Tissue engineering and regenerative medicine are interdisciplinary fields that apply principles of engineering and life sciences to develop biological substitutes, typically composed of biological and synthetic components, that restore, maintain or improve tissue function. The conventional science of art in biomaterials has been concerned with restoring damaged tissue using non-biological materials such as metals, ceramics and synthetic polymers. To overcome the limitations of using such non-viable materials, severals attempts to construct artificial organs mimicking natural tissue by combining modulated cells with extracellular matrix- hybridized synthetic polymers have produced many worthy results with biologically functioning artificial tissues. The process involved in manufacturing biomaterials mimicking living tissue is generally called tissue engineering.However recently, the extension of knowledge about cell biology and embryology has naturally moved the focus from tissue restroration to tissue regenaration. Especially, embryonic and mesenchymal stem cells are attractive resources due to their potential for the differentiation of various tissue cells in response to signal transduction mediated by cytokines. Although no one knows yet what is the exact factor responsible for a stem cell's ability to differentiate between specific cells to generate specific tissue, what has been agreed is that delivering stem cells into the body provides a strong potential for the regenaration of tissue. In this, the historical issues and future possibiliities involved in medical tissue restoration and tissue regeneration are discussed.
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Restoration of damaged tissue has long been atÂtempted with medical treatment consisting of the use of drugs and various devices. Such medical devices have been fabricated with materials developed in cooperation with surgical procedures intending to preserve the remaining normal tissue and to replace the diseased tissue with artificially produced prosÂtheses. Ranging from dressing materials that primarily protect against contamination to the body through open wounds during the healing process, to the highly advanced blood compatible materials that are used in producing artificial vessels, these materials have been regarded as playing a secondary role in treatment, after the primary role of surgery, in restoring lost tissue. The restoration of defects has usually been limited to the support of mechanical functions for skeletal and circulatory systems or to the replacement of morÂphological defects for esthetic discomfort. Therefore, the bioinert materials been most important in this field. Metal has been the representative biomedical material, fabricated into various restorative materials for hard tissues, in spite of unavoidable concerns about corrosion and the release of metal ions that produce immune reactions during contact with tisÂsue. Ceramics were introduced to medicine, especially as a restoring material for the skeletal system, in the 1960s and exhibited excellent biologically stable proÂperties. Calcium phosphate is a natural component of hard tissues, and material scientists chemically synÂthesized various ceramics as defect restoratives or as coating materials for metals to improve their interÂactions with tissue. But due to the brittle characÂteristics of ceramics, the physiological load bearing area was contraindicative of their use.
As the field of polymer science and its associated technology has grown, soft tissue restoration increased in scope. Since the first use of polyvinylchloride (PVC) to restore dissected vessels in 1952, synthetic poly- mers have been regarded as one of the most imporÂtant biomaterials. The malleable chemical and phyÂsical characteristics of synthetic polymers introduced the era of biochemically active materials in medical use. To protect against the formation of thrombosis oriented from blood plasma protein adhering to the polymer surface, many trials have explored the cheÂmical modification of the lumen of artificial blood vessels by hydrophilic-hydrophobic phase segregation and/or grafting protein repellant on polymer surface, and these have made an outstanding contribution to the progress in biomaterials science.3,4.
Although polymers have proven to be very useful materials, scientists had to consider carefully their interactions with tissues as their use entailed greater life risks than the use of metals and ceramics. And the need for control of polymer deterioration, which gradually occurs following contact with body fluid and which triggers unpredictable host immune reÂsponses that cannot be avoided since the polymer is synthesized by chemicals, has promoted rapid progÂress in biocompatibility research. Research in material biocompatibility has proceeded in cooperation with progress in the understanding of cell biology related to the host cellular response to biornaterials and the better understanding of molecular biology has allowed researchers to modify conventional restorative biomaÂterials to maintain biologically stable or functional activities by hybridizing tissue components with polymers.
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Auto graft is the best method for replacing defects, but the problem of deficiency of host donor site has never been overcome. Although the development of immune suppressing agents has expanded the alÂlograft era, the number of donors with perfectly matÂching recipient HLA is still limited, and the horror of the possible transmission to recipient of a life threatening virus, such as hepatitis and HIV, is anÂother clinical problem.'
