painting, the stories in Nezami's poems alongside those of Ferdowsi's "Shahnama" have been the most frequently illustrated literary works. According to the Encyclopædia Britannica, Nezami is "admired in Persian-speaking lands for his originality and clarity of style, though his love of language for its own sake and of philosophical and scientific learning makes his work difficult for the average reader." Nezami composed his verses in Persian language and Western encyclopedias such as Encyclopedia of Islam, Encyclopædia Iranica, Encyclopædia Britannica and orientalists of many countries consider Nezami as a significant Persian poet and hail him as the greatest exponent of romantic epic poetry in Persian literature.


title: Nizami Ganjavi

text: Amongst the many notable poets who have taken the "Five Treasures" of Nezami as their model may be mentioned Amir Khusro, Jalal Farahani, Khwaju Kermani, Mohammad Katebi Tarr-Shirini, Abdul Rahman Jami, Hatefi Jami, Vahshi Bafqi, Maktabi Shirazi, Ali-Shir Nava'i, Abdul Qader-e Bedel Dehlavi, Fuzûlî, Hashemi Kermani, Fayzi, Jamali and Ahmad Khani. Not only poets, but also historians such as Rawandi were influenced by Nezami's poetry and used his poems as a source for rendering history. Besides these, scores of poets have started their composition with the first line of the "Makhzan al-Asrar".


title: Nizami Ganjavi

text: According to Rudolf Gelpke, "Many later poets have imitated Nizami's work, even if they could not equal and certainly not surpass it; Persians, Turks, Indians, to name only the most important ones. The Persian scholar Hekmat has listed not less than forty Persian and thirteen Turkish versions of "Layli and Majnun"."


title: Nizami Ganjavi

text: According to Vahid Dastgerdi, "If one would search all existing libraries, one would probably find more than 1000 versions of "Layla and Majnun"."


title: Nizami Ganjavi

text: Jami in his Nafahatol Ons remarks that: "Although most of Nezami's work on the surface appear to be romance, in reality they are a mask for the essential truths and for the explanation of divine knowledge."


title: Nizami Ganjavi

text: Jami in his Baharestan mentions that "Nezami's excellence is more manifest than the sun and has no need of description. Hashemi of Kerman remarks: The empire of poetry obtained its law and order from Nezami's beautiful verses and To present words before Nezami's silent speech is a waste of time."


title: Nizami Ganjavi

text: Ganjavi's poems were very popular in the Indian subcontinent. Persian language and literature have had a great impact on the entire Indian subcontinent. Nizami Ganjavi has been imitated by many poets due to his unique style of speech and language of poetry. Poets who have imitated Ganjavi's woto include: Amir Khusro Delhi, Khwaju Kermani, Jami, Hatefi, Ghasemi, Vahshi Bafqi, 'Orfi Shirazi, Maktabi, Faizi, Ashraf Maraghi, Azar Bigdeli, Badriddin Hilali , Rumi Kermani, Maulana Navidi Shirazi and Salman Savaji.


title: Nizami Ganjavi

text: According to the book Persian Inscriptions on Indian Monuments in the Rashtrapati Bhavan in Ashoka Hall, the most important hall of the Indian Presidential Palace, Persian poems were written and decorated with paintings from Iran or Persia such as the Fateh Ali Shah, Shah Qajar and poems of Hafez, Khayyam and Nezami Ganjavi are painted on the ceiling and parts of the hall. A large oil painting illustration of Nezami Ganjavi and a large painting of a Persian lady on both sides of the Ashoka Hall of Rashtrapati Bhavan.


title: Nizami Ganjavi

text: The Khamsa was a popular subject for lavish manuscripts with painted miniatures at the Persian and Mughal courts in later centuries. Examples include the Khamsa of Nizami (British Library, Or. 12208), created for the Mughal(Gurkanid) Emperor Akbar in the 1590s.


title: Nizami Ganjavi

text: In the early 1940s and to mark the 800th anniversary of Nizami Ganjavi, Azerbaijani composer Uzeyir Hajibeyov planned to write seven songs based on Nizami's poem about the "Seven Beauties". However Hajibeyov wrote only two songs: "Sensiz" (Without You, 1941) and "Sevgili Janan" (Beloved, 1943). Another Azerbaijani composer Gara Garayev, composed Seven Beauties (ballet) in 1947–48 based on Nizami's eponymous poem that won an international acclaim. He also composed Leyli and Majnun (ballet) that premiered on 25 May 1969 at the Azerbaijan State Academic Opera and Ballet Theater in Baku and later was recorded as a film.


title: Nizami Ganjavi

text: A minor planet, called 3770 Nizami, was discovered by Soviet astronomer Lyudmila Chernykh in 1974 and named after him. Further, the Museum of Azerbaijan literature in Baku is named after Nizami.


