wound healing requires a concerted effort of remodeling of various components of the connective tissue in the presence of appropriate cytokines and growth factors . wound healing is a complex process involving a cascade of events , orchestrated by interactions between many cell types , soluble factors and matrix components . various steps like microbial control , subsidence of inflammation , regeneration of connective tissue , angiogenesis and epithelialisation should take place in a time - bound sequence . any acute wound initially goes through the phase of  haemostasis and inflammation  . immediately after the injury , the cell membranes release potent vasoconstrictors like prostaglandin 2 alpha and thromboxane a2 . the collagen in the wound sets off the clotting cascade through both the intrinsic and the extrinsic pathways . neutrophils undergo chemotaxis into the wound in the presence of interleukin-1 , tumour necrosis factor ( tnf)-alpha , transforming growth factor ( tgf)-beta , platelet factor-4 and bacterial products . the wound then enters into a  proliferative phase  in the vital presence of the activated macrophage . collagenases secreted by the activated macrophage debride the wound . interleukins and tnfs stimulate fibroblasts and tgf stimulates keratinocytes . epithelialisation , angiogenesis , granulation tissue and collagen deposition are the cardinal events that take place . in the proliferative phase , the fibrin clot is replaced by a template of fibrocytes that lay down collagen . platelet - derived growth factor ( pdgf ) and epidermal growth factor secreted , respectively , by platelets and macrophages lead to fibroblast activation . in response to tgf - beta 1 secreted by the macrophages , fibroblasts situated inside the wound stimulated by pdgf , fibroblasts lay down a provisional matrix composed of type iii collagen , glycosaminoglycans and fibronectin . an organised deposition of a matrix of collagen is the hallmark of the third phase of  remodeling or maturation  . this phase usually begins 1 week after the injury , and extends up to 1 year [ figure 1 ] . in the early part of the third phase ( 45 weeks ) , a lot of collagen deposition takes place and the tissue is indurated . if there are problems with matrix deposition , the strength of the wound is considerably impaired . the collagen in granulation tissue is fundamentally different from the collagen in the normal dermis . it has thinner fibres , probably due to greater hydroxylation and glycosylation of the lysine residues . the strength of the wound reaches a maximum of 80% at around 3 months after injury . these wounds develop whenever there is prolongation of one of the phases of normal healing . these fail to heal when other wounds of similar size would have otherwise healed . according to leaper and durani , any wound that that has not shown a 2040% reduction in area after 24 weeks of optimal treatment should be labeled as chronic . a chronicity may be considered when there is no complete healing after 6 weeks or if there is poor response to a treatment change . wound healing is said to be impaired when such sequential progression of events for normal healing does not take place and , instead , local injury and chronic inflammation persist.[157 ] wound healing is a complex process that is susceptible to abnormalities at many levels . low oxygen tension in the wound results in endothelial cell apoptosis , decreased neutrophil and fibroblast activity . oedema in the wound increases the distance between capillaries at the tissue level and hence local perfusion of oxygen is decreased . indeed , hyperoxia recruits bone marrow - derived progenitor cells into diabetic and ischaemic wounds . the resident fibroblasts in chronic wounds may be phenotypically senescent and show decreased responsiveness to tgf and pdgf . the presence of bacteria in the wound increases pro - inflammatory mediators and decreases growth factor levels . the neutrophils and macrophages release proteases and oxidants , which degrade cytokines and extracellular matrix . combined , tissue hypoxia and bacterial proliferation are two major local obstacles in the healing of any wound . the components of tissue engineering are ( 1 ) gene therapy , ( 2 ) cytokines and other growth factors , ( 3 ) scaffold and ( 4 ) cells . a stem cell is a cell that can self - replicate and give rise to more than one type of mature daughter cell . thus , stem cell incorporates a broad range of cells with different capacities for proliferation and differentiation . totipotent stem cells are capable of giving rise to an intact organism , including germinal tissues . pleuripotent stem cells can give rise to cells derived from all three germ layers . multipotent or organ - specific stem cells are capable of giving rise to the cells that comprise a single organ system or tissue . therefore , a stem cell is characterized by ( 1 ) unlimited self - renewal capacity , ( 2 ) long - term viability , ( 3 ) multi - lineage potential , ( 4 ) participation in tissue repair and ( 5 ) preservation of somatic homeostasis . a classical stem cell must be capable of asymmetric cell division , i.e. it must produce as progeny , one exact multipotent replica cell and a transit amplifying ( ta ) cell that performs a more specialized function . thus , replication of a single cell can potentially result in whole populations of cells . this will lead