As tissue consists of cells, extracellular matrix and ionic body fluid, the concept of tissue restoration with materials mimicking natural tissue has been consiÂdered. By modifying conventionally available biomaÂterials with tissue components including cells, bio materials can become biological material. Furthermore not only physical restoration, but also the possibility of replacing tissue defects with biochemically funcÂtioning materials instead of auto graft and/or allograft has been investigated.
Extracellular matrix plays the fundamental role of providing a suitable living environment for cells and maintaining tissue structures. By hybridizing extraÂcellular matrix with polymers, cultured cells can be combined with the materials, and the biological proÂperties of the resultant product are preferred for use as biomimicking material for tissue replacement.
A scaffold is the construction of an artificial tissue structure using polymers. Collagen, the main strucÂtural protein with cell adhesive properties in mamÂmalians, is the representative extracellular matrix mostly hybridized to polymers. Specific cell adhesive components in extracellular matrix such as glycoproÂteins like fibronectin, vitronectin and laminin, and peptide sequence like arginine-glysine-aspartic acid (RGD) are also selectively hybridized to the polymer surface to provide increased cell bindings. The culÂtured endothelial cells adhering onto the lumen of the polymer-made artificial vessel can almost completely prevent thrombosis, because the cell themselves are the cells' lining vascular lumens. Otherwise, the collagen hybridized polymer membrane demonstrates cell proliferative conduction to the collagen layer, and firstly is used as a dermal dressing material promoting natural skin wound healing by proliferating host dermal fibroblasts.12
Progress in both biodegradable polymer and cell culture technology has also greatly contributed to the success of artificially engineered tissue. Biodegradable polymers, which are dissolved in the bodily environÂment by hydrolysis or enzymes, play the role of strucÂture replacement in artificial tissue construction. SynÂthetic poly lactic acid (PLA) and poly glycolic acid (PGA) are representative scaffold materials utilized in tissue engineering, due to the ease with which their dissolving rate and physical properties may be conÂtrolled, and hence volumetric harmonization between the gradual degradation of scaffold polymer and the replacement tissue is achievable.
The discovery of cytokines, which are small moleÂcular peptides, in extracellular matrix has accelerated research in controlling the cell life cycle. In particular, research into the application of growth factors (GFs) during cell culture stimulated the in vitro cell expansion technology. The birth of molecular biology in the late 1970s provided an enormously valuable contribution to the comprehension of living subsÂtances, especially in defining peptide sequences. Gene cloning technology helped biomaterial researchers to modulate cells by replacing DNA in order to provide cellular affinity with the host tissue.
Artificial tissue made by modulated cells cultured in vitro or in vivo, in or on an extracellular matrix hybridized biodegradable polymer scaffold, with growth factors is currently the state of the art in the proÂduction of engineered biomaterial for tissue replaceÂment.
Because the engineered tissue consists of cells and extracellular matrix, preserving it in a ready-to-use condition while still maintaining cellular viability is also a critical problem. Cryopreservation, which is primarily designed to store cellular order, has also been applied to natural or engineered tissues. In general, cells demonstrate no metabolic activity beÂlow - 150Â°C, and they are usually cryopreserved at - 196Â°C. After thawing, the cell recovers metabolic activity, and this technology has made it possible to supply viable cells and tissues for transplantation.
Restoration and replacement of dysfunctional tissue have greatly progressed and contributed significantly to surgery in the 20th century. Especially, tissue replacement by engineered tissue is still one field of important research, since the goal of producing perÂfect artificial tissue with complete physiological funcÂtion has not been achieved.
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However, many researchers have been trying to expand cell manipulation engineering techniques into the field of internal medicine by utilizing the active cell inductive characteristics of growth factors to give self regeneration of damaged tissue, through the deÂliverance of GFs to the necessary tissue. GFs are frequently used in in vitro cell cultures to accelerate cell differentiation without concern for the future of cultured cell, but in the in vivo condition, the deÂlivered GF has the potential for promoting not only the normal but also the neoplasmic cells. To avoid this hazard and also to maintain the intensity of GF in tissue, an effective material that conjugates with GF to become a carrier is necessary, and various hybridized biodegradable polymers with extracellular matrix components are under investigation.