title: Nizami Ganjavi

text: Nezami was depicted on the obverse of the Azerbaijani 500 manat banknote of 1993–2006. In 2008, coinciding with the 800th anniversary of his death, the National Bank of Azerbaijan minted a 100 manat gold commemorative coin dedicated to his memory.


title: Nizami Ganjavi

text: The Nizami Museum of Literature is located in Baku, Republic of Azerbaijan. One of the Baku Metro stations is also named after Nizami Ganjavi. There is Institute of Literature named after Nizami and Cinema named after Nizami in Baku. One of the districts of Baku is called Nizami raion. The life of Nizami Ganjavi is shown in the Azerbaijani movie "Nizami" (1982), in which the leading role, role of Nizami Ganjavi, was played by Muslim Magomayev. The Nizami Mausoleum, built in honor of Nizami, stands just outside the city of Ganja in Azerbaijan. It is a tall cylindrical building, surrounded by gardens. To one side, there is a metal statue commemorating Nizami's epic poems. The mausoleum was originally built in 1947 in place of an old collapsed mausoleum and rebuilt in its present form when the Azerbaijani Republic regained its independence after the fall of the Soviet Union in 1991.


title: Nizami Ganjavi

text: Monuments to Nezami are found in many cities of Republic of Azerbaijan and Iran, as well as in Moscow, St. Petersburg and Udmurtiya (Russia), Kyiv (Ukraine), Beijing (China), Tashkent (Uzbekistan), Marneuli (Georgia), Chişinău (Moldova), Rome (Italy).


title: Nizami Ganjavi

text: German poet and writer Johann Wolfgang von Goethe wrote: "A gentle, highly gifted spirit, who, when Ferdowsi had completed the collected heroic traditions, chose for the material of his poems the sweetest encounters of the deepest love. "Majnun and Layli", "Khosrow and Shirin", lovers he presented; meant for one another by premonition, destiny, nature, habit, inclination, passion staunchly devoted to each other; but divided by mad ideas, stubbornness, chance, necessity, and force, then miraculously reunited, yet in the end again in one way or another torn apart and separated from each other."


title: Nizami Ganjavi

text: With regards to the recitation of his poetry, Peter Chelkowski states: "The memorization and recitation of their literary heritage has alway beens vital to Iranians, whose attitude towards the power of the written and spoken word is reverential. Even today the national passion for poetry is constantly expressed over radio and television, in teahouses, in literary societies, in daily conversation, and in the "Musha'areh", the poetry recitation contest. Nizami's work serves as a vehicle and a symbol of this tradition, for it unites universality with deep-rooted artistic endeavor, a sense of justice and passion for the arts and sciences with spirituallity and genuine piety. For richness and fineness of metaphor, accuracy, and profundity of psychological observation, and sheer virtuosity of storytelling, Nizami is unequalled".


title: Nizami Ganjavi

text: Nezami's story of "Layla and Majnun" also provided the namesake for a hit single by Eric Clapton, also called "Layla". Recorded with the group Derek and the Dominos, the song was released on the 1970 album "Layla and Other Assorted Love Songs". The album was influenced by Nezami and his poetry of unrequited love. The fifth song of the album, "I Am Yours", was based on a poem by Nezami, set to music by Clapton.


title: Nizami Ganjavi

text: In 2004, there was a conference on Nezami organized at the University of Cambridge. The proceedings of this conference were published under the title "Nizami: A Key to the Treasure of Hakim" in 2011.


title: The China Study

text: The China Study: The Most Comprehensive Study of Nutrition Ever Conducted and the Startling Implications for Diet, Weight Loss and Long-term Health is a book by T. Colin Campbell and his son, Thomas M. Campbell II. The book argues for health benefits of a whole food plant-based diet. It was first published in the United States in January 2005 and had sold over one million copies as of October 2013, making it one of America's best-selling books about nutrition.


title: The China Study

text: "The China Study" examines the link between the consumption of animal products (including dairy) and chronic illnesses such as coronary heart disease, diabetes, breast cancer, prostate cancer, and bowel cancer. The book is "loosely based" on the China–Cornell–Oxford Project, a 20-year study which looked at mortality rates from cancer and other chronic diseases from 1973 to 1975 in 65 counties in China, and correlated this data with 1983–84 dietary surveys and blood work from 100 people in each county.


title: The China Study

text: The authors conclude that people who eat a predominantly whole-food, vegan diet—avoiding animal products as a source of nutrition, including beef, pork, poultry, fish, eggs, cheese, and milk, and reducing their intake of processed foods and refined carbohydrates—will escape, reduce, or reverse the development of numerous diseases. They write that "eating foods that contain any cholesterol above 0 mg is unhealthy." The book recommends sunshine exposure or dietary supplements to maintain adequate levels of vitamin D, and supplements of vitamin B in case of complete avoidance of animal products. It criticizes low-carb diets, such as the Atkins diet, which include restrictions on the percentage of calories derived from carbohydrates The authors are critical of reductionist approaches to the study of nutrition, whereby certain nutrients are blamed for disease, as opposed to studying patterns of nutrition and the interactions between nutrients.