on to produce tissue regeneration along with retention of a population of identical stem cells . embryonic stem cells are formed from the inner cell mass of a pre - implantation blastocyst . these have the potential to differentiate into any type of cell ( multipotent ) . with suitable media and in the presence of growth factors , these can give rise to keratinocytes . however , the stability and oncogenicity of embryonic stem cells have to be further defined . cells have also been harvested from the peripheral blood , umbilical cord blood , amniotic membrane , adipose tissue , etc . organ systems also harbour indigenous holoclones of cells , with high - renewal capacity and low levels of differentiation . these are called resident stem cells . in the skin , these are the dermal sheath cells of the hair follicle . the uncommitted mesenchymal stem cells ( mscs ) , residing in the bone marrow stroma , are fibroblast - like cells that optimize the microenvironment of the haematopoietic cells . the same kinds of cells are also found in connective tissues across various organs in the body . these mscs are capable of differentiating into tissues like bone , cartilage , adipose tissue and endothelium , depending on their microenvironment ( niche ) . the adult bone marrow aspirate can provide 30% more multipotent stem cells as compared with umbilical cord blood . mscs  can be expanded ( multiplied ) due to their property of adhering to tissue culture surfaces . infusions of mscs have been found to upregulate the anti - inflammatory cytokines such as il-10 and il-12 while decreasing the concentrations of pro - inflammatory cytokines like interferon - gamma , il-1 , il-6 and macrophage inflammatory protein-1 alpha . in murine studies , mscs have been found to have anti - apoptotic effects , upregulation of bcl-2 and suppression of caspase enzymes in adjacent cells . in mice pre - treated with endotoxin , intrapulmonary infusions of mscs resulted in reduction in pulmonary vascular congestion , decreased alveolar wall thickening and increased survival . ex vivo expanded mscs are known to interact with a broad range of immunocytes , including t lymphocytes , b lymphocytes , nk cells and dendritic cells . these mscs then home in to the sites of injury and seed the wound . inside the microvasculature of the developing granulation tissue , endothelial progenitor cells , again from the marrow , augment new vessel formation ( vasculogenesis ) . integrating themselves into the wound , the mscs are postulated to directly participate in its repair . transplanted mscs are thought to impact locally through five major paths  ( 1 ) increased angiogenesis , ( 2 ) decreased local inflammation , ( 3 ) anti - apoptotic and chemotactic signaling , ( 4 ) normalization of extracellular matrix and ( 5 ) stimulation of nearby resident stem cells . they have been reported to secrete vascular endothelial growth factor ( vegf ) , fibroblast growth factor ( fgf ) , transforming growth factor ( tgf beta ) , hepatocyte growth factor , interleukins 10 and 13 and other cytokines and growth factors ( paracrine signaling ) , which help in remodeling of the extracellular matrix and in neovascularisation . even in an environment with low oxygen tension , up to 20% of fibroblasts in the wound are postulated to arise from bone marrow precursors . again , mscs have the potential to stimulate and differentiate the resident progenitor cells and promote recovery of injured local cells . the immunosuppressive properties of mscs also help in prolonged wound coverage by delay of allograft rejection . only around 5% of the stem cells that are injected into the wound engraftment levels of locally delivered stem cells were observed to be too low to significantly regenerate functional tissue , especially in cardiac myocytes and smooth muscle tissue . the injected human mscs have not been described to transform into keratinocytes and dermal appendage cells . the immuno - attenuative response afforded by the local presence of stem cells can be replicated by cell - free conditioned media derived from stem cells . all these evidence point to the theory that stem cells benefit through paracrine pathways , rather than by replacing functional tissue . thus , in contrast to any specific drug that affects a single pathway for its action , mscs exhibit their therapeutic power through diverse systemic and local interrelated routes . nearly half a century has elapsed since friedenstein and co - workers first isolated mscs from rat bone marrow . these cells have been experimented in diseases as diverse as myocardial infarction , segmental bone defect and lung fibrosis . cultured different clones of keratinocytes in vitro and introduced the concept of stem cells in wound care . another approach is the local application of stem cells for optimizing the regenerative capability of wounds . badiavas and falanga in 2003 introduced the use of bone marrow - derived cells in chronic wounds . three patients with recalcitrant wounds present for more than 1 year and resistant to standard treatment were chosen for the study . the authors reported healing of two of the wounds with three sittings of cell treatment alone . ichioka and colleagues used a collagen matrix impregnated with bone marrow aspirate on a chronic leg ulcer that had not healed for more than 1 year . humpert et al . examined the nature of wound healing in a type 2 