Microdeformation in wound healing Cornelia Wiegand, PhD1; Richard White, PhD2 1. Department of Dermatology, University Medical Center Jena, Jena, Germany 2. Institute of Health and Society, University of Worcester, Worcester, United Kingdom

Reprint requests: Dr. C. Wiegand, Department of Dermatology, University Medical Center Jena, Erfurter Str. 35, D-07743 Jena, Germany. Tel: +49 3641 937584; Fax: +49 3641 937437; Email: [email protected] Manuscript received: June 6, 2013 Accepted in final form: August 12, 2013 DOI:10.1111/wrr.12111

ABSTRACT Mechanical forces greatly influence cellular organization and behavior. Cells respond to applied stress by changes in form and composition until a suitable state is reestablished. However, without any mechanical stimuli cells stop proliferating, discontinue migration, go into cell-cycle arrest, and eventually die. Hence, one can assume that pathologies closely depending on cell migration like cancer or atherosclerosis might be governed by biophysical parameters. Moreover, mechanical cues will have fundamental effects in wound healing. Especially negative pressure wound therapy has the potential to endorse wound healing by induction of both macrodeformation (wound contraction) and microdeformation (tissue reactions at microscopic level). So far, the capacity for researchers to study the link between mechanical stimulation and biological response has been limited by the lack of instrumentation capable of stimulating the tissue in an appropriate manner. However, first reports on application of micromechanical forces to wounds elucidate the roles of cell stretch, substrate stiffness, and tissue deformation during cell proliferation and differentiation. This review deals with their findings and tries to establish a link between the current knowledge and the questions that are essential to clinicians in the field: What is the significance of mirodeformations for wound healing? Does “dead space” impede propagation of mechanical cues? How can microdeformations induce cell proliferation? What role do fibroblasts, myofibroblasts, and mesenchymal stem cells play in chronic wounds with regard to micromechanical forces?

CELLULAR RESPONSES TO MECHANICAL SIGNALS Research into tissue engineering, or mechanobiology, has defined how cellular organization and behavior is affected by mechanical forces. The principles of mechanobiology have been applied to bone growth and strength, blood vessels and cardiac muscle, but not yet to skin. In vitro studies in 3D cell cultures have shown how mechanical stresses influence the organization of tissues, including tumorigenesis, stem cell differentiation, and capillary morphogenesis.1 Cells and tissues have adapted to respond to mechanical forces in the “nontraumatic” range in an appropriate manner. Mainly they respond to the applied stress by changes in form and composition until a suitable stress state is reestablished.2 Mechanical signals can modulate almost all cell functions, including migration2,3 and proliferation.4–7 The first mechanically responsive transmembrane-signaling protein was described by Martinac et al. in 1987.8 Since then, other transmembrane proteins have been identified that allow the cell to explore the biophysical state around them and to react to it.9,10 The process was termed mechanotransduction.3 Moreover, it was suggested that other cellular structures play an important role in mechanosensing, such as integrins11 or the cytoskeleton itself.12 Both are also involved directly in cell migration via actinomyosin-transduced cell contraction and integrinWound Rep Reg (2013) 21 793–799 © 2013 by the Wound Healing Society

mediated binding and release of extracellular matrix ligands for cell movement. Hence, integrins and cytoskeleton accomplish two tasks in cell migration, serving as sensors and actuators at the same time.2 Further studies established a link between stretching of cells and cell proliferation.4,6 It could be shown that cells allowed to stretch can proliferate in response to soluble growth factors in vitro but cells without mechanical stress will assume a spherical shape, go into cell-cycle arrest, and die by apoptosis.7 Recently, these effects were investigated more closely in vivo. Saxena et al. used the rat ear model to analyze the biological response of soft tissue to


Alpha smooth muscle actin Basic fibroblast growth factor Extracellular matrix Matrix metalloproteinase Mesenchymal stem cell Negative pressure wound therapy Polymorphonuclear Reactive nitrogen species Reactive oxygen species Transforming growth factor beta Tissue inhibitor of metalloproteinase Vascular endothelial growth factor


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forces. The gene expression studies revealed that the hypoxia pathway might be an important modulator of cellular reactions to mechanical stress.13 Hence, it is apparent that cells perceive mechanical stimuli from their miroenvironment through distinct protein complexes and are able to respond by regulation of specific genes and the induction of cellular programs5 modulating their own behavior and modifying their surroundings. This allows the assumption that those pathologies closely depending on cell migration such as cancer or atherosclerosis2 might be governed by biophysical parameters. Moreover, mechanical cues will have fundamental effects in wound healing, stimulating both cell migration and cell proliferation.

