Regenerative medicine is the "process of replacing or regenerating human cells, tissues or organs to restore or establish normal function". This field holds the promise of regenerating damaged tissues and organs in the body by replacing damaged tissue and/or by stimulating the body's own repair mechanisms to heal previously irreparable tissues or organs. the induction of regeneration by biologically active molecules administered alone or as a secretion by infused cells (immunomodulation therapy.
They assist the damaged tissue to heal itself by repositioning growth factors and cytokines back into the damaged extracellular matrix.[
"the application of regenerative medicine – defined to include the repair of living cells and extracellular material
Exposures of these epithelia to environmental insult, together with genetic factors and ageing, result in debilitating conditions such as chronic ulcers, wound healing defects, Congenital mutations in single genes result in devastating diseases of the skin and other epithelia “regenerative medicine” or “cell therapy” refers to treatments that are founded on the concept of producing new cells to replace malfunctioning or damaged cells as a vehicle to treat disease and injury. Our focus is the development of effective methods to generate replacement cells . We believe that replacing damaged or malfunctioning cells with fully functional ones may be a useful therapeutic strategy in treating many of these diseases and condition from stem cell. Understanding and manipulating the complex relationship between the cells and the scaffolding materials, however, represents the great challenge for tissue engineers. What cells should be used, for example, and should the combination of cells and materials occur in vitro or in vivo? What scaffolding material will best facilitate development? How will the tissue construct be functionally integrated?
In the area of biomaterial scaffold development, Institute researchers are working to use biodegradable materials – both natural and synthetic – with appropriate mechanical properties that can be modified to incorporate biological activity, such as growth factors and structural adhesive proteins. Institute researchers are studying novel ways to process materials into three-dimensional structures and to populate these structures with surface-bound biological signaling molecules.
Chronic skin wounds are wounds that have failed to proceed through an orderly and timely reparative process to produce anatomic and functional integrity. Approximately 30 million patients are affected by chronic wounds in the United States alone, and an estimated $150 billion dollars is spent annually on the treatment of such wounds. Approximately 7 million patients are affected by chronic wounds in the United States alone, and an estimated $25 billion dollars is spent annually on the treatment of such wounds. Unfortunately, these numbers continue to increase as a result of an aging patient population and the increased prevalence of diabetes, obesity, and atherosclerosis worldwide. To this end, concentrated scientific efforts have continued to focus on the biological mechanisms that underlie wound complications with the ultimate goal of finding the most effective therapeutic modalities for afflicted patients
Unfortunately, these numbers continue to increase as a result of an aging patient population and the increased prevalence of diabetes, obesity, and atherosclerosis worldwide.
Wound healing requires the progressive activation of cell-matrix interactions during hemostasis, inflammation, proliferation and remodeling. These events are coordinated by paracrine, juxtacrine, and intercrine expression of cytokines and growth factors . Key biological processes include cell migration and proliferation, angiogenesis, and fibroplasia. As such, wound healing is a form of regenerative response that has been adapted to deal with environmental insults such as infection and contamination. Thus, the outcome of healing in the adult is repair – the restoration of tissue integrity – rather than perfect replacement of tissue architecture. Key targets of investigation in the wound healing arena are the acceleration of retarded wound healing and the suppression of an excessive (fibrotic) healing response. Current data support the concept that these processes can be modulated by altering the signaling within the wound environment or by directlymodifyingextracellularmatrixmetabolism.
the full spectrum of matrix molecules come into play during tissue repair, somewhat dependent on the site of injury. Collagens I, III, and V are the major matrix constituents to replace the provisional, blood-derived matrix of fibrin, fibronectin, and thrombospondin. Collagen architecture is then modified by proteoglycans such as decorin, and the new connective tissue will contain adhesive glycoproteins as well as space-filling proteoglycans. Cell migration, movement, and traction during these changes is largely dependent on the dynamic changes in patterns and levels of integrin expression in the formation of 3d cell structure for assuming normal metabolism functions as original which is possible by only genetic transcription .
After connective tissue production, fibroblasts congregate around the wound margin .During wound contraction, myofibroblasts decrease the size of the wound by gripping the wound edges and contracting using a mechanism that resembles that of smooth muscle cells. When the cells' roles are close to complete, unneeded cells undergo apoptosis.
Background: Open wound closure by wound contraction produces a healed defect made up mostly of dermis. Generating thicker collagen fibers condenses granulation tissue, which pulls surrounding skin into the defect.
The Problem: What is the mechanism for open wound contraction? Is it through the generation of contractile force using sustained myosin ATPase, thus causing cell contraction or by rapid myosin ATPase that condenses collagen fibrils into fibers?
Basic/Clinical Science Addressed: The mechanism for wound contraction is not often debated after the discovery of the myofibroblast. Myofibroblasts are the major cell phenotype in maturing granulation tissue. It is concluded, not quite accurately, that myofibroblasts are responsible for wound contraction. As wound contraction progresses, polarized light microscopy reveals birefringence patterns associated with ever-increasing thickening of collagen fibers.
Collagen fibers thicken by eliminating water between fibrils. Wound contraction requires collagen synthesis and granulation tissue compaction. Both myofibroblasts and fibroblasts synthesize collagen, but fibroblasts, not myofibroblasts, compact collagen. Free-floating fibroblast-populated collagen lattices (FPCL) contract by rapid myosin ATPase, thus resulting in thicker collagen fibers by elongated fibroblasts. The release of an attached FPCL, using sustained myosin ATPase, produces rapid lattice contraction, now populated with contracted myofibroblasts in the absence of thick collagen fibers.