diabetic patient after the use of topical mononuclear bone marrow cells . an in vitro study revealed that the levels of bfgf , vegf and collagen synthesis were much higher in bone marrow stromal cells than in dermal fibroblasts . the question is whether these stem cells differentiate into elements of connective tissue in the microarchitecture of the wound . the consensus postulated is that the wounds change their character from a chronic non - healing one to an acute regenerating one . currently , this change of character requires surgical debridement . by removing diseased tissue , debridement recruits fresh fibroblasts , burd reports the use of autologous bone marrow on chronic non - healing leg ulcers . document using this procedure in a patient who sustained a 40% total burn surface area tbsa burn . they applied allogenic fibroblast - like mscs on the burn wounds prior to skin grafting . they reported that there was a decrease in serous discharge from the wound after the application of stem cells . the patient had less pain after the procedure . on follow - up , they noted neo - angiogenesis , increased epithelialisation and increased graft uptake in the wound . they hypothesize that healing would accelerate if inflammatory cells are brought to the wound from the bone marrow . they describe the topical application of autologous bone marrow on two patients with chronic non - healing ulcers . a small residual raw area persisted that healed totally with a split - thickness skin graft . falanga and colleagues expanded autologous bm - mscs ex vivo and combined them with fibrin spray for topical application . they studied the efficacy of this system in healing of four acute and six chronic wounds . the authors reported healing of these wounds within 8 weeks with the topical application alone . the chronic wounds that were chosen by the authors were refractory wounds present for more than 1 year . all of those healed within 1620 weeks , with up to three sittings of the fibrin  msc delivery system . lataillade et al . reported the use of mscs in a patient who sustained a severe radiation burn injury to his left buttock . the patient underwent multiple sittings of debridement followed by split - skin grafting and local stem cell injection . these cells were cultured from bone marrow aspirate and underwent a two - step expansion process ex vivo , before local injection . the wounds were of diverse origin and included post - burn , diabetic and decubitus ulcers . the mscs were cultured and expanded and impregnated into a collagen sponge that served as a dermal replacement . adipose - derived stem cells ( ascs ) are similar to mscs in morphology , differentiation and paracrine secretion under hypoxic conditions . plastic surgeons , lately adipose - tissue engineers , take advantage of their abundance in liposuction specimens for cell - assisted lipotransfer . ascs were used along with suitable scaffolds to regenerate bone in human calvarial and maxillectomy defects . a stem cell is a cell that can self - replicate and give rise to more than one type of mature daughter cell . thus , stem cell incorporates a broad range of cells with different capacities for proliferation and differentiation . totipotent stem cells are capable of giving rise to an intact organism , including germinal tissues . pleuripotent stem cells can give rise to cells derived from all three germ layers . multipotent or organ - specific stem cells are capable of giving rise to the cells that comprise a single organ system or tissue . therefore , a stem cell is characterized by ( 1 ) unlimited self - renewal capacity , ( 2 ) long - term viability , ( 3 ) multi - lineage potential , ( 4 ) participation in tissue repair and ( 5 ) preservation of somatic homeostasis . a classical stem cell must be capable of asymmetric cell division , i.e. it must produce as progeny , one exact multipotent replica cell and a transit amplifying ( ta ) cell that performs a more specialized function . thus , replication of a single cell can potentially result in whole populations of cells . this will lead on to produce tissue regeneration along with retention of a population of identical stem cells . embryonic stem cells are formed from the inner cell mass of a pre - implantation blastocyst . these have the potential to differentiate into any type of cell ( multipotent ) . with suitable media and in the presence of growth factors , these can give rise to keratinocytes . however , the stability and oncogenicity of embryonic stem cells have to be further defined . on the contrary , cells have also been harvested from the peripheral blood , umbilical cord blood , amniotic membrane , adipose tissue , etc . organ systems also harbour indigenous holoclones of cells , with high - renewal capacity and low levels of differentiation . these are called resident stem cells . in the skin , these are the dermal sheath cells of the hair follicle . the uncommitted mesenchymal stem cells ( mscs ) , residing in the bone marrow stroma , are fibroblast - like cells that optimize the microenvironment of the haematopoietic cells the same kinds of cells are also found in connective tissues across various organs in the body . these mscs are capable of differentiating into tissues like bone , cartilage , adipose tissue and endothelium , depending on their microenvironment ( niche ) . the adult bone marrow aspirate can provide 30% more