THE IMPORTANCE AND PROCESSES INVOLVED IN REPAIRS AND REGENERATION OF CELLS AND TISSUES OF THE BLOOD
Repairs and regeneration in humans is the regrowth of lost tissues or organs in response to injury. This is in contrast to wound healing, which involves closing up the injury site with a scar. Some tissues such as skin and large organs including the liver regrow quite readily, while others have been thought to have little or no capacity for regeneration. However ongoing research, particularly in the heart and lungs, suggests that there is hope for a variety of tissues and organs to eventually become regeneration-capable.
There are many animals that can regenerate complex body parts with full function and form after amputation or injury. Invertebrates (animals without a spinal cord) such as the flatworm or planarian can regenerate both the head from a tail piece, and the tail from a head piece. Among vertebrates (animals with a spinal cord), fish can regenerate parts of the brain, eye, kidney, heart and fins. Frogs can regenerate the limb, tail, brain and eye tissue as tadpoles but not as adults. And salamanders can regenerate the limb, heart, tail, brain, eye tissues, kidney, brain and spinal cord throughout life. (Anthony, Darrell, Marsha and Sunil, 2010).
THE IMPORTANCE AND PROCESSES INVOLVED IN REPAIRS AND REGENERATION OF CELLS AND TISSUES OF THE BLOOD
CONCEPT OF REGENERATION
Regeneration means the regrowth of a damaged or missing organ part from the remaining tissue. As adults, humans can regenerate some organs, such as the liver. If part of the liver is lost by disease or injury, the liver grows back to its original size, though not its original shape. And our skin is constantly being renewed and repaired. Unfortunately many other human tissues don’t regenerate, and a goal in regenerative medicine is to find ways to kick-start tissue regeneration in the body, or to engineer replacement tissues.
MEANING OF TISSUE
Tissue is a cellular organisational level between cells and a complete organ. A tissue is an ensemble of similar cells and their extracellular matrix from the same origin that together carry out a specific function. Organs are then formed by the functional grouping together of multiple tissues.
DEFINITION OF CELLS
Cells are the basic building blocks of all living things. The human body is composed of trillions of cells. Cells have many parts, each with a different function. Some of these parts, called organelles, are specialized structures that perform certain tasks within the cell.
HISTORY OF HUMAN TISSUE REGENERATION
In humans with non-injured tissues, the tissue is naturally regenerated over time; by default these tissues have new cells available to replace expended cells. (Atala, 2009). For example, the body regenerates a full bone within 10 years, while non-injured skin tissue is regenerated within two weeks. With injured tissue, the body usually has a different response – this emergency response usually involves building a degree of scar tissue over a time period longer than a regenerative response, as has been proven clinically and via observation. There are many more historical and nuanced understandings about regeneration processes. In full thickness wounds that are under 2mm, regeneration generally occurs before scarring. In 2008, in full thickness wounds over 3mm, it was found that a wound needed a material inserted in order to induce full tissue regeneration. Anthony, Darrell, Marsha, & Sunil (2010).
There are some human organs and tissues that regenerate rather than simply scar, as a result of injury. These include the liver, fingertips, and endometrium. More information is now known regarding the passive replacement of tissues in the human body, as well as the mechanics of stem cells. Advances in research have enabled the induced regeneration of many more tissues and organs than previously thought possible. (McManus, Rich 2012). The aim for these techniques is to use these techniques in the near future for the purpose of regenerating any tissue type in the human body.
By 2016, regeneration had been operationalised and induced by four main techniques: regeneration by instrument; regeneration by materials; regeneration by 3d printing; and regeneration by drugs. By 2016, regeneration by instrument, regeneration by materials and by regeneration drugs had been generally operationalised in vivo (inside living tissues). Whilst by 2016, regeneration by 3d printing had been generally operationalised by in vitro (inside the lab) in order to be build and prepare tissue for transplantation.
THE PROCESSES INVOLVED IN REPAIRS AND REGENERATION OF CELLS AND TISSUE OF THE BLOOD
Tissue regeneration comes in as many forms as there are tissues to regenerate (McMinn, 1969), which includes virtually everything except teeth. Some tissues may regenerate better than others, but in all cases it is important not to confuse tissue regeneration with various forms of compensatory growth (Goss, 1978). The latter phenomena do not require injury as an antecedent, but are triggered by increased functional demands. Physiological regeneration—the turnover of tissue components—is still another type of growth whereby synthesis and degradation at various levels of organization are normally in balance. Whether or not this represents a special case of the more general phenomenon of wound healing is a possibility worth serious consideration.
Among the more somatic tissues of the body (as distinguished from visceral ones), the healing of injuries in skin, muscle, tendons, bone, blood vessels, and nerves is especially relevant to epimorphic regeneration because these are the tissues normally present in appendages. Each one of them is capable of repair following injury, a repair more appropriately classified as wound healing than regeneration proper.