Discussion: In vivo and in vitro studies show that rapid myosin ATPase is the motor for wound contraction. Myofibroblasts maintain steady mechanotension through sustained myosin ATPase, which generates cell contraction forces that fail to produce thicker collagen fibers. The hypothesis is that cytoplasmic microfilaments pull collagen fibrils over the fibroblast’s plasma membrane surface, bringing collagen fibrils in closer contact with one another.
The self-assembly nature of collagen fixes collagen fibrils in regular arrays generating thicker collagen fibers.
Conclusion: Wound contraction progresses through fibroblasts generating thicker collagen fibers, using tractional forces; rather than by myofibroblasts utilizing cell contraction forces.
Abbreviations and Acronyms
aSMA = alpha smooth muscle actin
ADR = attached delayed released
ECM = extracellular matrix
FF = free floating
FPCL = fibroblast-populated collagen lattice
MLC = myosin light chain
MLCK = myosin light chain kinase
MLCP = myosin light chain phosphatase
Wound contraction, literally a shrinkage of open skin wounds, leaves a remarkably small scar as the surrounding normal skin moves centripetally to close the wound. It has aroused the curiosity of students. of healing for many years (Fig. 1). For the most part, it is a benign and clinically beneficent process. It should not be confused with scar ‘‘contracture’’ that pulls deeper tissues, not only skin, toward the injury site, thus limiting normal motion; The current preponderance of data indicates that cellular forces do participate, but they are provided mainly by fibroblast locomotion providing the forces that organizes newly deposited collagen in such a manner that collagen fibrils are fixed in a progressively more compact configuration by the elimination of water. Myofibroblasts appear in normal as well as granulation tissue, a variety of fibrotic conditions, and are associated with tension. They are considered a cellular icon of fibrosis. A major identifying feature of the myofibroblast phenotype is alpha smooth muscle actin (aSMA) within cytoskeletal stress fibers. However, full-thickness excisional wounds in rats contract by 50% in the first 7 days of healing before myofibroblasts first appear. A socalled proto-myofibroblast, containing cytoskeletal stress fibers, but not aSMA, by cell contraction forces has been proposed to explain this initial contraction.3 The identification of contracted myofibroblasts has been limited to released splinted wounds that have been physically restrained to contract.4,5 Collagen deposition has been increasingly involvedas a vital component. In vitro, soluble native collagen spontaneously polymerizes into a gel
under physiologic conditions. In vivo, fibroblast locomotion forces direct the arrangement of collagen fibrils into thicker, longer fibers through their physical translocation. The orderly configuration of collagen fibrils in contraction results from their packing closer together by eliminating water. By this mechanism, small, loosely arranged, collagen fibrils in young granulation tissue are arranged by cell forces, and collagen self-assembly generates a denser matrix. This physical compaction of collagen is a major force in wound contraction. Contracted wounds are unique in their content of normal-appearing, large, birefringent fibers that are revealed by polarized light microscopy (Fig. 2). Orderly packing of young collagen fibrils into growing collagen fibers requires rapid myosin ATPase activity. Myosin ATPase activity causes myosin to slide along an actin filament analogous to muscle contraction. Optimizing microfilament
contraction requires phosphorylation of the myosin’s regulatory peptide, myosin light chain (MLC). When MLC is phosphorylated at serine-19, myosin ATPase activity is optimized.6 This is under the control of myosin light chain kinase (MLCK), a key enzyme in rapid myosin ATPase activity, where ATP donates a phosphate to serine-19 (Fig. 3).With rapid myosin ATPase activity, there is a rapid turnover of the phosphorylated MLC through myosin light chain phosphatase (MLCP),which removes MLC serine-19 phosphate, a relaxation step required for myosin to again interact with MLCK. In contrast, the critical step for sustained myosin ATPase activity is the inhibition ofMLCP that prevents the relaxation step and prolongs the longevity ofMLC serine-19.7 This chronic, long-lived cytoskeletalmicrofilament contractile state is associatedwith contractile generated forces of smooth muscle cells within vascular and intestinal walls. Generated contractile forces from sustained myosin ATPase activity promote chronic tension and are independent of forces responsible for cell locomotion
.During maturation and remodeling, collagen is remodeled and realigned along tension lines, and apoptosis removes unnecessary cells.
This process is fragile and susceptible to interruption or failure that can cause the formation of non-healing chronic wounds. Among the factors that may contribute are diabetes, venous or arterial disease, infection, and metabolic deficiencies of old age.[
Concurrently, re-epithelialization of the epidermis occurs, whereby epithelial cells proliferate and 'crawl' atop the wound bed, covering the new tissue bed. The mitotic activity of cells within a wound is sensitive to local fluctuations in temperature and is significantly slowed down at temperature extremes. In wounds healing by secondary intention epithelialisation occurs once granulation tissue fills the wound bed. New epithelial cells, which have a translucent appearance and are usually whitish-pink, originate from the wound margin or from the remnants of hair follicles, sebaceous or sweat glands. They divide and migrate along the surface of the granulation tissue until they form a continuous layer approximately 20 days after injury and can last for many months, or even years in complex wounds. Initially scar tissue is raised and reddish. As the scar matures, its blood supply decreases and it becomes flatter, paler and smoother.
Mature scar tissue is a vascular and contains no hairs, sebaceous or sweat glands.
Scar formation is a normal consequence of the process of tissue repair in adults.
Underlying procedure for wound closure .