SIGNIFICANCE OF MICRODEFORMATION FOR WOUND HEALING Chronic wounds have become a rising charge for our aging society. Pathologies such as diabetes or venous insufficiencies predispose patients to chronic wounds, causing pain, leading to severe infections or resulting even in amputation. Several studies have shown that exudates from non-healing wounds contain elevated levels of proteases, like matrix metalloproteinases (MMPs) and polymorphonuclear elastase.14–16 The excessive action of elastase leads to considerably reduced amounts of growth factors17 and proteinase inhibitors like tissue inhibitors of matrix metalloproteases,18 leaving unchecked MMP-2 (gelatinase A) to cleave collagens, elastin, and fibronectin, consequently leading to the destruction of extracellular matrix (ECM).16 Moreover, the liberation of proinflammatory cytokines by macrophages and granulocytes is markedly increased19 and the concentrations of reactive oxygen and nitrogen species are distinctly higher, compared with the conditions in acute wounds.20 Consequently, chronic wounds persist in the inflammatory phase of the normal healing process and often remain nonhealing for month or even years. Hence, for the treatment of chronic wounds it has been assumed that changing the predominant destructive state to a more physiological wound milieu will allow the wound to heal eventually. Various studies have shown that negative pressure wound therapy (NPWT) successfully promotes healing not only by providing a moist wound environment but also by direct effects such as increasing blood flow,21 reducing edema22 and wound area,23 as well as stimulation of granulation tissue formation,24,25 cell proliferation,26 and angiogenesis.24–26 Moreover, it has been suggested that NPWT influences the microenvironment of the wound by removal of inflammatory proteases27 and reduction of the bacterial load.25 Furthermore, NPWT induces two types of tissue deformation: macrodeformation (wound contraction) and microdeformation (tissue reactions at microscopic level). It has been theorized that microdeformations of the wound surface promote cell proliferation through mechanotransduction pathways.5,28 Micromechanical forces are known to induce cell proliferation and division (Figure 1). Plastic surgeons use tissue expansion to expand soft-tissue envelopes in reconstructive surgery, and orthopedic surgeons and maxillofacial surgeons use distraction osteogenesis to lengthen bones.5 Hence, it can be assumed that applying micromechanical forces to wounds in vivo will endorse wound healing. However, the capacity for researchers to study the link between mechanical stimulation and biological response is 794

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still limited, owing to the lack of instrumentation capable of stimulating the tissue in an appropriate manner.29

INDUCTION OF CELL PROLIFERATION BY MICRODEFORMATION THROUGH VACUUM THERAPY It is thought that the mechanical stress applied by NPWT initiates a signaling cascade which promotes wound healing by inducing cell migration and proliferation.30 Histological examinations showed that during NPWT, small tissue blebs (termed “tissue mushrooms”) extend into the pores of the dressing, resulting in shearing strains at the wound-dressing interface.30 In addition, fluid removal may exert mechanical strain (hydrostatic pressure gradients and fluid shear forces).31 These physical effects cause a deformation of the cytoskeleton which initiates signaling cascades (Figure 1). A wide variety of molecular responses, such as changes in ion concentration and permeability of membrane ion channels, release of second messengers, stimulation of molecular pathways, and alterations in gene expression, has been observed following mechanical strain on the wound bed.30,32 A study by Lu et al. showed that fibroblast proliferation and gene expression of COL1A1, α-smooth muscle actin (α-SMA), basic fibroblast growth factor, and transforming growth factor beta (TGFβ) 1 were significantly increased by NPWT.31 Moreover, wound area in patients under NPWT was 2.5 times more likely to be reduced within 1 week compared with standard moist wound therapy.33 Interestingly, the degrees of microand macrodeformation of the wound bed were found to be similar after NPWT, regardless if foam or gauze was used as wound filler.30 This indicates that not the interactions of dressing material and wound per se mediate these effects, but that NPWT induces mechanical forces by tension and compression of the tissue that lead to formation of granulation tissue and the acceleration of wound healing. The study by Saxena et al. showed that most elements stretched by NPWT underwent deformations of 5 to 20% strain.5 This is comparable with the in vitro strain levels, which were found to endorse cell proliferation. Moreover, it was shown that NPWT leads to the formation of more physiological blood vessels. It most likely affects neovascularization through a combination of a direct effect of the mechanical forces on preexisting blood vessels and the establishment of hypoxia and vascular endothelial growth factor gradients.34 Hence, application of micromechanical forces may be a useful method to increase wound healing by induction of cell proliferation and angiogenesis. DOES “DEAD SPACE” BETWEEN DRESSING AND WOUND SURFACE STOP MICRODEFORMATIONS? The mechanical responsiveness of the ECM is an important determinant of cell fate.35 To understand the organization of tissue maintenance and wound healing, the key question is how cells communicate among each other and how they respond to their environment.36 For cell adhesion in the tissue, the biochemical information (e.g., cell type, soluble cytokines, ECM proteins, etc.) needs to be supplemented with topographical properties (e.g., cell orientation or ECM fiber Wound Rep Reg (2013) 21 793–799 © 2013 by the Wound Healing Society

