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Significance: Opioid use disorder and transition to injection drug use (IDU) are an urgent, nationwide public health crisis. Wounds and skin and soft tissue infections (SSTIs) are common complications of IDU that disproportionately affect people who inject drugs (PWID) and are a major source of morbidity and mortality for this population. Critical Issues: Injections in a nonsterile environment and reusing or sharing needles facilitates bacterial inoculation, with subsequent risk of serious complications such as sepsis, gangrene, amputation, and death. PWID are susceptible to infections with a wide spectrum of organisms beyond common culprits of SSTI, including Clostridium and Bacillus spp., as well as Candida. Recent Advances: Syringe services programs (SSPs) are cost-effective and successful in reducing harms associated with IDU. SSPs provide new equipment to PWID and aid in discarding used equipment. SSPs aim to reduce the risks of unhygienic injecting practices, which are associated with transmission of infections and blood-borne pathogens. Future Directions: Concurrently run SSPs and wound care clinics are uniquely positioned to facilitate care to PWID. Providing new, sterile equipment as well as early wound care intervention can reduce morbidity and mortality as well as health care expenditures by reducing the number of SSTI and injection-related wounds that require hospital admission. Establishment of wound care clinics as part of an SSP represents an untapped potential to reduce harm.

Significance: Keloid and hypertrophic scarring are common following acute wounds. However, the variability in scarring outcomes between individuals and in particular, the association between genetic factors and scarring, is not well understood. This scoping review aims to summarize the methodology used in studies of genetic influences on the development of keloid or hypertrophic scarring in adults and children after acute wounding. The objectives were to determine the study designs used, the characteristics of participants included, the tools used to assess scarring and the length of follow-up after wounding. Recent Advances: The review was conducted according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Medline, Excerpta Medica Database (EMBASE), Web of Science, Biosciences Information Service (BIOSIS), Prospective Register of Systematic Reviews (PROSPERO), The Human Genetic Epidemiology (HuGE) Navigator (database of genetic association studies), and the genome-wide association study Catalog were searched from January 2008 to April 2020. Cohort studies and case-control studies that examined the association between one or more genetic variations and the development of keloid or hypertrophic scarring were eligible for inclusion. A narrative synthesis that grouped studies by wound type was conducted. Critical Issues: Nine studies met the inclusion criteria (five in burns, four surgical wounds, and none in other types of acute wounds). Seven assessed hypertrophic scarring, one keloid scarring, and one both scar types. Seven studies used a prospective cohort design. All studies used subjective methods (clinician or patient observation) to assess scarring. There was considerable variation in how scar scales were operationalized. Future Directions: This review identified a small body of evidence on genetic susceptibility to scarring after acute wounding. Further studies are needed, and in a wide range of populations, including patients with wounds caused by trauma.

Abnormal wound repair results from disorders in granulation tissue remodeling, and can lead to hypertrophic scarring and fibrosis. Excessive scarring can compromise tissue function and decrease tissue resistance to additional injuries. The development of potential therapies to minimize scarring is, thus, necessary to address an important clinical problem.It has been clearly established that multiple cytokines and growth factors participate in the regulation of cutaneous wound healing. More recently, it has become apparent that these factors do not necessarily activate isolated signaling pathways. Rather, in some cases, there is cross-modulation of several cellular pathways involved in this process. Two of the key pathways that modulate each other during wound healing are activated by transforming growth factor-β and by extracellular matrix proteins acting through integrins.The pathogenesis of excessive scarring upon wound healing is not fully understood, as a result of the complexity of this process. However, the fact that many pathways combine to produce fibrosis provides multiple potential therapeutic targets. Some of them have been identified, such as focal adhesion kinase and integrin-linked kinase. Currently, a major challenge is to develop pharmacological inhibitors of these proteins with therapeutic value to promote efficient wound repair.The ability to better understand how different pathways crosstalk during wound repair and to identify and pharmacologically modulate key factors that contribute to the regulation of multiple wound-healing pathways could potentially provide effective therapeutic targets to decrease or prevent excessive scar formation and/or development of fibrosis.

