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. 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. 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. 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. 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. 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. 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. long fiber generation 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. bioartificial organs main article: bioartificial organ 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. lung 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. skin 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. heart 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. kidney 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. 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 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. biomimetics 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. constructing neural networks in soft material 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. 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. 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. market 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. beginning 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