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Microdeformation in wound healing

micromechanical forces/ mechanical stress

mechanotransduction pathways5,28,30

regulation of tissue organiziation36

cell proliferation4-7 cell differentation36 cell migration2-3

cell stretch4,6,29 substrate stiffness4,6,29 tissue deformation4,6,29

Determination of cell fate35,36

key questions for effects of microdeformations in wound healing

• biochemical information: • cell type • soluble cytokines • ECM proteins • topographyical properties: • cell orientation • ECM fiber organization • mechanical characteristics: • fiber elasticity • substrate stiffness

What is the significance of microdeformations for wound healing?

Does ‘dead space’ impede propagation of mechanical cues?

How can microdeformations induce cell proliferation?

What role do fibroblasts, myofibroblasts and MSCs play?

Mechanical signals promote cell proliferation and migration5,28,30 as well as increase the expression of ECM components, contractile elements and growth factors30 which are necessary for wound healing.

Structural requirements for physiological cell functions are lacking in chronic wounds. Loss of stimulatory mechanical signals impedes cell proliferation39 and cell migration42. Hence, formation of dead space hampers healing.

Mechanical strain causes a deformation of the cytoskeleton which initiates signaling cascades30,32 leading for example to the release of growth factors31,34 which promote cell proliferation.

Fibroblasts synthesize connective tissue44 and restore mechanical strength. Aged fibroblasts display a decreased proliferation and migration rate47,50 and the number of proliferating and migrating fibroblasts is reduced in nonhealing wounds46. Myofibroblasts are contractile cells that remodel the ECM to decrease wound surface area45. In the absence of mechanical stimuli, due to diminished mechanical properties of the ECM in chronic wounds, they fail to perform their task. MSCs exert anti-inflammatory and antimicrobial effects, induce angiogenesis and recruit cells48-49. They are controlled by cell tension and mechanical stimuli53-54. Loss of transduction of mechanical forces in chronic wounds may shut down MSCs activity.

Figure 1. Micromechanical forces regulate tissue organization via mechanotransduction pathways. Hence, cell fate is determined by biochemical information, topographical properties, and mechanical characteristics. Four key questions have been posed to elucidate how microdeformations may affect wound healing. ECM, extracellular matrix; MSC, mesenchymal stem cell.

organization) and mechanical characteristics (e.g., fiber elasticity, substrate stiffness) of the structure the cell attaches to. It was observed that cells prefer to grow along ECM fibers and that tissue explants condense collagen gels into aligned parallel fiber bundles. This “contact guidance” serves as a large-scale organization principle for motile cells in tissue development, providing a bidirectional cue for cell migration. In addition, unidirectional movement (“hapotaxis”) is conveyed by spatial distribution of chemotactic signals.36 Moreover, cells can use actively generated internal forces (“active mechanosensing”) in order to explore the properties of their environment, allowing them to navigate through the ECM according to its mechanical resistance (“mechanotaxis”).36 Recently, it was shown that fibroblasts stiffen their cytoplasm to migrate into a wound.37 Additionally, cells may up-regulate cytoskeleton and cell-matrix adhesion in response to stiffer substrates or prefer to migrate toward more rigid or strained substrates.36 This is most likely due to the fact that soluble growth factors and attachment to ECM proteins, although indispensable, are not enough to stimulate cell proliferation.7 Progression through the cell cycle in addition needs a suitable Wound Rep Reg (2013) 21 793–799 © 2013 by the Wound Healing Society

