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Cited by 3,562Wound Healing and TreatmentsTissue Engineering and Regenerative MedicinePlanarian Biology and Electrostimulation

Wound repair and regeneration: Mechanisms, signaling, and translation

Open access
Eming, Sabine A., Martin, Paul, Tomic-Canic, Marjana·2014·Science Translational Medicine
DOI 10.1126/scitranslmed.3009337PMC PMC4973620
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Abstract

The combination of an advanced scientific understanding of tissue repair and regeneration and the identification of knowledge gaps and the limitations of past clinical trials will provide a strong basis to advance viable clinical approaches for treating patients with wound-healing pathologies.

AI snapshot

Written from the paper’s full text.

TL;DR

This review synthesizes mechanisms of skin wound repair and regeneration, emphasizing how dysregulated inflammation, angiogenesis, matrix turnover, infection, stem cells, and senescence contribute to chronic wounds and scarring. It argues that translating this biology into therapies requires combination approaches, better animal models, patient stratification, and meaningful clinical endpoints.

Key findings

  • Chronic wounds and impaired healing are common and serious: venous leg ulcers affect up to 3–4% of elderly people; type 2 diabetes prevalence is 6.4% globally and projected near 8% by 2030; 2–3% of diabetic patients develop a foot ulcer yearly and 15% over their lifetime; 5-year mortality for diabetic foot or ischemic ulcers exceeds that of prostate or breast cancer, and is about 50% after diabetic-related amputation.
  • Nonhealing wounds are linked to prolonged inflammation with elevated IL-1β and TNFα, increased MMPs and serine proteases, impaired angiogenesis/vasculogenesis, microbial biofilm, stem/progenitor depletion, and cellular senescence; scarring is associated with inflammatory signaling and TGFβ/osteopontin pathways.
  • Approved therapies remain limited: in the past 15 years only Regranex (rhPDGF-BB, approved in 1997 for diabetic foot ulcers) and two biologic devices (Apligraf and Dermagraft) received FDA efficacy approval; VEGF-A clinical translation has not convincingly produced functional vessels; no FDA-approved stem cell product exists for skin wounds.
  • Animal models have identified many repair genes and pathways: mouse studies have examined more than 100 genes; bone marrow–derived MSCs can contribute up to 30% of wound fibroblasts; Drosophila and zebrafish offer live imaging and genetic screens; fetal/embryonic tissues can heal scarlessly before an inflammatory response.

Methods

  • Narrative review of tissue repair and regeneration, centered on skin but drawing implications for other epithelial-mesenchymal organs.
  • Evidence base includes human wound samples, mainly venous leg ulcers and diabetic foot ulcers, and animal models including pig, mouse, Drosophila, zebrafish, and salamander/newt.
  • No systematic review, meta-analysis, or new primary data are described; the synthesis is qualitative.

Limitations

  • The paper states that mechanisms of repair failure remain poorly understood; animal models rarely recapitulate complex human chronic wounds; clinical research is hindered by multimorbid heterogeneous patients, few large high-quality trials, reimbursement variation, cautious industry investment, limited funding, and low public awareness.
  • Evident from the text: as a narrative review, it does not report a formal search strategy, inclusion criteria, risk-of-bias assessment, or quantitative pooling; conclusions reflect selected literature and expert perspective.
  • The paper also notes that many clinical studies are small or uncontrolled, endpoints vary, and complete closure is often the only accepted primary outcome, limiting comparison across trials.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1126/scitranslmed.3009337

Cites

Statistics

Nothing to recompute.

Claims the paper makes

0 of 122 cited sources checked · 0 supported · 0 flagged

  • Findingcitation

    The 5-year mortality rate for patients with diabetic foot ulcers or ischemic ulcers is much higher than that of prostate or breast cancer.

    “Although not an immediately obvious concept, the 5-year mortality rate for patients suffering from DFU or ischemic ulcers is much higher than that of prostate or breast cancer (11-13).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [11] Armstrong DG Wrobel J Robbins JM Guest editorial: Are diabetes-related wounds and amputations worse than cancer? Int. Wound J 2007 4 286 287 18154621 source

      Not checked in the free run.

    • cites [12] Aulivola B Hile CN Hamdan AD Sheahan MG Veraldi JR Skillman JJ Campbell DR Scovell SD LoGerfo FW Pomposelli FB Jr. Major lower extremity amputation: Outcome of a modern series Arch. Surg 2004 139 395 399 15078707 source

      Not checked in the free run.

    • cites [13] Sargen MR Hoffstad O Margolis DJ Geographic variation in Medicare spending and mortality for diabetic patients with foot ulcers and amputations J. Diabetes Complications 2013 27 128 133 23062327 PMC3673572 source

      Not checked in the free run.

  • Premisecitation

    Keloids and hypertrophic scars can be histologically differentiated by their arrangement of collagen fibers, presence of αSMA-positive myofibroblasts, and extent of angiogenesis.

    “Furthermore, keloids and hypertrophic scars can be histologically differentiated by their diverse arrangement of collagen fibers, presence of α-smooth muscle actin (αSMA)–positive myofibroblasts, and extent of angiogenesis (16).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [16] Canady J Karrer S Fleck M Bosserhoff AK Fibrosing connective tissue disorders of the skin: Molecular similarities and distinctions J. Dermatol. Sci 2013 70 151 158 23631956 source

      Not checked in the free run.

