Advanced therapies for chronic wounds: NPWT, engineered skin, growth factors, extracellular matrices
chronic leg ulcers; clinical-trial; Dermatology; diabetic foot ulcers; double-blind; efficacy; extracellular-matrix; growth factors; multicenter; negative pressure wound therapy; randomized-trial; safety; vacuum-assisted closure; venous leg; wound care; wounds
Advanced wound care implies the use of products or procedures that are specialized. Although dermatologists are used to being specialists of the skin, hair, and nails, chronic wound care has evolved such that there are some specific treatment options that are more commonly ordered and performed in wound care clinics. Wound care clinics are staffed by specialists and generalists including dermatologists, but also orthopedic surgeons, vascular surgeons, infectious disease specialists, internists, family practitioners, hyperbaric oxygen-trained physicians from a variety of backgrounds, podiatrists, physician assistants, and nurse practitioners. The care of chronic wounds has almost become its own specialty, with so-called advanced therapies now including the use of growth factors, extracellular matrices, engineered skin, and negative pressure wound therapy. It is critical that the dermatologists understand the treatments such that they can appropriately apply or order them directly, or be involved with the care of their patients receiving these therapies.
Shankaran V; Brooks M; Mostow E
Dermatologic Therapy
2013
2013-05
Journal Article
<a href="http://doi.org/10.1111/dth.12050" target="_blank" rel="noreferrer noopener">10.1111/dth.12050</a>
Invited review: Role of mechanophysiology in aging of ECM: effects of changes in mechanochemical transduction
age; apoptosis; collagen; connective tissue; dermal fibroblasts; expansion; extracellular-matrix; gene-expression; growth-factor responsiveness; guinea-pig; human articular chondrocytes; mechanical forces; mechanical strain; phosphorelay system; Physiology; silicone implant; skin; Sport Sciences; tissue
Mechanical forces play a role in the development and evolution of extracellular matrices (ECMs) found in connective tissue. Gravitational forces acting on mammalian tissues increase the net muscle forces required for movement of vertebrates. As body mass increases during development, musculoskeletal tissues and other ECMs are able to adapt their size to meet the increased mechanical requirements. However, the control mechanisms that allow for rapid growth in tissue size during development are altered during maturation and aging. The purpose of this mini-review is to examine the relationship between mechanical loading and cellular events that are associated with downregulation of mechanochemical transduction, which appears to contribute to aging of connective tissue. These changes result from decreases in growth factor and hormone levels, as well as decreased activation of the phosphorelay system that controls cell division, gene expression, and protein synthesis. Studies pertaining to the interactions among mechanical forces, growth factors, hormones, and their receptors will better define the relationship between mechanochemical transduction processes and cellular behavior in aging tissues.
Silver F H; DeVore D; Siperko L M
Journal of Applied Physiology
2003
2003-11
Journal Article
<a href="http://doi.org/10.1152/japplphysiol.00429.2003" target="_blank" rel="noreferrer noopener">10.1152/japplphysiol.00429.2003</a>
Mechanobiology of force transduction in dermal tissue
3-dimensional collagen lattices; age-related-changes; bullous pemphigoid antigen; collagen; Dermatology; epidermal growth-factor; extracellular-matrix; fibrils; gap junctions; guinea-pig skin; human-skin fibroblasts; increases inositol trisphosphate; integrins; mechanical properties; mechanochemical transduction; protein-kinase-c; secondary messengers; skin; smooth-muscle cells
Background/aims: The influence of mechanical forces on skin has been examined since 1861 when Langer first reported the existence of lines of tension in cadaver skin. Internal tension in the dermis is not only passively transferred to the epidermis but also gives rise to active cell-extracellular matrix and cell-cell mechanical interactions that may be an important part of the homeostatic processes that are involved in normal skin metabolism. The purpose of this review is to analyse how internal and external mechanical loads are applied at the macromolecular and cellular levels in the epidermis and dermis. Methods: A review of the literature suggests that internal and external forces applied to dermal cells appear to be involved in mechanochemical transduction processes involving both cell-cell and cell-extra-cellular matrix (ECM) interactions. Internal forces present in dermis are the result of passive tension that is incorporated into the collagen fiber network during development. Active tension generated by fibroblasts involves specific interactions between cell membrane integrins and macromolecules found in the ECM, especially collagen fibrils. Forces appear to be transduced at the cell-ECM interface via re-arrangement of cytoskeletal elements, activation of stretch-induced changes in ion channels, cell contraction at adherens junctions, activation of cell membrane-associated secondary messenger pathways and through growth factor-like activities that influence cellular proliferation and protein synthesis. Conclusions: Internal and external mechanical loading appears to affect skin biology through mechanochemical transduction processes. Further studies are needed to understand how mechanical forces, energy storage and conversion of mechanical energy into changes in chemical potential of small and large macromolecules may occur and influence the metabolism of dermal cells.