physical context to respond to these two chemical stimuli.5 These structural requirements are often lacking in chronic wounds as the ECM is degraded, and so do not provide a scaffold on which cells normally stretch and proliferate. The absence of ECM and the accumulation of wound fluid may further cause an area of “dead space,” a void within a viscus or between wound bed and dressings/tissue flaps.38 Across this gap, micromechanical stimuli, required for promotion of cell migration and cell proliferation, might not be transferred (Figure 1). Laparotomy wound failure has been associated with early fascial separation that creates a dead space. The diminished wound tension leads to the loss of stimulatory mechanical (Figure 1) signals necessary for fibroblast proliferation, alignment, and contractile function, and often progresses to hernia formation.39 In accordance, prophylactic muscle flaps in vascular surgery, which are specifically aimed to avoid the creation of dead space, have been shown to improve the healing outcome.40 Moreover, the presence of dead space may act as a source for infections contributing to the delay in healing.41 Dead space may harbor microorganisms because it does not possess a defense mechanism42 as 795

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neutrophils and macrophages fail to invade the infected space without matrix components present to support migration.

IS VACUUM THERAPY THE ONLY POSSIBILITY TO INDUCE MICRODEFORMATIONS IN WOUNDS? The porosity of polyurethane foams plays a crucial role during NPWT for wound healing outcomes. It was shown that larger pore sizes result in greater wound bed deformation, leading to enhanced granulation tissue thickness and increased induction of contractile myofibroblasts.43 However, microdeformations of the wound bed surface can also be induced if wounds are treated with foam or gauze at atmospheric pressure. It was found that even without the application of NPWT, the sponge struts of the foam and the threads of the gauze caused imprints in the underlying wound bed tissue.5,30 Moreover, the effects of the mechanical forces could be mimicked by stimulation of the hypoxia pathway using interference RNA or other gene therapy methods. Recently, it was shown that this pathway is involved in the biological responses to tissue deformation and micromechanical strains.13 These findings might enable the design of clinical therapies relying on pharmaceutical intervention rather than exposing the patient to mechanical treatments that can have negative effects (e.g., wound separation, wound pain, etc.).

WOULD CLOSE ADHERING DRESSINGS WITH SPECIAL FEATURES BE ENOUGH TO INDUCE MICRODEFORMATIONREGULATED CELL PROLIFERATION? Increased understanding of mechanobiology elucidates the roles of cell stretch, substrate stiffness, and tissue deformation during cell proliferation and differentiation.4,6,29 It has been speculated that mechanical strain per se has profound influence on wound healing, even without the appliance of NPWT.30 A study by Saxena et al. has shown that application of foam to the wound without vacuum was enough to stimulate granulation tissue formation. However, if the foam was not in close contact to the tissue, no significant granulation was observed.5 This is in accordance with the clinical demand to ensure a close association of the applied dressing to the wound bed38 to avoid the formation of dead space. Dressings that feature the capacity to maintain this intimate contact are those providing a flexible structure and high conformability as well as consisting of hydrogel-like materials or easily forming gels upon contact with fluids. Such dressings offer several advantages as they mold themselves over the wound surface, facilitating the absorption of exudate and eliminating dead space as well as inducing microdeformations and conveying cell proliferation. To test this hypothesis, microfabrication techniques are currently used to develop adhering dressings capable of inducing controlled and distributed tissue microdeformation. These “microchamber” dressings have already been used together with NPWT to repeatedly induce controlled deformation on the wound bed. It was shown that dressings with 500- and 1,000-μm-wide microchambers produce the most distinct deformations compared with the 200-μm-wide microchamber dressing which showed an 796

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attenuated tissue deformation.29 It would be of great interest to evaluate these dressings for direct effect on wound healing without NPWT.