Skin heals wounds by the familiar immigration of epidermis over the underlying granulation tissue, the latter to become the scar which constitutes the regenerated dermis. Skeletal muscle is equally famous for its regenerative capacities following incision, crushing, mincing, ischemia, burns, or freezing. It does so by virtue of satellite cells which give rise to myoblasts capable of fusing into multinucleate fibers (discontinuous regeneration), or simply by sprouting from the severed ends of muscle fibers (continuous regeneration).
Severed tendons will complete their continuity by the accumulation of a mass of cells between the cut ends and subsequent synthesis of new collagen fibers to bridge the gap. Broken bones are repaired by a similar mechanism. A callus is formed out of cells derived from the nearby injured bone. Differentiation then follows the familiar sequence of chondrogenesis, osteogenesis, and remodeling. The repair of blood vessels can be achieved in a number of ways. Interrupted endothelium is resurfaced by the immigration of new cells from peripheral regions. Meanwhile the denuded intima undergoes a considerable thickening reminiscent of atherosclerotic plaque formation.
The possible regeneration of entire cross sections of blood vessels, if this indeed occurs at all, has not been adequately investigated, although there is evidence for such regrowth between the cut ends of transected veins and arteries. More commonly, however, the reestablishment of vascular continuity is achieved by the sprouting of new capillaries and by collateral vascularization. Finally, in the regeneration of peripheral nerves, distal fibers separated from their nerve cell bodies undergo Wallerian degeneration. Proximal stumps give rise to new sprouts that, if allowed to follow their old pathways, will regenerate toward their end organs as they become enveloped in new Schwann cells.
Thus, all of the tissues normally present in an appendage are themselves capable of limited regeneration, a regrowth more akin to wound healing than to epimorphic regeneration. It is worth noting, however, that the latter is not achieved by the additive regenerations of all of the tissues involved. It is conceivable that such a mode of appendage regeneration could have evolved, but the question is, why did it not? If each of the tissues in the cross section of a stump were to grow out on its own, they would at best have been able only to complete the continuity of the particular segments that were present in the stump itself.
Each muscle, for example, might have regenerated as far distally as its particular insertion. Each skeletal element might have been expected to reconstitute only itself. Even if tissue regeneration were capable of reestablishing the morphological integrity of these individual muscles or skeletal elements, it is difficult to imagine how more distal muscles and bones might have been regenerated de novo without at least some remnants from which they could take their origins. Thus, the segmental nature of most appendages would seem to militate against their regeneration by means of exaggerated versions of tissue regeneration alone. This may explain why the blastema was invented in the first place.
Recent research in different regenerating animals has shown that there are various stem cell strategies for regenerating body parts built from multiple tissues, such as muscle, nerve and skin. If we understand the principles and molecules these animals use to regenerate adult tissues, can these lessons be applied to regenerating or engineering human tissue?
Scientist Peter Reddien’s research group in the USA recently solved a long-standing question in planarian (flatworm) regeneration – can a single stem cell regenerate a whole animal? The answer is yes, it can. This shows that adult planaria have pluripotent stem cells – cells that can make ALL the cell types of the animal’s body. How these pluripotent cells are controlled in the flatworm’s body so that they do not form tumors is an important question that several research groups are now studying.
But not all animals use pluripotent cells in regeneration. The stem cells that regenerate a frog tail and a salamander limb have very different properties from a planarian stem cell. In these animals, each tissue – such as muscle, nerve, or skin – has its own set of stem cells that just make the different types of cells in that particular tissue. In other words, a muscle stem cell cannot make skin and skin stem cells can’t make muscle. These multi-potent tissue-specific stem cells are probably very similar to the stem cells in our own bodies that renew or repair tissues such as our skin or muscle. Why can such stem cells regenerate an entire limb in a salamander, but only repair damage to a single tissue type in our own bodies? This is another question that scientists are working on now.
As well as using stem cells, regeneration can work by causing differentiated cells that had stopped dividing to ‘go back’ to dividing and multiplying in order to replace the lost tissue. This has recently been shown to happen in heart regeneration in zebrafish, where a heart muscle cell called the cardiomyocyte divides to replenish missing cardiac tissue. This regenerative phenomenon has also been found in newly born mouse hearts, but is rapidly lost as the mice mature. More research is needed to understand how differentiated cells can be made to divide and produce new heart tissue, and why this capacity is lost in humans.
REPAIRS AND REGENERATION TECHNIQUES
By 2016, the concept of regeneration had been operationalised and induced by four main techniques: regeneration by instrument; regeneration by materials; regeneration by 3d printing; and regeneration by drugs.By 2016, regeneration by instrument, regeneration by materials and by regeneration drugs had been generally operationalised in vivo (inside living tissues). Whilst by 2016, the regeneration by 3d printing had been generally operationalised by in vitro (inside the lab) in order to be build and prepare tissue for transplantation.