Silver F H; Siperko L M; Seehra G P
Skin Research and Technology
2003
2003-02
Journal Article
<a href="http://doi.org/10.1034/j.1600-0846.2003.00358.x" target="_blank" rel="noreferrer noopener">10.1034/j.1600-0846.2003.00358.x</a>
Inhibition of cardiac myofibroblast formation and collagen synthesis by activation and overexpression of adenylyl cyclase
adrenomedullin; angiotensin-ii; cardiac fibroblast; cyclic AMP; extracellular-matrix; failure; fibrosis; gene-expression; growth-factor-beta; heart; lung fibroblasts; modulation; necrosis-factor-alpha; phenotypic; rat ventricular myocytes; Science & Technology - Other Topics; smooth muscle actin
Transformation of fibroblasts to myofibroblasts, characterized by expression of alpha-smooth muscle actin (alpha-SMA) and production of extracellular matrix (ECM) components, is a key event in connective tissue remodeling. Approaches to inhibit this transformation are needed in tissues, such as the heart, where excessive ECM production by cardiac fibroblasts (CFs) causes fibrosis, myocardial stiffening, and cardiac dysfunction. We tested whether adenylyl cyclase (AC) activation (increased cAMP levels) modulates the transformation of adult rat CF to myofibroblasts, as assessed by immunofluorescent microscopy, immunoblotting, and collagen synthesis. A 24-h incubation of CF with TGF-beta or angiotensin II increased alpha-SMA expression, which was inhibited by the AC agonist forskolin and a cAMP analog that activates protein kinase A. Treatment with forskolin blunted serum-, TGF-beta-, and angiotensin II-stimulated collagen synthesis. CFs engineered to overexpress type 6 AC had enhanced forskolin-promoted cAMP formation, greater inhibition by forskolin of TGF-beta-stimulated alpha-SMA expression, and a decrease in the EC50 of forskolin to reduce serum-stimulated collagen synthesis. The AC stimulatory agonist adrenomedullin inhibited collagen synthesis in CF that overexpressed AC6 but not in controls. Thus, AC stimulation blunts collagen synthesis and, in parallel, the transformation of adult rat CF to myofibroblasts. AC overexpression enhances these effects, "uncovering" an inhibition by adrenomedullin. These findings implicate cAMP as an inhibitor of ECM formation by means of blockade of the transformation of CF to myofibroblasts and suggest that increasing AC expression, thereby enhancing cAMP generation through stimulation of receptors expressed on CF, could provide a means to attenuate and prevent cardiac fibrosis and its sequelae.
Swaney J S; Roth D M; Olson E R; Naugle J E; Meszaros J G; Insel P A
Proceedings of the National Academy of Sciences of the United States of America
2005
2005-01
Journal Article
<a href="http://doi.org/10.1073/pnas.0408704102" target="_blank" rel="noreferrer noopener">10.1073/pnas.0408704102</a>
Suppression of transforming growth factor-beta effects in rabbit subconjunctival fibroblasts by activin receptor-like kinase 5 inhibitor
anti-scarring agent; Biochemistry & Molecular Biology; choroidal; extracellular-matrix; fibrosis; glaucoma; identification; in-vivo; mitomycin-c; neovascularization; Ophthalmology; Surgery; tgf-beta
Purpose: Transforming growth factor-beta (TGF-beta) activity has been implicated in subconjunctival scarring in eyes following glaucoma filtration surgery (GFS). The purpose of this study is to determine whether an inhibitor for activin receptor-like kinase (ALK) 5 (also known as TGF-beta receptor type I) could suppress TGF-beta activity and thereby promote filtering bleb survival after GFS in a rabbit model. Methods: An ALK-5 inhibitor, SB-505124, was used. A docking study was performed to investigate the interaction between the inhibitor and the receptor. Immunofluorescence for connective tissue growth factor (CTGF) and alpha-smooth muscle actin (alpha-SMA) was performed in cultured rabbit subconjunctival fibroblasts. Immunoblotting for phosphorylated Smad2 (pSmad2), CTGF, and alpha-SMA was also performed. In an in vivo rabbit GFS model, SB-505124 was delivered in a lactose tablet during surgery. Eyes were examined by slit-lamp and intraocular pressure (IOP) was measured until the time of bleb failure or up to 28 days after surgery. Tissue sections on day 5 after surgery were histologically evaluated after staining with hematoxylin and eosin. The sections were also immunostained for CTGF and alpha-SMA. In addition, cell outgrowth from dissected subconjunctival tissues placed in a cell culture flask with media was investigated. Results: The docking study indicated hydrogen bond interactions between SB-505124 and amino acids His-283 and Ser-280 ALK-5. Suppression of pSmad2, CTGF, and alpha-SMA by SB-505124 was observed in cultured fibroblasts. Filtering blebs in the GFS with SB-505124 group were maintained for more than 10 days, and the period of bleb survival was significantly longer than that in controls. IOP levels after surgery seemed to be related to bleb survival. Histologically, subconjunctival cell infiltration and scarring at the surgical site in the GFS with SB-505124 and mitomycin C (MMC) groups were much subsided compared to controls. Suppression of CTGF and alpha-SMA by SB-505124 was also observed by immunofluorescence. Cell outgrowth from explants dissected from eyes to which SB-505124 was applied during GFS was robust while outgrowth was poor from those treated with MMC. Conclusions: The ALK-5 inhibitor SB-505124 was efficacious both in vitro and in vivo in suppressing the TGF-beta action. The inhibitor may provide a novel therapy for preventing ocular inflammation and scarring.