FIBROBLASTS, MYOFIBROBLASTS, AND NONHEALING WOUNDS The fibroblast is the precursor of the provisional wound matrix in which the respective cell migration and organization take place.44 It is mainly active throughout the proliferative phase of the wound healing process, where the main focus is on covering the wound surface, forming granulation tissue, and restoring blood vessels. Synthesis of collagen, fibronectin, and other ECM substances (e.g., hyaluronic acid, glycosaminglycans, proteoglycans) by fibroblasts presents the basis for new connective tissue formation, closing existing gaps and restoring mechanical strength of the wounded area (Figure 1). At the end of this phase, the number of fibroblasts declines successively and they are replaced by myofibroblasts.44 Myofibroblasts are modified fibroblasts characterized by a well-developed contractile apparatus and robust actin stress fibers, mainly α-SMA.45 Their task is to contract the wound to decrease the surface of the developing scar. Myofibroblasts undergoing differentiation exhibit profound changes in gene expression with the goal to amplify their capacity to serve as contractile cell and as an effector for ECM remodeling.45 α-SMA is induced under conditions of increased isomeric tension or under stimulation with TGF-β1. When present, it is rapidly incorporated into actin stress fibers and results in an increased capacity for contractile force generation by the myofibroblasts. In intact granulation tissue, the appearance of actin stress fibers correlates with the generation of contractile forces.45 Despite the lack of sufficient wound closure, higher numbers of myofibroblasts have been observed in nonhealing compared with healing wounds.46 In accordance, the number of proliferating fibroblasts was found to be reduced and fibroblast migration was weaker in the nonhealing wound group compared with the healing wound group in vitro.46 This finding is surprising as myofibroblasts have generally been associated with the late proliferative phase.44 However, a lower number of proliferating fibroblasts would account for the reduced amount of synthesized provisional ECM in chronic wounds, which would hamper cell attachment and migration and create more dead space. Although differentiation of myofibroblasts has been mainly attributed to increased mechanical forces, it could be that an alternative pathways exist, which, in the absence of sufficient mechanical stimuli, leads to the increase of their numbers in an attempt to “pull the wound together.” Then again, another study has shown that stiffer fibroblasts may be isolated from older compared with young patients.47 The hitch of the research by Schwarz et al. is that patients in the healing and nonhealing wounds group were not age matched, and hence patients from the healing wound group were significantly younger than those from the nonhealing wound group.46 However, aging significantly increases fibroblast stiffness in vivo due to a shift in the degree of actin polymerization to the filamentous form.47 This results in both an age-associated loss of cell flexibility and impairment of cell motility. The reduced cellular contraction capacity and cell organization as well as the diminished mechanical properties of the ECM are possible reasons for the delay in wound repair and regeneration in chronic wounds. Wound Rep Reg (2013) 21 793–799 © 2013 by the Wound Healing Society

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MESENCHYMAL STEM CELL-BASED WOUND REPAIR Mesenchymal stem cells (MSCs) feature interesting properties that make them promising agents for the treatment of chronic wounds.48 They are mainly isolated from bone marrow, but can be found throughout the body in adipose tissue, periosteum, tendon, muscle, synovial membrane, skin, and other tissues.49 Various studies have shown that MSCs play a significant role in tissue homeostasis and wound repair.48,49 Administration of MSCs to both acute and diabetic wounds in rodents accelerated wound closure by increasing epithelization, granulation tissue formation, and angiogenesis. Moreover, direct application of bone marrow-derived MSCs induced wound closure in chronic wounds and systemic administration of MSCs promoted healing in diabetic patients.49 Endogenous MSCs are involved in all stages of wound healing, where they contribute to enhance wound closure and restore skin tissue by anti-inflammatory effects, antimicrobial activity, induction of angiogenesis, and recruitment of fibroblast and epithelial cells to the wound site.48,49 It is known that aged fibroblasts display a decreased proliferation and migration rate. In accordance, in vitro experiments revealed that such senescent fibroblasts isolated from chronic wounds exhibit a reduced migratory capacity after stimulation with MSCs.50 Similarly, bone marrow-derived MSCs from chronic wound patients show deficiencies in inducing fibroblast migration. The specific mechanisms that trigger these effects are not known. However, it has been observed that MSCs from elderly people show a significantly different morphology, signs of oxidative damage, DNA-methylation changes affecting cell differentiation, and reduced proliferation on culture.51 MSCs act through complex interactions with endogenous cells and tissues, and they can modify their activities and functions depending on the biomolecular context.52 Hence, it is not surprising that MSCs are mechanosensitive and that their cytoskeleton tension depends on matrix rigidity. Existing data suggest that cytoskeleton structure and cell tension are critical controllers of MSCs survival, self-renewal, and differentiation.53,54 Loss of mechanical forces due to dead space in chronic wounds may shut down MSCs’ activity and hinder progression from the inflammatory to the proliferative phase (Figure 1). HIGH MECHANICAL FORCES LEAD TO HYPERTROPHIC SCARRING Hypertrophic scars are characterized by the excess deposition of ECM components, primarily fibrillar collagens, which results in severe functional and esthetic defects. Understanding the pathophysiology is critical for developing effective therapeutic strategies for this and other fibrotic diseases. Potential causes for hypertrophic scarring involve mechanical loading, inflammation, bacterial colonization, and foreignbody reactions.55 A recent study by Aarabi et al. has shown that application of mechanical stress to a healing wound during the proliferative phase induced hypertrophic scarring in a mouse model.56 They showed that initiation of the Akt pathway inhibits fibroblast apoptosis and leads to their accumulation in the healing wound. There they continue to deposit ECM components, building a dense, fibrotic collagen matrix. Fibrotic programs may further be activated through induction of inflammatory signals by mechanotransduction pathways. Wound Rep Reg (2013) 21 793–799 © 2013 by the Wound Healing Society