Ø Regeneration by instrument
A cut by a knife or a scalpel generally scars though a piercing by a needle does not scar. In 1976, a 3 by 3cm scar on a non-diabetic was regenerated by insulin injections and the researchers, highlighting earlier research, argued that the insulin was regenerating the tissue. The anecdotal evidence also highlighted that a syringe was one of two variables that helped bring regeneration of the arm scar. The syringe was injected into the four quadrants three times a day for eighty-two days. After eighty-two days, after many consecutive injections, the scar was resolved and it was noted no scar was observable by the human eye. After seven months the area was checked again and it was once again noted that no scar could be seen.
In 1997, it was proven that wounds created with an instrument that are under 2mm can heal scar free, but larger wounds that are larger than 2mm healed with a scar.
In 2013 it was proven in pig tissue that full thickness micro columns of tissue, less than 0.5mm in diameter could be removed and that the replacement tissue, was regenerative tissue, not scar. The tissue was removed in a fractional pattern, with over 40% of a square area removed; and all of the fractional full thickness holes in the square area healed without scarring. In 2016 this fractional pattern technique was also proven in human tissue.
Ø Regeneration with materials
Generally humans, in vivo, can regenerate injured tissues for limited distances of up to 2mm. The further the wound distance is from 2mm the more the wound regeneration will need inducement. By 2009, via the use of materials, a max induced regeneration could be achieved inside a 1 cm tissue rupture. Bridging the wound, the material allowed cells to cross the wound gap; the material then degraded. This technology was first used inside a broken urethra in 1996. In 2012, using materials, a full urethra was restored in vivo.
Ø Regeneration by 3D printing
In 2009, the regeneration of hollow organs and tissues with a long diffusion distance, was a little more challenging. Therefore, to regenerate hollow organs and tissues with a long diffusion distance, the tissue had to be regenerated inside the lab, via the use of a 3D printer.
In 2012, within 60 days it was possible, inside the lab, to grow tissue the size of half a postage stamp to the size of a football field; and most cell types could be grown and expanded outside of the body, with the exception of the liver, nerve and pancreas, as these tissue types need stem cell populations.
The first organ ever induced and made in the lab was the bladder, which was created in 1999. In 2014, there had been various tissues regenerated by the 3d printer and these tissues included: the bladder, muscle, vagina, penis and the thymus.
In 2015 researchers developed a proof of principle biolimb inside a laboratory; they also estimated that it would be at least a decade for any testing of limbs in humans. The limb demonstrated, fully functioning skin, muscles, blood vessels and bones. In April 2019 researchers 3d printed a human heart. The prototype heart was made by human stem cells but only to the size of a rabbits heart. In 2019, the researchers hoped to one day place a scaled up version of the heart inside humans.
Ø Regeneration with drugs
Lipoatrophy is the localised loss of fat in tissue. It is common in diabetics who use conventional insulin injection treatment. In 1949 a much more pure form of insulin was, instead of causing lipoatrophy, shown to regenerate the localised loss of fat after injections in to diabetics. In 1984 it was shown that different insulin injections have different regenerative responses with regards to creating skin fats in the same person. It was shown in the same body that conventional forms of insulin injections cause lipoatrophy and highly purified insulin injections cause lipohypertrophy. In 1976 the regenerative response was shown to work in a non-diabetic after a 3 x 3cm lipoatrophic arm scar was treated with pure monocomponent porcine soluble insulin. A syringe injected insulin under the skin equally in the four quadrants of the defect. To layer four units of insulin evenly into the base of the defect, each quadrant of the defect received one unit of insulin three times a day, for eighty-two days. After eighty-two days of consecutive injections the defect regenerated to normal tissue.
In 2016 scientists could transform a skin cell into any other tissue type via the use of drugs. The technique was noted as safer than genetic reprogramming which, in 2016, was a concern medically. The technique, used a cocktail of chemicals and enabled efficient on site regeneration without any genetic programming. In 2016 it was hoped to one day use this drug to regenerate tissue at the site of tissue injury.
IMPORTANCE OF REPAIRS AND REGENERATION OF CELLS AND TISSUE OF THE BLOOD
Regeneration involves the capacity for renewal or recomposition of tissues, organs or even organisms, after considerable physical injury or damage, resulting from pathologies, tumors, congenital diseases or traumas, for example. As a consequence of tissue regeneration, both the composition and the tissue properties are restored, and the newly formed tissue is highly similar to the original tissue. The regenerative capacity is directly related to the presence of stem cells or progenitor cells, which are capable of proliferation and differentiation (Tanaka and Reddien, 2011). Tissues that maintain a high proliferative capacity, such as the hematopoietic system, have regenerative capacity even in adult organisms (Sephel & Woodward 2011)
Cell proliferation occurs in repair processes in general, accompanied by intense production of extracellular matrix, with large amounts of collagen, resulting in the formation of fibrous tissue to occupy the injured area. Although there is lesion filling, both the composition and the tissue properties are different from the original tissue, and the tissue organization pattern is not restored, leading to an altered performance of its functions. Skin healing processes with the presence of scars are examples of tissue repair (Hench, 1998).