title: The China Study

text: The book was first published in 2005. A revised and expanded edition was published in 2016. The book has also been published in German, Polish, Slovenian, Italian, Chinese, Japanese, Korean, Romanian, Swedish and Urdu.


title: The China Study

text: Sanjay Gupta, CNN's chief medical correspondent, said in his documentary "The Last Heart Attack" in 2011 that "The China Study" had changed the way people all over the world eat. Former American President Bill Clinton became a supporter when he adopted a plant-based diet after a heart attack.


title: The China Study

text: Wilfred Niels Arnold, professor of biochemistry at the University of Kansas Medical Center, reviewed the book in "Leonardo reviews" in 2005: "[T]he authors anticipate resistant and hostile sources, sail on with escalating enthusiasm, and furnish a working hypothesis that is valuable. In fact, the surprising data are difficult to interpret in any other way."


title: The China Study

text: Harriet Hall, writing for "Science-Based Medicine", said that the book had references which do not support directly the claims made by the authors and that it did not explain the exceptions to his data, such as high rates of stomach cancer in China.


title: The China Study

text: Stephan Guyenet reviewing the book for "Red Pen Reviews" commented that "The China Study" is a "scholarly and well-written book" but three of its key scientific claims are "not very well supported overall".


title: Toronto Star

text: The Toronto Star is a Canadian English-language broadsheet daily newspaper. The newspaper is the country's largest daily newspaper by circulation. It is owned by Toronto Star Newspapers Limited, a subsidiary of Torstar Corporation and part of Torstar's Daily News Brands division. The newspaper's offices are located at One Yonge Street in the Harbourfront neighbourhood of Toronto.


title: Toronto Star

text: The newspaper was established in 1892 as the Evening Star and was later renamed the Toronto Daily Star in 1900, under Joseph E. Atkinson. Atkinson was a major influence in shaping the editorial stance of the paper, with the paper having reflected his values until his death in 1948. The paper was renamed the "Toronto Star" in 1971. The newspaper introduced a Sunday edition in 1973.


title: Toronto Star

text: The "Star" was created in 1892 by striking "Toronto News" printers and writers, led by future mayor of Toronto and social reformer Horatio Clarence Hocken, who became the newspaper's founder, along with another future mayor, Jimmy Simpson.


title: Toronto Star

text: The "Star" was first printed on "Toronto World" presses, and at its formation, "The World" owned a 51 percent interest in it as a silent partner. That arrangement only lasted for two months, during which time it was rumoured that William Findlay "Billy" Maclean, "The World"s proprietor, was considering selling the "Star" to the Riordon family. After an extensive fundraising campaign among the "Star" staff, Maclean agreed to sell his interest to Hocken.


title: Toronto Star

text: The paper did poorly in its first few years. Hocken sold out within the year, and several owners followed in succession until railway entrepreneur William Mackenzie bought it in 1896. Its new editors, Edmund E. Sheppard and Frederic Thomas Nicholls, moved the entire "Star" operation into the same building used by the magazine "Saturday Night".


title: Toronto Star

text: Joseph E. "Holy Joe" Atkinson, backed by funds raised by supporters of Prime Minister Wilfrid Laurier, bought the paper on 13 December 1899. The supporters included Senator George Cox, William Mulock, Peter Charles Larkin and Timothy Eaton. Atkinson became the controlling shareholder of the "Star". The "Star" was frequently criticized for practising the yellow journalism of its era. For decades, the paper included heavy doses of crime and sensationalism, along with advocating social change.


title: Toronto Star

text: Atkinson was the "Star"s editor from 1899 until his death in 1948. The newspaper's early opposition and criticism of the Nazi regime saw it become one of the first North American papers to be banned in Germany. Atkinson had a social conscience. He championed many causes that would come to be associated with the modern welfare state: old age pensions, unemployment insurance, and health care. The Government of Canada Digital Collections website describes Atkinson as:


title: Toronto Star

text: a "radical" in the best sense of that term... The "Star" was unique among North American newspapers in its consistent, ongoing advocacy of the interests of ordinary people. The friendship of Atkinson, the publisher, with Mackenzie King, the prime minister, was a major influence on the development of Canadian social policy.


title: Toronto Star

text: Shortly before his death in 1948, Joseph E. Atkinson transferred ownership of the paper to a charitable organization given the mandate of continuing the paper's liberal tradition. In 1949, the Province of Ontario passed the "Charitable Gifts Act", barring charitable organizations from owning large parts of profit-making businesses, that effectively required the "Star" to be sold.