  • Interpretationcitation

    It is unlikely that animal models that perfectly recapitulate the complex network of pathological factors in chronic human wounds will be developed in the near future.

    “Furthermore, based on current knowledge, it is unlikely that animal models that perfectly recapitulate the complex network of pathological factors in chronic human wounds will be developed in the near future (Fig. 3) (20).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [20] Nunan R Harding KG Martin P Clinical challenges of chronic wounds: Searching for an optimal animal model to recapitulate their complexity Dis. Model. Mech 2014 7 1205 1213 25359790 PMC4213725 source

      Not checked in the free run.

  • Premisenone given

    The failure of chronic wounds to heal properly has been attributed in part to deregulation of proteases and their inhibitors.

    “The failure of chronic wounds to heal properly has been attributed, in part, to deregulation of proteases and their inhibitors.”
    Quote in the paperNot a substantial claim
  • Premisecitation

    Continued presence of a high bacterial load in wounds results in a sustained influx of pro-inflammatory cells and increased inflammation, leading to delayed healing.

    “In addition, continued presence of a high bacterial load in wounds results in a sustained influx of pro-inflammatory cells and increased inflammation also leading to delayed healing (Fig. 3) (33-35).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [33] Pastar I Nusbaum AG Gil J Patel SB Chen J Valdes J Stojadinovic O Plano LR Tomic-Canic M Davis SC Interactions of methicillin resistant Staphylococcus aureus USA300 and Pseudomonas aeruginosa in polymicrobial wound infection PLOS One 2013 8 e56846 23451098 PMC3579943 source

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    • cites [34] Frank DN Wysocki A Specht-Glick DD Rooney A Feldman RA St Amand AL Pace NR Trent JD Microbial diversity in chronic open wounds Wound Repair Regen 2009 17 163 172 19320883 source

      Not checked in the free run.

    • cites [35] Roche ED Renick PJ Tetens SP Ramsay SJ Daniels EQ Carson DL Increasing the presence of biofilm and healing delay in a porcine model of MRSA-infected wounds Wound Repair Regen 2012 20 537 543 22672311 source

      Not checked in the free run.

  • Classified as probably not a substantial claim. 21
  • May combine two claims. 33

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingcitation

    The 5-year mortality rate for patients with diabetic-related amputations is about 50%.

    “In addition, the 5-year mortality rate for patients with diabetic-related amputations is about 50% (13).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [13] Sargen MR Hoffstad O Margolis DJ Geographic variation in Medicare spending and mortality for diabetic patients with foot ulcers and amputations J. Diabetes Complications 2013 27 128 133 23062327 PMC3673572 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisenone given

    Major etiologic factors in pressure ulcer development are biomechanical forces (confined pressure, shearing forces, and friction), moisture, and local ischemia.

    “Major etiologic factors involved in their development are biomechanical forces (confined pressure, shearing forces, and friction), moisture, and local ischemia.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Darker-skinned populations have a higher occurrence of keloids than lighter-skinned populations.

    “although it is widely accepted that darker-skinned populations have a higher occurrence of keloids than lighter-skinned populations (17).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [17] Shih B Bayat A Genetics of keloid scarring Arch. Dermatol. Res 2010 302 319 339 20130896 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Premisenone given

    In all soft tissues and organs comprising connective tissue, parenchymal tissue can be replaced by excessive extracellular matrix deposition, leading gradually to tissue fibrosis and loss of organ function.

    “In all soft tissues and organs comprising connective tissue, the parenchymal tissue can be replaced by the deposition of excessive ECM, leading gradually to tissue fibrosis and, ultimately, to loss of organ function.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisenone given

    Arterial ulcerations result from reduced arterial blood supply, which causes tissue hypoxia and tissue damage.

    “Arterial ulcerations are a consequence of reduced arterial blood supply resulting in tissue hypoxia and tissue damage (Fig. 1D).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    In polymicrobial wound communities, individual species may alter virulence and quantity as well as formation of a biofilm, which further impedes the host response and delays repair.

    “Furthermore, in these polymicrobial wound communities, individual species may alter virulence and quantity as well as formation of a biofilm, which further impedes the efficacy of the “host response” and thus delays repair (33) (see Microbiome section).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [33] Pastar I Nusbaum AG Gil J Patel SB Chen J Valdes J Stojadinovic O Plano LR Tomic-Canic M Davis SC Interactions of methicillin resistant Staphylococcus aureus USA300 and Pseudomonas aeruginosa in polymicrobial wound infection PLOS One 2013 8 e56846 23451098 PMC3579943 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Venous leg ulcers are the most severe symptom of chronic venous disease.

    “VLUs are the most severe symptom of chronic venous disease (5).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [5] Bergan JJ Schmid-Schönbein GW Smith PD Nicolaides AN Boisseau MR Eklof B Chronic venous disease N. Engl. J. Med 2006 355 488 498 16885552 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Premisenone given

    Larger injuries or physiological or common disease states including age, infection, diabetes/vascular disease, and cancer can negatively affect the healing process.