Besides the natural processes of regeneration and repair, it is possible, through medical intervention, to fill lesions with natural or synthetic materials, aiming at the recovery of the compromised area, and conferring certain properties to the tissue, avoiding, for example, exacerbation of the initial lesion or the evolution of degenerative processes.
The three approaches can be used in tissue engineering, targeting regenerative medicine, as they allow the recovery of compromised areas in different degrees. However, the primary objective is regeneration, recomposition of the original tissue and resumption of the biomechanical and molecular properties, with the normal performance of their functions.
Tissue regeneration involves cell recruitment, growth, proliferation and differentiation, with the latter representing a crucial stage for the success of regeneration, avoiding the formation of fibrous tissue characteristic of the repair. Tissues with greater regenerative capacity, such as the skin and liver, intrinsically present cells able to migrate to occupy the affected region, and the same cells maintain the proliferative capacity, enabling occupation of the lesion. In other tissues the regenerative capacity is even more impaired. In the cartilage, for example, the cells remain embedded in the extracellular matrix, and the absence of blood vessels inhibits the presence of other types of component cell in the tissue; even the cell migration and proliferation processes are compromised. In general, regeneration and repair processes do not occur naturally in these cases, requiring surgical intervention to stimulate the subchondral bone marrow, thus enabling the presence of cells capable of tissue repair in the compromised area. Other scientific techniques and methodologies seek alternatives to enable the processes both of repair and of tissue regeneration.
Anyhow the final stage of the abovementioned processes, cell differentiation, is critical. An understanding of the mechanisms that lead to the differentiation process in adult organisms allows the proposition of improvements in existing technologies and of alternatives geared towards the optimization of guided tissue regeneration processes, in regenerative medicine.
The main goal of tissue regeneration are:
- Musculoskeletal tissues: Musculoskeletal injuries impact millions of people globally and affect their health and well-being as well as of their companion and athletic animals. Soft-tissue injuries represent almost half of these and are associated with unorganized scar tissue formation and long time-depending healing processes. Cell based therapeutic strategies have been developed in the past decades aiming at the treatment and reversion of such disorders. Stem cells are appealing in the field, being a responsive undifferentiated population, with ability to self-renew and differentiate into different lineages. Mesenchymal stem cells can be obtained from several adult tissues, including the synovial membrane. Synovia-derived mesenchymal stem cells can be found in individuals of any age and are associated to intrinsic regenerative processes, through both paracrine and cell-to-cell interactions, thus, contributing to host healing capacity. Studies have demonstrated the potential benefit of synovia-derived mesenchymal stem cells in these regenerative processes in both human and veterinary medicine.
- Bone regeneration: Bone regeneration is a surgical technique that uses barrier membranes to direct, or guide, the growth of new bone at the site of the defect. The principle is that the barrier membranes create and maintain a space above the bone defect; this allows the slower mesenchymal cells with osteogenic potential to populate the defect and regenerate without interference from the more quickly proliferating overlying soft tissues. Protection of the clot in the defect, exclusion of gingival connective tissue cells, and preparation of an enclosed space in which osteogenic cells can migrate from the bone are three essential elements of a successful outcome. Many types of grafts have been used as space maintainers between the membrane and the bone defect. Autografts, allografts, and xenografts have all been used successfully, either alone or in combination, for bone regeneration using particulate materials.
Tissue repair and regeneration of the blood cells is an essential mechanism to maintain the integrity and function of the body in response to a variety of both acute and chronic injuries and disease states. One of the major challenges to achieve clinically meaningful tissue regeneration and repair is a better understanding of the mechanisms involved in both native or endogenous, as well as exogenous stem cell homing of transplanted cells. Both approaches involve a complex network of factors and sequence of events that drive the trafficking and homing of stem cells to the area of injury to optimize repair.
Tissue repair is a dynamic restorative cell proliferation and tissue regeneration response stimulated in order to overcome acute toxicity and recover organ/tissue structure and function.
Lastly, humans have limited regeneration ability, all the organ tissues can regrow, but it is very limited except the liver. Studies can find new methods to deal with regeneration. Recently, scientists are investigating the genes and factors which are active during regeneration. Scientists already understand some forms of regeneration sufficiently to manipulate and modify key events for therapeutic causes. So, in future, people will not need to use prosthesis, it will be more comfortable than using prosthesis because limbs will not lose their function and the regeneration of disabled people.
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