Significance: There is no effective drug therapy for scarring and fibrotic disease. The cytokine transforming growth factor beta (TGF-β) promotes tissue repair, but its excessive action can lead to over exuberant scarring and fibrotic disease. However, owing to the multifunctional nature of TGF-β, broad targeting of the canonical Smad–TGF-β signaling pathway in vivo is likely to have unintended, deleterious consequences. Recent Advances: (1) The myofibroblast is the essential cell type that mediates tissue repair and fibrosis. (2) TGF-β is an essential contributor to myofibroblast differentiation and activity. (3) TGF-β selectively promotes tissue repair and fibrosis via the noncanonical focal adhesion kinase (FAK) pathway; FAK mediates myofibroblast differentiation, and hence may represent a novel intervention point for drugs treating fibrotic disease. Critical Issues: Excessive scarring (e.g., in hypertrophic scars, keloids, and scleroderma) is characterized by enhanced TGF-β signaling and is a major cl...

The skin is our largest organ, with the primary role of protection against assaults from the outside world. It also suffers frequent damage, from minor scrapes to, more rarely, complete destruction such as in third-degree burns. It is therefore, by its nature, an organ that would benefit tremendously from being able to regenerate itself.This review highlights the axolotl, a less well-known model organism capable of scarless wound healing and regeneration. Axolotls are salamanders with unsurpassed healing and regenerative capacities. Understanding how these animals can regenerate their tissues could help identify the pathways that need to be activated or inhibited in humans to improve wound healing.Presently, there are no therapies leading to skin regeneration or scarless wound healing. Various animal models have thus been developed for use in research, such as mice and pigs, to help us understand how wound healing could be improved or stimulated. However, these more common models cannot regenerate and, consequently, cannot direct us toward a solution to regenerate damaged tissues. Axolotls, on the other hand, can regenerate perfectly and therefore may offer avenues to identify molecular targets for therapeutic intervention.Identifying signaling pathways regulating tissue regeneration in vertebrate models is important. The use of animals such as axolotls, which hold the secret of full regeneration, will likely play a significant role in helping us achieve scarless wound healing for humans.

This review highlights the critical role of transforming growth factor beta (TGF-β)1-3 within different phases of wound healing, in particular, late-stage wound healing. It is also very important to identify the TGF-β1-controlling factors involved in slowing down the healing process upon wound epithelialization.TGF-β1, as a growth factor, is a known proponent of dermal fibrosis. Several strategies to modulate or regulate TGF's actions have been thoroughly investigated in an effort to create successful therapies. This study reviews current discourse regarding the many roles of TGF-β1 in wound healing by modulating infiltrated immune cells and the extracellular matrix.It is well established that TGF-β1 functions as a wound-healing promoting factor, and thereby if in excess it may lead to overhealing outcomes, such as hypertrophic scarring and keloid. Thus, the regulation of TGF-β1 in the later stages of the healing process remains as critical issue of which to better understand.One hypothesis is that cell communication is the key to regulate later stages of wound healing. To elucidate the role of keratinocyte/fibroblast cross talk in controlling the later stages of wound healing we need to: (1) identify those keratinocyte-released factors which would function as wound-healing stop signals, (2) evaluate the functionality of these factors in controlling the outcome of the healing process, and (3) formulate topical vehicles for these antifibrogenic factors to improve or even prevent the development of hypertrophic scarring and keloids as a result of deep trauma, burn injuries, and any type of surgical incision.

Wound healing is a complex physiological process involving a multitude of growth factors, among which transforming growth factor beta (TGF-β) has the broadest spectrum of effects. Animal studies have provided key information on the mechanisms of TGF-β action in wound healing and have guided the development of therapeutic strategies targeting the TGF-β pathway to improve wound healing and scarring outcome.Development of tissue-specific expression systems for overexpression or knockout of TGF-β signaling pathway components has led to novel insight into the role of TGF-β signaling in wound healing. This work has also identified molecules that might serve as molecular targets for the treatment of pathological skin conditions such as chronic wounds and excessive scarring (fibrosis).Many of the mouse models with genetic alterations in the TGF-β signaling pathway develop an underlying skin abnormality, which may pose some limitations on the interpretation of wound-healing results obtained in these animals. Also, TGF-β's pleiotropic effects on many cell types throughout all phases of wound healing present a challenge in designing specific strategies for targeting the TGF-β signaling pathway to promote wound healing or reduce scarring.Further characterization of TGF-β signaling pathway components using inducible tissue-specific overexpression or knockout technology will be needed to corroborate results obtained in mouse models that display a skin phenotype, and to better understand the role of TGF-β signaling during distinct phases of the wound-healing process. Such studies will also provide a better understanding of how TGF-β mediates its autocrine, paracrine, and double paracrine effects on cellular responses