    “Although minor injuries in healthy individuals generally heal well, larger injuries or the presence of a variety of physiological or common disease states including age, infection, diabetes/vascular disease, and cancer can negatively affect the healing process in ways that are currently poorly understood (Fig. 1).”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisenone given

    Hypertrophic scars generally regress within 6 months.

    “hypertrophic scars generally regress within 6 months”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationcitation

    Chronic wound repair is a mortal disease similar to cancer.

    “Perhaps, it is now the time to recognize that chronic wound repair is a mortal disease similar to cancer (11).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [11] Armstrong DG Wrobel J Robbins JM Guest editorial: Are diabetes-related wounds and amputations worse than cancer? Int. Wound J 2007 4 286 287 18154621 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Premisenone given

    Atherosclerotic disease is the second most common underlying cause of nonhealing skin wounds of the lower leg.

    “Atherosclerotic disease represents the second most common underlying cause for nonhealing skin wounds of the lower leg.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Inflammation is prolonged in chronic wounds, and these wounds might be trapped in a chronic inflammatory state that fails to progress.

    “Inflammation is prolonged in chronic wounds (Fig. 3), and it is believed that these wounds might be trapped in a chronic inflammatory state that fails to progress (24).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [24] Eming SA Hammerschmidt M Krieg T Roers A Interrelation of immunity and tissue repair or regeneration Semin. Cell Dev. Biol 2009 20 517 527 19393325 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Premisenone given

    Pressure ulcers particularly affect multimorbid and elderly patients, especially those who are bed- or wheelchair-bound.

    “Pressure ulcers particularly affect multimorbid and elderly patients, especially those that are bed- or wheelchair-bound.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisenone given

    Vascular insufficiency, diabetes mellitus, and local-pressure effects are the major causes and categories of nonhealing skin wounds.

    “Vascular insufficiency, diabetes mellitus, and local-pressure effects are the major causes and categories of nonhealing skin wounds, although systemic factors, including compromised nutritional or immunological status, advanced age, chronic mechanical stress, and other comorbidities, contribute to poor wound healing (Fig. 1).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    IL-1β and TNFα are increased in chronic wounds, and this increase leads to elevated metalloproteinases that excessively degrade the local extracellular matrix and impair cell migration.

    “IL-1β and TNFα are increased in chronic wounds, and this increase has been shown to lead to elevated metalloproteinases that excessively degrade the local ECM and thus impair cell migration (30).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [30] Tarnuzzer RW Schultz GS Biochemical analysis of acute and chronic wound environments Wound Repair Regen 1996 4 321 325 17177727 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisenone given

    In human skin, two categories of pathological scarring after injury are distinguished: hypertrophic scars and keloids.

    “In human skin, two categories of pathological scarring after injury are distinguished: hypertrophic scars and keloids (Fig. 1, C and F).”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Premisenone given

    Diabetes mellitus is the most common metabolic disease associated with impaired wound-healing conditions.

    “Diabetes mellitus is the most common metabolic disease associated with impaired wound-healing conditions.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisenone given

    Keloids extend beyond the margins of the original tissue damage, do not tend to regress spontaneously, and show a genetic predisposition.

    “In contrast to hypertrophic scars, keloids extend beyond the margins of the original tissue damage, do not tend to regress spontaneously (hypertrophic scars generally regress within 6 months), and show a genetic predisposition.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Multiple treatment regimens for hypertrophic scars and keloids are practiced, but none are optimal and effective, and molecular-targeted therapeutics remain elusive.

    “Although multiple treatment regimens are practiced, including silicone gel sheeting, pressure therapy, corticosteroids, cryotherapy, 5-fluorouracil, laser therapy, and radiation, none of these are optimal and effective, and therapeutics based on molecular targets remain elusive (2).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [2] Reish RG Eriksson E Scars: A review of emerging and currently available therapies Plast. Reconstr. Surg 2008 122 1068 1078 18827639 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Venous leg ulcers are the most common form of leg ulcers and their incidence among the elderly is increasing up to 3 to 4%.

    “VLUs are the most common form of leg ulcers with an increasing incidence among the elderly of up to 3 to 4% (5) (Figs. 1A and 3).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [5] Bergan JJ Schmid-Schönbein GW Smith PD Nicolaides AN Boisseau MR Eklof B Chronic venous disease N. Engl. J. Med 2006 355 488 498 16885552 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisenone given

    Hypertrophic scars develop after surgery, trauma, particularly burns, or spontaneously in predisposed patients.

    “Hypertrophic scars develop after surgery, trauma, particularly burns, or spontaneously in predisposed patients.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Premisenone given

    Failure of one or several cellular processes in tissue repair is generally linked to an underlying clinical condition such as vascular disease, diabetes, or aging, which are frequently associated with healing pathologies.

    “Failure of one or several of these cellular processes is generally linked to an underlying clinical condition, such as vascular disease, diabetes, or aging, which are all frequently associated with healing pathologies.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    The relevance of platelets and their products for successful tissue reconstitution is reflected in the clinical use of platelet-rich plasma to promote healing and in impaired healing in preclinical models recapitulating platelet disorders.