multipotent stem cells as compared with umbilical cord blood . mscs  can be expanded ( multiplied ) due to their property of adhering to tissue culture surfaces . infusions of mscs have been found to upregulate the anti - inflammatory cytokines such as il-10 and il-12 while decreasing the concentrations of pro - inflammatory cytokines like interferon - gamma , il-1 , il-6 and macrophage inflammatory protein-1 alpha . in murine studies , mscs have been found to have anti - apoptotic effects , upregulation of bcl-2 and suppression of caspase enzymes in adjacent cells . in mice pre - treated with endotoxin , intrapulmonary infusions of mscs resulted in reduction in pulmonary vascular congestion , decreased alveolar wall thickening and increased survival . ex vivo expanded mscs are known to interact with a broad range of immunocytes , including t lymphocytes , b lymphocytes , nk cells and dendritic cells . these mscs then home in to the sites of injury and seed the wound . inside the microvasculature of the developing granulation tissue , they differentiate into dermal fibroblasts , myofibroblasts , lymphoid tissue and antigen presenting cells . endothelial progenitor cells , again from the marrow , augment new vessel formation ( vasculogenesis ) . integrating themselves into the wound , transplanted mscs are thought to impact locally through five major paths  ( 1 ) increased angiogenesis , ( 2 ) decreased local inflammation , ( 3 ) anti - apoptotic and chemotactic signaling , ( 4 ) normalization of extracellular matrix and ( 5 ) stimulation of nearby resident stem cells . they have been reported to secrete vascular endothelial growth factor ( vegf ) , fibroblast growth factor ( fgf ) , transforming growth factor ( tgf beta ) , hepatocyte growth factor , interleukins 10 and 13 and other cytokines and growth factors ( paracrine signaling ) , which help in remodeling of the extracellular matrix and in neovascularisation . even in an environment with low oxygen tension , up to 20% of fibroblasts in the wound are postulated to arise from bone marrow precursors . again , mscs have the potential to stimulate and differentiate the resident progenitor cells and promote recovery of injured local cells . the immunosuppressive properties of mscs also help in prolonged wound coverage by delay of allograft rejection . only around 5% of the stem cells that are injected into the wound engraftment levels of locally delivered stem cells were observed to be too low to significantly regenerate functional tissue , especially in cardiac myocytes and smooth muscle tissue . the injected human mscs have not been described to transform into keratinocytes and dermal appendage cells . the immuno - attenuative response afforded by the local presence of stem cells can be replicated by cell - free conditioned media derived from stem cells . all these evidence point to the theory that stem cells benefit through paracrine pathways , rather than by replacing functional tissue . thus , in contrast to any specific drug that affects a single pathway for its action , mscs exhibit their therapeutic power through diverse systemic and local interrelated routes . nearly half a century has elapsed since friedenstein and co - workers first isolated mscs from rat bone marrow . these cells have been experimented in diseases as diverse as myocardial infarction , segmental bone defect and lung fibrosis . cultured different clones of keratinocytes in vitro and introduced the concept of stem cells in wound care . another approach is the local application of stem cells for optimizing the regenerative capability of wounds . badiavas and falanga in 2003 introduced the use of bone marrow - derived cells in chronic wounds . three patients with recalcitrant wounds present for more than 1 year and resistant to standard treatment were chosen for the study . the authors reported healing of two of the wounds with three sittings of cell treatment alone . ichioka and colleagues used a collagen matrix impregnated with bone marrow aspirate on a chronic leg ulcer that had not healed for more than 1 year . examined the nature of wound healing in a type 2 diabetic patient after the use of topical mononuclear bone marrow cells . an in vitro study revealed that the levels of bfgf , vegf and collagen synthesis were much higher in bone marrow stromal cells than in dermal fibroblasts . the question is whether these stem cells differentiate into elements of connective tissue in the microarchitecture of the wound . the consensus postulated is that the wounds change their character from a chronic non - healing one to an acute regenerating one . currently , this change of character requires surgical debridement . by removing diseased tissue , debridement recruits fresh fibroblasts , burd reports the use of autologous bone marrow on chronic non - healing leg ulcers . document using this procedure in a patient who sustained a 40% total burn surface area tbsa burn . they applied allogenic fibroblast - like mscs on the burn wounds prior to skin grafting . they reported that there was a decrease in serous discharge from the wound after the application of stem cells . the patient had less pain after the procedure . on follow - up , they noted neo - angiogenesis , increased epithelialisation and increased graft uptake in the wound . they hypothesize that healing would accelerate if inflammatory cells are brought to the wound from