Cultured host cell delivery has also been studied, but the difficulty of obtaining cells with differentiaÂtion potential has lead researchers 1:0 consider alloÂgenic or xenogenic cell delivery. Cell encapsulation by semi-permeable synthetic membrane designed to proÂtect against attack by host immune substances but to permit the transportation of metabolic substances has been investigated. Further, following the first sucÂcess of embryonic stem (ES) cell culture in 1981, various mice with recombinant genes have been produced.2o,21 Trials in host gene transfection to alÂlogenic or xenogenic cells have been pursued after the historical birth of the gene duplicated sheep "Dolly" in 1997 at the Roslin Institute in Scotland. Dolly demonstrates that researchers have the technology to duplicate an individual by using already differentiated and matured cells. In 1998, Thomson reported a success with human ES cell culture, and this lead to a new method for the regeneration of tissue by deÂlivering cells of multi-differentiation potential with the lowest rate of host immune rejection, in spite of an on-going ethical debate on the morals of harvesting embryo or fetus.
Stem cells have an endless self-renewal and difÂferentiation potential to specific cells in accordance with varying signals. The cells appear during the embryonic and fetal organogenesis process, and even exist in specific adult tissues like bone marrow and epidermis that continuously reproduce cells. Fertilized ovum is a totipotent stem cell that is ready to form the embryo, fetus and placenta. The inner cell mass (ICM) of the blastocyst that later converts into the complete body is called the pluripotent stem cell mass, and the cultured ICM cells are defined as the embryonic stem (ES) cells that can be differentiated into any kind of cells. The pluripotency of the.Ef cells is evaluated by inserting the cells into the other blastocyst. If the delivered cell is well mixed with the transferred ICM, and presently differentiated to all kinds of tissue cells afterward, it is defined as an ES cell.
As the ES cells are free from host immune reaction, because the immune system has not yet been established at that stage, they are recognized as ideal cells for transplantation. But using ES cells is illegal in the field of cell therapy for tissue reÂgeneration due to the ethics of human rights. ThereÂfore, researchers are examining the multipotent stem
cells that are converted from ES cells, that are ready to differentiate to specific tissue cells, and that even appear in adult tissue where continuous new cell supply is necessary. Hematopoietic stem (HS) cell is a progenitor cell of blood cells and lymphocytes, Mesenchymal stem (MS) cell is differentiated to osÂteoblast, chondrocyte, myocyte, keratinocyte and conÂnective tissue to form stroma and the recently found neural stem (NS) cells is a progenitor cell of the central nervous system that has the potential to become a neuron or glial cell. Actually, it is preferable to use multipotent stem cells rather than ES cells in the field of cell therapy, because the future of the cells can be predicted, and they can be collected from adult hosts.25
However, host stem cell delivery is not practical at present, because large numbers of stem cells are reÂquired for transplantation. Therefore, researches is continuing about immortalizing cell lines using retroÂvirus mediated human gene transfer to porcine stem cell.26 With the outstandingly rapid advancement of molecular biology in the late 1990s, even the chroÂmosomes released the secret of their gene arrangeÂments in 2000. Understanding the structure of inÂdividual genes will certainly promote the development of various ways to achieve the complete self-reÂgeneration of host tissue in the coming 21st century.
Tissue engineering aims to provide functional tissue and organ replacements to individuals with important and often life-threatening diseases. Currently, tissue equivalents are either prefabricated or assembled within a laboratory prior to implantation into a patient (i.e., engineered tissue substitutes); or acellular scaffolds are introduced directly into the patient to promote endogenous tissue repair and regeneration (i.e., tissue engineered substitutes) Tissue restoration, tissue engineering and regenerative medicine shares many characteristics with technological fields such as cell-based therapies such as stem cell transplantation, and therapeutic cloning. However, many requirements, including the need to obtain viable and functional cells, to grow tissues and organs in controlled bioreactor conditions, to induce specific and localized cell responses, and to provide adequate growing substrates, have until now largely confined tissue engineering to the research laboratory. Tissue restoration, tissue engineering and regenerative medicine has reported new and original experimental and theoretical research that provide strong and sound engineering basis related to 1) methods for culturing tissue substitutes, 2) culture processes used to grow tissue substitutes, 3) cell-material interactions 4) surface chemistry affecting cell and tissue and 5) non-invasive and non-destructive imaging methods to follow tissue growth in tissue cultures.