    “The relevance of platelets and their products for successful tissue reconstitution is reflected in the clinical use of platelet-rich plasma to promote healing (22) and impaired healing in preclinical models recapitulating platelet disorders (23).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [22] Martinez-Zapata MJ Martí-Carvajal AJ Solà I Expósito JA Bolíbar I Rodríguez L Garcia J Autologous platelet-rich plasma for treating chronic wounds Cochrane Database Syst. Rev 2012 10 CD006899 23076929

      Not checked in the free run.

    • cites [23] Deppermann C Cherpokova D Nurden P Schulz JN Thielmann I Kraft P Vögtle T Kleinschnitz C Dütting S Krohne G Eming SA Nurden AT Eckes B Stoll G Stegner D Nieswandt B Gray platelet syndrome and defective thrombo-inflammation in Nbeal2-deficient mice J. Clin. Invest 2014 124 237 250 23863626 PMC4011026 source

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  • May combine two claims.

    Premisenone given

    Injury leads to immediate activation of the clotting cascade, which through assembly of a fibrin clot assures hemostasis and provides the basic matrix architecture to initiate invasion and recruitment of inflammatory and other cells.

    “Injury leads to immediate activation of the clotting cascade, which, through the assembly of a fibrin clot, assures hemostasis and provides the basic matrix architecture to initiate the invasion and recruitment of inflammatory and other cells.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisenone given

    In normal physiological conditions, restoration of a functional epidermal barrier is highly efficient, whereas postnatal repair of the deeper dermal layer is less so and results in scar formation with substantial loss of original tissue structure and function.

    “In normal physiological conditions, restoration of a functional epidermal barrier is highly efficient (Fig. 2), whereas postnatal repair of the deeper dermal layer is less so and results in scar formation with a substantial loss of original tissue structure and function.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisenone given

    All wounds are colonized to some degree, and a major role of the inflammatory phase is to bring microbes down to steady-state levels that can be tolerated and cleared by healthy tissues.

    “All wounds are colonized to some degree, and a major role of the inflammatory phase of wound healing is to bring microbes down to steady-state levels that can be tolerated and cleared by healthy tissues.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Many mouse models of pathological wound healing accurately mirror some systemic causes of impaired healing, such as diabetes in db/db mice, but seldom account for other important associations such as age and wound microbial load.

    “Also important to note is that many models of pathological wound healing in mice, although accurately mirroring some of the systemic causes of impaired healing—for example, the diabetic (db/db) mouse—seldom make allowance for other important associations, such as age and wound microbial load.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [20] Nunan R Harding KG Martin P Clinical challenges of chronic wounds: Searching for an optimal animal model to recapitulate their complexity Dis. Model. Mech 2014 7 1205 1213 25359790 PMC4213725 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Social isolation reduces cortisol levels and lowers KGF and VEGF at the wound site, leading to significantly retarded healing.

    “Similarly, social isolation leading to reduced cortisol levels and associated lowering of KGF and VEGF at the wound site lead to significantly retarded healing (113).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [113] Pyter LM Yang L da Rocha JM Engeland CG The effects of social isolation on wound healing mechanisms in female mice Physiol. Behav 2014 127 64 70 24486329 source

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  • May combine two claims.

    Premisecitation

    Despite limitations, mouse models have been instrumental in preclinical testing, leading to clinical trials and approval of products such as Regranex (PDGF-BB).

    “Despite the limitations of mouse models, they have been instrumental in pre-clinical testing, leading to clinical trials and approval of products such as Regranex (PDGF-BB) (62, 115, 116).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [62] Smiell JM Wieman TJ Steed DL Perry BH Sampson AR Schwab BH Efficacy and safety of becaplermin (recombinant human platelet-derived growth factor-BB) in patients with nonhealing, lower extremity diabetic ulcers: A combined analysis of four randomized studies Wound Repair Regen 1999 7 335 346 10564562 source

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    • cites [115] Greenhalgh DG Sprugel KH Murray MJ Ross R PDGF and FGF stimulate wound healing in the genetically diabetic mouse Am. J. Pathol 1990 136 1235 1246 2356856 PMC1877595

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    • cites [116] Chan RK Liu PH Pietramaggiori G Ibrahim SI Hechtman HB Orgill DP Effect of recombinant platelet-derived growth factor (Regranex®) on wound closure in genetically diabetic mice J. Burn Care Res 2006 27 202 205 16566566 source

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  • May combine two claims.

    Premisecitation

    There is evidence linking the wound inflammatory response to regenerative capacity, but the mechanism is unclear.

    “Just as inflammation appears to play key roles in mammalian skin healing, there is also evidence for a link between the wound inflammatory response and regenerative capacity, but the mechanism is unclear.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Zebrafish can regenerate missing fins, and salamanders can regenerate whole limbs.

    “Zebrafish can grow back missing fins, whereas salamanders are famously able to regenerate whole limbs (130).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [130] Murawala P Tanaka EM Currie JD Regeneration: The ultimate example of wound healing Semin. Cell Dev. Biol 2012 23 954 962 23059793 source

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  • Classified as probably not a substantial claim.

    Interpretationnone given

    Timely restoration of blood vessel supply remains an unresolved need in all aspects of regenerative medicine.

    “Timely restoration of blood vessel supply in therapeutic tissue repair approaches remains an unresolved need in all aspects of regenerative medicine.”
    Quote in the paperSubstantial claim

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    Premisecitation

    Covalent attachment of growth factors and recombinant fibronectin fragments into a fibrin scaffold can provide spatiotemporally controlled release and enhance growth factor-matrix interactions, reducing morphogen concentrations required for effective tissue generation.