the bone marrow . they describe the topical application of autologous bone marrow on two patients with chronic non - healing ulcers . a small residual raw area persisted that healed totally with a split - thickness skin graft . falanga and colleagues expanded autologous bm - mscs ex vivo and combined them with fibrin spray for topical application . they studied the efficacy of this system in healing of four acute and six chronic wounds . the authors reported healing of these wounds within 8 weeks with the topical application alone . the chronic wounds that were chosen by the authors were refractory wounds present for more than 1 year . all of those healed within 1620 weeks , with up to three sittings of the fibrin  msc delivery system . lataillade et al . reported the use of mscs in a patient who sustained a severe radiation burn injury to his left buttock . the patient underwent multiple sittings of debridement followed by split - skin grafting and local stem cell injection . these cells were cultured from bone marrow aspirate and underwent a two - step expansion process ex vivo , before local injection . the wounds were of diverse origin and included post - burn , diabetic and decubitus ulcers . the mscs were cultured and expanded and impregnated into a collagen sponge that served as a dermal replacement . adipose - derived stem cells ( ascs ) are similar to mscs in morphology , differentiation and paracrine secretion under hypoxic conditions . plastic surgeons , lately adipose - tissue engineers , take advantage of their abundance in liposuction specimens for cell - assisted lipotransfer . ascs were used along with suitable scaffolds to regenerate bone in human calvarial and maxillectomy defects . a pilot study was conducted in our hospital on burn patients using bone marrow mscs expanded in vitro ( publication pending ) . two wounds of similar size were compared . both wounds underwent closure by split - skin grafting . the test wound was injected with up to 23 million mscs at the time of grafting . while a majority of the test wounds healed faster than their counterparts , we did encounter some areas of concern for clinical application of stem cells . falanga refined the local delivery of stem cells by incorporating them in fibrin as a spray . he postulated that incorporating into fibrin might be ideal for transporting cells and soluble mediators into sites of injury . envisaged that 3d constructs of mscs , with enhanced anti - inflammatory properties , could be mass produced as off - the - shelf medication . future technology could involve the use of biogels , biodegradable matrices and microparticles that integrate into the wound bed without the risk of foreign body reaction or infection . dermal matrix carrier has been found to improve the therapeutic effects of bone marrow and ascs in murine models . composite skin with xenogenic dermis seeded with epidermal stem cells and dermal papilla cells has also favoured wound healing . impregnating the carrier with growth factors that induce the commitment of resident stem cells into keratinocytes is also another possibility . genetic modulation and transfection of cutaneous stem cells for induction into keratinocyte lineage has also been postulated . msc mobilization strategies with factors such as granulocyte macrophage colony stimulating factor gm - csf are envisaged . development of smart biomaterials that would augment the transit of circulating stem cells is also sought after . this can potentially avoid the application of exogenous cells , using the patient 's own cells for wound healing . the amount of stem cells required for optimisation of the wound is also not standardised . the number and location of stem cells within skin may contribute to rapid healing seen in the foetus . however , cells migrate to distant organs like spleen , when therapeutically administered numbers exceed 1 10 . adequate culture , expansion and characterisation of stem cells take 3 weeks to 1 month in the laboratory the current status of stem cells in chronic wounds would be as an additional tool to the existing therapeutic armamentarium . future goals of stem cell therapy for chronic wounds should focus on rapid expansion of cells in vitro . another option would be to maximise the number of precursor cells resident in the wound . effective delivery and optimal engraftment of these cells are also of paramount importance . a bioengineered dermal epidermal composite enriched with expanded autologous stem cells that can immune - modulate the wound it covers remains a challenge for reconstructive surgery .
chronic wounds continue to be a major challenge for the medical profession , and plastic surgeons are frequently called in to help in the management of such wounds . apart from the obvious morbidity to the patient 
 , these problem wounds can be a major drain on the already scarce hospital resources . sometimes , these chronic wounds can be more taxing than the underlying disease itself . 
 although many newer methods are available to handle such situations , the role of stem cells in the management of such wounds is an exciting area that needs to be explored further . 
 a review of literature has been done regarding the role of stem cells in the management of chronic wounds . 
 the abnormal pathology in such wounds is discussed and the possible role of stem cells for optimal healing in such cases would be detailed .