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Although an initial inflammatory reaction is abundant for physiological wound repair, a chronic inflammatory environment can trigger fibrosis.57–59 Mechanical forces propagate acute inflammatory pathways, creating an inveterate inflammation and subsequently leading to excessive scar formation. This process has been shown to be in part regulated by T lymphocyte-derived Th2 cytokines (IL-4, IL-13) and chemokines (MCP-1) that in term activate other cell populations including macrophages and fibroblasts.57 In conclusion, mechanical forces greatly influence wound healing through alterations in cell proliferation and differentiation as well as cytokine release and matrix protein secretion. However, structural requirements for propagation of mechanical cues are lacking in chronic wounds. Moreover, cells from elderly patients with chronic wounds display significant changes in phenotype and behavior that could account for the deficiencies observed in MSCs to induce cell migration or the unresponsiveness of fibroblasts to proliferate and recreate the ECM. Absence of ECM and accumulation of wound fluid lead to formation of “dead space” across which micromechanical stimuli cannot be transferred. Furthermore, neutrophils and macrophages fail to invade this area and microbial contamination may progress to wound infection. Hence, there is the clinical demand for closely adhering dressings that maintain an intimate contact with the wound bed to avoid the creation of dead space. What is more, it can be assumed that application of micromechanical forces to chronic wounds in vivo, either by NPWT or specially designed dressings, will endorse wound healing by induction of microdeformations.

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47. Schulze C, Wetzel F, Kueper T, Malsen A, Muhr G, Jaspers S, et al. Stiffening of human skin fibroblasts with age. Biophys J 2010; 99: 2434–42. 48. Zou JP, Huang S, Pen Y, Liu HW, Cheng B, Fu XB, et al. Mesenchymal stem cells/multipotent mesenchymal stromal cells (MSCs): potential role in healing cutaneous chronic wounds. Int J Low Extrem Wounds 2012; 11: 244–53. 49. Maxson S, Lopez EA, Yoo D, Danilkovitch-Miagkova A, LeRoux MA. Role of Mesenchymal stem cells in wound repair. Stem Cells Transl Med 2012; 1: 142–9. 50. Rodriguez-Menocal L, Salgado M, Ford D, van Badiavas E. Stimulation of skin and wound fibroblast migration by mesenchymal stem cells derived from normal donors and chronic wound patients. Stem Cells Transl Med 2012; 1: 221–9. 51. Kapetanaki MG, Mora AL, Rojas M. Influence of age on wound healing and fibrosis. J Pathol 2013; 229: 310–22. 52. Jackson WM, Nesti LJ, Tuan RS. Clinical translation of wound healing therapies based on mesenchymal stem cells. Stem Cells Transl Med 2012; 1: 44–50.

Wound Rep Reg (2013) 21 793–799 © 2013 by the Wound Healing Society

Microdeformation in wound healing

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Microdeformation in wound healing.

Mechanical forces greatly influence cellular organization and behavior. Cells respond to applied stress by changes in form and composition until a sui...
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