    “In experimental models of bone or skin repair, it has been shown that covalent attachment of growth factors and recombinant fibronectin fragments into a fibrin scaffold can provide spatiotemporally controlled release of the growth factor and enhance growth factor–matrix interactions that ultimately significantly reduce the morphogen concentrations required for effective tissue generation (142).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [142] Martino MM Tortelli F Mochizuki M Traub S Ben-David D Kuhn GA Müller R Livne E Eming SA Hubbell JA Engineering the growth factor microenvironment with fibronectin domains to promote wound and bone tissue healing Sci. Transl. Med 2011 3 100ra189 21918106 source

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  • May combine two claims.

    Premisecitation

    Without the initial nerve signal, the wound stump heals but no limb grows back in newts.

    “Without this initial nerve signal, the wound stump heals, but no limb grows back in newts.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [131] Kumar A Brockes JP Nerve dependence in tissue, organ, and appendage regeneration Trends Neurosci 2012 35 691 699 22989534 source

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  • May combine two claims.

    Premisecitation

    ECM controls organ development and function through cell anchorage, integrin-mediated activation and signaling, transduction of mechanical forces, and sequestering, release, and activation of soluble growth factors.

    “These studies have revealed that ECM controls organ development and subsequent function through cell anchorage, integrin-mediated activation and signaling, transduction of mechanical forces, and the sequestering, release, and activation of soluble growth factors.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [137] Bateman JF Boot-Handford RP Lamandé SR Genetic diseases of connective tissues: Cellular and extracellular effects of ECM mutations Nat. Rev. Genet 2009 10 173 183 19204719 source

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  • May combine two claims.

    Premisecitation

    New models of skin healing in adult zebrafish show considerable parallels with mammalian wound repair, including similar but faster reepithelialization and transient scarring, driven by conserved signaling pathways.

    “In addition to studies of inflammation, there are now new models of skin healing in adult zebrafish that reveal considerable parallels with mammalian wound repair, including similar, yet faster reepithelialization and transient scarring, all driven by conserved signaling pathways (129).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [129] Richardson R Slanchev K Kraus C Knyphausen P Eming S Hammerschmidt M Adult zebrafish as a model system for cutaneous wound-healing research J. Invest. Dermatol 2013 133 1655 1665 23325040 PMC3644348 source

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  • May combine two claims.

    Premisereasoning

    Drosophila and zebrafish models offer translucency for live imaging and greater genetic tractability than mice, enabling study of fundamental tissue repair mechanisms not possible in humans.

    “Although they have their own limitations, Drosophila and zebrafish models offer translucency for live imaging and even greater genetic tractability than mice, to study fundamental tissue repair mechanisms not possible in humans.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [117] Razzell W Wood W Martin P Swatting flies: Modelling wound healing and inflammation in Drosophila Dis. Model. Mech 2011 4 569 574 21810906 PMC3180219 source

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    • cites [118] Henry KM Loynes CA Whyte MK Renshaw SA Zebrafish as a model for the study of neutrophil biology J. Leukoc. Biol 2013 94 633 642 23463724 source

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  • May combine two claims.

    Premisecitation

    Chick embryo studies suggest a reciprocal positive association between nerves and wound repair, and clinical anecdotes hint that poor innervation makes for poor healing.

    “Little is known about the role of nerves during skin healing, although studies in the chick embryo suggest a reciprocal positive association between nerves and wound repair (Fig. 4) (132), and several clinical anecdotes hint that poor innervation makes for poor healing.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [132] Harsum S Clarke JD Martin P A reciprocal relationship between cutaneous nerves and repairing skin wounds in the developing chick embryo Dev. Biol 2001 238 27 39 11783991 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Marfan syndrome is caused by mutations in the fibrillin-1 gene, leading to reduced extracellular fibrillin-rich microfibrils that normally act as a TGFβ reservoir.

    “For example, Marfan syndrome, a connective tissue disorder, is caused by mutations in the gene that encodes fibrillin-1, leading to reduced levels of extracellular fibrillin-rich microfibrils, which normally act as a TGFβ reservoir.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [138] Habashi JP Judge DP Holm TM Cohn RD Loeys BL Cooper TK Myers L Klein EC Liu G Calvi C Podowski M Neptune ER Halushka MK Bedja D Gabrielson K Rifkin DB Carta L Ramirez F Huso DL Dietz HC Losartan, an AT1 antagonist, prevents aortic aneurysm in a mouse model of Marfan syndrome Science 2006 312 117 121 16601194 PMC1482474 source

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    Premisecitation

    Identification of particular polymicrobial organisms or observation of high protease levels such as MMPs or ADAMs in the wound bed are already being used to modify treatment plans and improve outcomes.