Sapitro J; Dunmire J J; Scott S E; Sutariya V; Geldenhuys W J; Hewit M; Yue Byjt; Nakamura H
Molecular Vision
2010
2010-09
Journal Article
n/a
Small Intestinal Submucosa Wound Matrix And Full-thickness Venous Ulcers: Preliminary Results
collagen; Dermatology; extracellular-matrix; foot ulcers; repair; Surgery
Demling R H; Niezgoda J A; Haraway G D; Mostow E N
Wounds-a Compendium of Clinical Research and Practice
2004
2004-01
Journal Article or Conference Abstract Publication
n/a
Growth And Repair Factors, Osteoactivin, Matrix Metalloproteinase And Heat Shock Protein 72, Increase With Resolution Of Inflammation In Musculotendinous Tissues In A Rat Model Of Repetitive Grasping
carpal-tunnel-syndrome; disorders; endothelial-cells; extracellular-matrix; gene-expression; Heat shock protein; human fibroblasts; Metalloproteinases; muscle; musculoskeletal; Orthopedics; Osteoactivin; Overuse; posttranscriptional; regulation; Restorative repair; Rheumatology; skeletal-muscle regeneration; Tendon; transgenic expression; upper extremity
Frara N; Abdelmagid S M; Tytell M; Amin M; Popoff S N; Safadi F F; Barbe M F
Bmc Musculoskeletal Disorders
2016
2016-01
Journal Article or Conference Abstract Publication
<a href="http://doi.org/10.1186/s12891-016-0892-3" target="_blank" rel="noreferrer noopener">10.1186/s12891-016-0892-3</a>
Perineuronal nets and subtypes of GABAergic cells differentiate auditory and multisensory nuclei in the intercollicular area of the midbrain.
ab_10807945; ab_141607; ab_2278725; ab_2336066; ab_2336132; ab_2336874; ab_2336875; ab_2336881; ab_2534012; ab_2535710; ab_2665454; ab_2735091; ascending projections; descending projections; dorsal column nuclei; efferent connections; external nucleus; extracellular-matrix; Guinea pigs; inferior colliculus; intercollicular tegmentum; lateral lemniscus; medial geniculate-body; nucleus of the brachium of the inferior colliculus; nucleus of the brachium of the inferior colliculus; rostral pole of the inferior colliculus; rrid; RRID: AB_10807945; RRID: AB_141607; RRID: AB_2278725; RRID: AB_2336066; RRID: AB_2336132; RRID: AB_2336874; RRID: AB_2336875; RRID: AB_2336881; RRID: AB_2534012; RRID: AB_2535710; RRID: AB_2665454; RRID: AB_2735091; RRID: SCR_001775; scr_001775; superior colliculus; VGLUT2; VGLUT2
The intercollicular region, which lies between the inferior and superior colliculi in the midbrain, contains neurons that respond to auditory, visual, and somatosensory stimuli. Golgi studies have been used to parse this region into three distinct nuclei: the intercollicular tegmentum (ICt), the rostral pole of the inferior colliculus (ICrp), and the nucleus of the brachium of the IC (NBIC). Few reports have focused on these nuclei, especially the ICt and the ICrp, possibly due to lack of a marker that distinguishes these areas and is compatible with modern methods. Here, we found that staining for GABAergic cells and perineuronal nets differentiates these intercollicular nuclei in guinea pigs. Further, we found that the proportions of four subtypes of GABAergic cells differentiate intercollicular nuclei from each other and from adjacent inferior collicular subdivisions. Our results support earlier studies that suggest distinct morphology and functions for intercollicular nuclei, and provide staining methods that differentiate intercollicular nuclei and are compatible with most modern techniques. We hope that this will help future studies to further characterize the intercollicular region.
Beebe Nichole L; Noftz William A; Schofield Brett R
The Journal of comparative neurology
2020
2020-04-17
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journalArticle
<a href="http://doi.org/10.1002/cne.24926" target="_blank" rel="noreferrer noopener">10.1002/cne.24926</a>