title: Toronto Star

text: Atkinson's will had directed that profits from the paper's operations were "for the promotion and maintenance of social, scientific and economic reforms which are charitable in nature, for the benefit of the people of the province of Ontario" and it stipulated that the paper could be sold only to people who shared his social views. The five trustees of the charitable organization circumvented the Act by buying the paper themselves and swearing before the Supreme Court of Ontario to continue what became known as the "Atkinson Principles":


title: Toronto Star

text: These principles continue to affect the "Star"s editorial stances. In February 2006, "Star" media columnist Antonia Zerbisias wrote on her blog:


title: Toronto Star

text: Besides, we are the "Star" which means we all have the Atkinson Principles—and its multi-culti values—tattooed on our butts. Fine with me. At least we are upfront about our values, and they almost always work in favour of building a better Canada.


title: Toronto Star

text: Under Atkinson, the "Star" launched several other media initiatives, including a weekend supplemental magazine, the "Star Weekly", from 1910 to 1973. From 1922 to 1933, the "Star" was also a radio broadcaster on its station CFCA, broadcasting on a wavelength of 400 metres (749.48 kHz); its coverage was complementary to the paper's reporting. The station was closed following the establishment of the Canadian Radio Broadcasting Commission (CRBC) and the introduction of a government policy that, in essence, restricted private stations to an effective radiated power of 100 watts. The "Star" would continue to supply sponsored content to the CRBC's CRCT station—which later became CBC station CBL—an arrangement that lasted until 1946.


title: Toronto Star

text: In 1971, the newspaper was renamed "The Toronto Star" and moved to a modern International-style office tower at One Yonge Street by Queens Quay. The original "Star" building at 80 King Street West was demolished to make room for First Canadian Place.


title: Toronto Star

text: The "Star" expanded during the 1970s with the introduction of a Sunday edition in 1973 and a morning edition in 1981.


title: Toronto Star

text: In 1992, its printing plant was moved to the Toronto Star Press Centre at the Highway 407 & 400 interchange in Vaughan. In September 2002, the logo was changed, and "The" was dropped from the masthead. During the 2003 Northeast blackout, the "Star" printed the paper at a press in Welland, Ontario. The newspaper's former printing plant was housed at One Yonge Street until the Toronto Star Press Centre opened.


title: Toronto Star

text: Until the mid-2000s, the front page of the "Toronto Star" had no third-party advertising aside from upcoming lottery jackpot estimates from the Ontario Lottery and Gaming Corporation (OLG).


title: Toronto Star

text: On May 28, 2007, the "Star" unveiled a redesigned paper that featured larger type, narrower pages, fewer and shorter articles, renamed sections, a more prominent focus on local news, and less focus on international news, columnists, and opinion pieces. However, on January 1, 2009, the "Star" reverted to its previous format. "Star P.M.", a free newspaper in PDF format that could be downloaded from the newspaper's website each weekday afternoon, was discontinued in October 2007, thirteen months after its launch.


title: Toronto Star

text: On January 15, 2016, Torstar confirmed the closure of its Vaughan printing presses and indicated that it would outsource printing to Transcontinental Printing, leading to the layoff of all 285 staff at the plant, as Transcontinental had its own existing facility, also in Vaughan. The newspaper said the closure was effected so it could better focus on its digital outlets.


title: Toronto Star

text: In February 2018, the "Toronto Star" suspended its internship program indefinitely to cut its costs. Long a source of Canada's next generation of journalists, the paid positions were seen as a vital part of the national industry, and their suspension, a sign of its continuing decline. In 2020, the internship program returned.


title: Toronto Star

text: In April 2018, the "Toronto Star" expanded its local coverage of Vancouver, Calgary, Edmonton and Halifax with rebranded daily newspapers, previously known as "Metro", as "StarMetro", which was a joint venture between Torstar (90%) and Swedish media company Metro International (10%). In October 2018, the "Toronto Star" acquired iPolitics, a political news outlet.


title: Toronto Star

text: On December 20, 2019, all "StarMetro" editions ceased publication amid the popularity and resultant growth of news apps on mobile devices. Local coverage once again became restricted to the Golden Horseshoe conurbation.


title: Toronto Star

text: The newspaper was acquired by NordStar Capital on May 26, 2020, after the board of Torstar voted to sell the company to the investment firm for —making Torstar a privately held company. The deal was expected to be approved by Torstar's shareholders and to close by the end of 2020. Canadian Modern Media Holdings made an offer of $58million on July 9, 2020; NordStar subsequently increased its offer to $60million, effectively ending the bidding war. A vast majority of shareholders subsequently voted in favour of the deal. The takeover was approved by an Ontario judge on July 27, 2020. An appeal of the judgement by another prospective purchaser failed on July 31 when Ontario Superior Court Justice Michael Penny dismissed the motion. The deal was expected to close during the following week.