    “The identification of particular polymicrobial organisms (179) or the observation of high protease levels, such as MMPs or ADAMs (a disintegrin and metalloproteinases), found in the wound bed (180) are already being used to modify treatment plans and improve outcomes.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [179] Rhoads DD Cox SB Rees EJ Sun Y Wolcott RD Clinical identification of bacteria in human chronic wound infections: Culturing vs. 16S ribosomal DNA sequencing BMC Infect. Dis 2012 12 321 23176603 PMC3542000 source

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    • cites [180] Snyder RJ Driver V Fife CE Lantis J Peirce B Serena T Weir D Using a diagnostic tool to identify elevated protease activity levels in chronic and stalled wounds: A consensus panel discussion Ostomy Wound Manage 2011 57 36 46 22156177

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  • May combine two claims.

    Interpretationreasoning

    Assessing tissue biopsies from patients can predict healing capacity and define the necessary extent of tissue debridement.

    “Thus, by assessing tissue biopsies from patients, one can begin to predict the healing capacity and define the necessary extent of tissue debridement (Fig. 5).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Changes in microbial communities stimulate expression of epidermal antimicrobials and inflammatory molecules, indicating crosstalk between microorganisms and the host.

    “Changes in microbial communities, in turn, stimulated expression of epidermal antimicrobials and inflammatory molecules, underscoring crosstalk between microorganisms and the host (164).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [164] Zeeuwen PL Boekhorst J van den Bogaard EH de Koning HD van de Kerkhof PM Saulnier DM van Swam II van Hijum SA Kleerebezem M Schalkwijk J Timmerman HM Microbiome dynamics of human epidermis following skin barrier disruption Genome Biol 2012 13 R101 23153041 PMC3580493 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Polymicrobial presence (bioburden) is well documented in chronic wounds and can play a major role in impaired wound healing even without clinical signs of infection.

    “Polymicrobial presence (bioburden) has been well documented in chronic wounds and can play a major role in impaired wound healing, even in the absence of clinical signs of infection (Fig. 3) (163, 165).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [163] Misic AM Gardner SE Grice EA The wound microbiome: Modern approaches to examining the role of microorganisms in impaired chronic wound healing Adv. Wound Care 2014 3 502 510 PMC4086514 25032070 source

      Not checked in the free run.

    • cites [165] Gardner SE Hillis SL Heilmann K Segre JA Grice EA The neuropathic diabetic foot ulcer microbiome is associated with clinical factors Diabetes 2013 62 923 930 23139351 PMC3581190 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Hormones, particularly estrogens and androgens, are contributing factors in aging and have been implicated as regulators of wound healing in experimental models and patients.

    “Hormones, particularly estrogens and androgens, are contributing factors in aging and have been implicated as regulators of wound healing in experimental models and patients (112, 163, 172, 173).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [112] Emmerson E Hardman MJ The role of estrogen deficiency in skin ageing and wound healing Biogerontology 2012 13 3 20 21369728 source

      Not checked in the free run.

    • cites [163] Misic AM Gardner SE Grice EA The wound microbiome: Modern approaches to examining the role of microorganisms in impaired chronic wound healing Adv. Wound Care 2014 3 502 510 PMC4086514 25032070 source

      Not checked in the free run.

    • cites [172] Hardman MJ Ashcroft GS Estrogen, not intrinsic aging, is the major regulator of delayed human wound healing in the elderly Genome Biol 2008 9 R80 18477406 PMC2441466 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Age-related changes can be reversed by systemic hormone replacement therapy or topical estrogen in both male and female subjects.

    “Furthermore, age-related changes can be reversed by the systemic administration of hormone replacement therapy (175) or by topical estrogen in both male and female subjects (176).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [175] Ashcroft GS Dodsworth J van Boxtel E Tarnuzzer RW Horan MA Schultz GS Ferguson MW Estrogen accelerates cutaneous wound healing associated with an increase in TGF-β1 levels Nat. Med 1997 3 1209 1215 9359694 source

      Not checked in the free run.

    • cites [176] Ashcroft GS Greenwell-Wild T Horan MA Wahl SM Ferguson MW Topical estrogen accelerates cutaneous wound healing in aged humans associated with an altered inflammatory response Am. J. Pathol 1999 155 1137 1146 10514397 PMC1867002 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Genomic, proteomic, and lipidomic analyses of human wounds have improved understanding of mechanisms guiding repair and impairment and identified potential biomarkers such as c-myc, β-catenin, S100 proteins, MMPs, and glycerophosphocholines, glycerophosphoglycerols, glycerophosphoinositols, and triacylglycerols.

    “For example, genomic, proteomic, and lipidomic analyses of human wounds have already improved our understanding of the mechanisms that guide the repair process and its impairment, and have identified several potential biomarkers, such as c-myc and β-catenin (7, 178), S100 proteins and MMPs (48), or glycerophosphocholines, glycerophosphoglycerols, glycerophosphoinositols, and triacylglycerols (181”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [7] Stojadinovic O Pastar I Vukelic S Mahoney MG Brennan D Krzyzanowska A Golinko M Brem H Tomic-Canic M Deregulation of keratinocyte differentiation and activation: A hallmark of venous ulcers J. Cell. Mol. Med 2008 12 2675 2690 18373736 PMC3828883 source

      Not checked in the free run.

    • cites [178] Stojadinovic O Brem H Vouthounis C Lee B Fallon J Stallcup M Merchant A Galiano RD Tomic-Canic M Molecular pathogenesis of chronic wounds: The role of β-catenin and c-myc in the inhibition of epithelialization and wound healing Am. J. Pathol 2005 167 59 69 15972952 PMC1603435 source

      Not checked in the free run.

    • cites [48] Krisp C Jacobsen F McKay MJ Molloy MP Steinstraesser L Wolters DA Proteome analysis reveals antiangiogenic environments in chronic wounds of diabetes mellitus type 2 patients Proteomics 2013 13 2670 2681 23798543 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Elderly male patients have the highest incidence of venous leg ulcers, and this correlates with reduced estrogen levels.

    “Elderly male patients have the highest incidence of VLUs, and this correlates with a reduced level of estrogen (174).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [174] Ashworth JJ Smyth JV Pendleton N Horan M Payton A Worthington J Ollier WE Ashcroft GS Polymorphisms spanning the 0N exon and promoter of the estrogen receptor-beta (ERβ) gene ESR2 are associated with venous ulceration Clin. Genet 2008 73 55 61 18070128 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S2 (checkable).

    Interpretationreasoning

    Heterogeneity of patients and their wounds, even within the same chronic wound category, indicates a need for better diagnostic stratification of patients included in clinical trials.

    “Heterogeneity of patients and their wounds (even within the same category of chronic wound) indicates a need for better diagnostic stratification of patients who are being included in clinical trials.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S2 (checkable). May combine two claims.

    Interpretationreasoning

    Targeting a single molecule or cellular process will not work alone; combinatorial treatment approaches are needed.

    “From our early understanding of the pathomechanisms involved in inhibition of healing, it became clear that targeting a single molecule or a cellular process will not work alone; rather, combinatorial treatment approaches are needed.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based). May combine two claims.

    Interpretationreasoning

    Aging may increase risk and, when combined with an additional comorbidity such as diabetes, extended pressure, or ischemia, leads to compromised wound healing.

    “It is possible that aging increases risk and, when combined with an additional comorbidity (diabetes, extended pressure, or ischemia), leads to compromised wound healing.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Cardiac stem cell therapy is relatively well tolerated and feasible.

    “Those studies have proven that cardiac stem cell therapy is relatively well tolerated and feasible (152).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [152] Donndorf P Strauer BE Steinhoff G Update on cardiac stem cell therapy in heart failure Curr. Opin. Cardiol 2012 27 154 160 22249215 source

      Not checked in the free run.

51 of 51

  • The paper relies on this without support.

    Most chronic skin wounds occur on the lower extremities.

    “Most chronic skin wounds occur on the lower extremities.”

  • The paper relies on this without support.

    Mouse skin is loose and not attached to underlying deep tissues, so the balance of reepithelialization and connective tissue contraction differs from human skin, where the epidermal wound edge is indirectly associated with deeper wound tissues.

    “Mouse skin is loose and not attached to the underlying deep tissues, so the balance of contributions by reepithelialization and connective tissue contraction is different from human skin, where the epidermal wound edge is indirectly associated with the deeper wound tissues (Fig. 2).”

  • The paper relies on this without support.

    Human skin is much less hairy than mouse skin.

    “Another clear difference is that human skin is much less hairy than its murine equivalent.”

  • The paper relies on this without support.

    Zebrafish larvae have equivalents of all innate immune cells, unlike Drosophila, which has a single immune cell lineage.

    “For example, rather than a single immune cell lineage, as in Drosophila, they have equivalents of all our innate immune cells.”

  • The paper relies on this without support.

    Most wound-healing pathologies result from a combination of underlying systemic disease with regional or anatomical factors that cause tissue stress, an ulcerative lesion, and/or scar formation.

    “When considering therapeutic strategies to restore diseased or damaged tissues, it is crucial to realize that most wound-healing pathologies are due to a combination of underlying systemic disease with regional/anatomical factors that cause tissue stress, an ulcerative lesion, and/or scar formation (Figs. 1 to 3).”

  • The paper relies on this without support.

    Most clinical studies on collagen- and fibrin-based materials have not been controlled or have been compared only to standard wound dressings, and their mechanisms of healing action remain speculative.

    “However, most of the clinical studies on collagen- and fibrin-based materials have not been controlled (for example, ECM alone without cellular component) or have been compared only to standard wound dressings, and their mechanisms of healing action remain speculative.”

  • The paper relies on this without support.

    Currently applied and FDA-approved cellular products for regenerative therapies use primary human cells.

    “The currently applied and FDA-approved cellular products for regenerative therapies in the clinic use primary human cells.”

  • The paper relies on this without support.

    Primary cells have low yields and proliferation rates, and for some tissues such as neurons, heart, and muscle, cells do not divide at all.

    “Primary cells have obvious limitations; yields and proliferation rates are low, and for some tissues—for example, neurons, heart, and muscle—cells do not divide at all.”

  • The paper relies on this without support.

    Most patients with chronic wounds have increased age regardless of their underlying systemic disease.

    “One feature that most patients with chronic wounds have in common, regardless of their underlying systemic disease, is increased age.”
9 of 9

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Mouse skin does not attach to underlying tissues, so initial wound area reduction is largely due to contraction, whereas in humans re-epithelialization plays a major role.

    “For example, mouse skin does not attach to underlying tissues, therefore the initial reduction in would area is largely due to contraction of the connective tissue, whereas in human re-epithelialization plays a major role.”

    From Transition from inflammation to proliferation: a critical step during wound healing (2016) · cites this paper as [11]

    In “Unexpected roles of wound genes and pathways” (page unavailable), the paper says mouse skin is loose and unattached to deep tissues, and that contraction and reepithelialization contribute differently to mouse and human wound repair. It does not specify that contraction causes most initial wound-area reduction in mice or that reepithelialization plays the major role in humans. (LLM, conf=0.87)

    Experimental — accuracy not yet measured

  • Mouse skin has much more hair compared with human skin, which may affect healing differently.

    “Also mouse skin has much more hair compared with human skin, which may affect healing differently [11].”

    From Transition from inflammation to proliferation: a critical step during wound healing (2016) · cites this paper as [11]

  • There is no satisfactory treatment available for excessive dermal fibrosis and scarring such as hypertrophic scars and keloids.

    “To date, there is no satisfactory treatment available [11].”

    From Transition from inflammation to proliferation: a critical step during wound healing (2016) · cites this paper as [11]

  • Mesenchymal cells are the main source of pathological extracellular matrix deposition in lung fibrosis, which leads to architectural disruption and reduced lung function.

    “Mesenchymal cells are the key source of pathological ECM deposition during lung fibrosis, ultimately leading to architectural disruption and reduced lung function.”

    From Fibrosis: from mechanisms to medicines (2020) · cites this paper as [1]

  • The inflammatory phase overlaps considerably with initial hemostasis and occurs during the first 72 h after tissue injury.

    “The inflammatory phase overlaps considerably with initial hemostasis, occurring during the first 72 h after tissue injury [16].”

    From Immunology of Wound Healing (2018) · cites this paper as [16]

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • Keratinocyte-culture discovery is dated to two different decades

    Minor

    The text places Rheinwald and Green's finding in the 1980s, but the cited paper reporting it is dated 1975.

  • The named drug was approved before the stated 15-year window

    Minor

    The paper says Regranex is the sole drug to have gained FDA efficacy approval in the past 15 years, yet dates its approval to 1997. The paper cites work from 2014, placing 1997 more than 15 years before its writing.

2 of 2

No citation lists for this paper

No citation lists for this paper yet — checked again daily.

References 188 · Cited by 3,562

Research works printed but not linked: 1

  1. Larcher F., Espada J., Díaz-Ley B., Jaén P., Juarranz A., Quintanilla M., New experimental models of skin homeostasis and diseases. Actas Dermosifiliogr. 10.1016/j.ad.2014.03.008 (2014). · DOI

Authors
Eming, S. A., Martin, P., & Tomic-Canic, M.
Affiliations
  • University of Cologne (DE)
  • University of Bristol (GB)
  • Wound Healing and Regenerative Medicine Research Program, Department of Dermatology, University of Miami Miller School of Medicine, Miami, FL 33136, USA.
Corresponding author
  • Eming, Sabine A.
  • Martin, Paul
ORCID
Venue
Science Translational Medicine
Publisher
American Association for the Advancement of Science (AAAS)
Published
2014-12-03
Volume
6
Issue
265
Pages
265sr6-265sr6
ISSN
  • 1946-6234 (ISSN-L)
  • 1946-6242
DOI
10.1126/scitranslmed.3009337
PMC
PMC4973620
OpenAlex
W2127903487
Cited by
3,562
References
188
Citations by year
2026: 461 · 2025: 449 · 2024: 457 · 2023: 399 · 2022: 459 · 2021: 356 · 2020: 307 · 2019: 216 · 2018: 195 · 2017: 124 · 2016: 95 · 2015: 39 · 2013: 1
FWCI
10.60
Type
journal article
Language
en
Open access
Locations
  • Science Translational Medicine (publishedVersion)
  • PubMed (publishedVersion)
  • Kölner Universitäts PublikationsServer (Universität zu Köln) (publishedVersion)
  • PubMed Central (acceptedVersion)
  • Bristol Research (University of Bristol) (submittedVersion)
Funders
  • Wellcome Trust (097791, 097791/Z/11/Z)
  • Cancer Research UK
  • British Heart Foundation (PG/12/13/29434)
  • Medical Research Council (MR/J002577/1)
  • Biotechnology and Biological Sciences Research Council
  • National Institute of Nursing Research (R01NR013881)
  • National Institute of Diabetes and Digestive and Kidney Diseases (R01DK098055, RC1DK086364)
  • National Institute of Arthritis and Musculoskeletal and Skin Diseases (R21AR060562)
Topics
  • Health Sciences › Medicine › Rehabilitation › Wound Healing and Treatments
  • Health Sciences › Medicine › Surgery › Tissue Engineering and Regenerative Medicine
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Planarian Biology and Electrostimulation
Keywords
wound healing, tissue regeneration, inflammation, angiogenesis, extracellular matrix deposition, cell recruitment, diabetic wound healing, vascular disease, aging, translational therapy
MeSH terms
Aging, Animals, Cicatrix, Fibrosis, Humans, Infections, Inflammation, Neovascularization, Pathologic, Peptide Hydrolases, Regeneration, Skin, Stem Cells, Wound Healing, Signal Transduction, Biomarkers, Mice, Translational Research, Biomedical

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Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-05.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-05.

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