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Fibroblasts and wound healing: An update

Fibroblasts and wound healing: an update
Heather E desJardins-Park1, Deshka S Foster1& Michael T Longaker*,1
1Hagey Laboratory for Pediatric Regenerative Medicine, Department of Surgery, Division of Plastic Surgery, Stanford University
School of Medicine, Stanford, CA 94305, USA
*Author for correspondence:
Increased comprehension of dermal fibroblast heterogeneity may yield both mechanistic
insights into existing therapies and inspiration for novel therapeutics targeting specific cell
populations in wound healing and scarring
First draft submitted: 30 May 2018; Accepted for publication: 13 June 2018; Published online:
31 July 2018
Keywords: broblast injury regeneration scar stem cell therapy wound healing
Wound healing and regenerative medicine are intimately linked. While any dermal wound in an adult human, even
if treated, will result in scarring [1], the ‘holy grail’ of wound healing is ‘scarless wound healing’: wound repair via
the regeneration of functional, native tissue. Scarring and pathological wound healing states, such as hypertrophic
scarring and keloids, represent an enormous clinical and financial burden on our healthcare system. Unfortunately,
there are few truly effective therapies that hasten healing while reducing scar burden.
In the setting of skin injury, wound healing following hemostasis occurs in three overlapping stages: inflammation,
proliferation and remodeling [2]. Fibroblasts are critical in all three phases, playing a key role in the deposition of
extracellular matrix (ECM) components, wound contraction and remodeling of new ECM. Since our previous
review [3], recent work continues to show the striking heterogeneity of skin fibroblasts. The concept that dermal
fibroblasts represent multiple distinct subpopulations is an important advancement in our understanding of skin
pathophysiology and serves as a new perspective from which the innovation of novel wound therapies may be
possible. Herein, we will discuss recent advancements in the understanding of fibroblast heterogeneity as it pertains
to cutaneous wound healing and relevant developments in clinical wound therapies.
Dening broblast subpopulations
Recent basic science research in wound healing has increased its focus on understanding the lineages, identities
and roles of fibroblasts in various tissues. Rigorous characterization of dermal fibroblast heterogeneity based on cell
surface markers has proved challenging, as cell surface marker expression is highly variable and no single marker
identifies this cell type [4]. However, in recent years, distinct populations of dermal fibroblasts have been elucidated.
In 2013, Driskell et al. showed that dermal fibroblasts arise from two different lineages. The upper dermal lineage
is involved with hair follicles, while the lower synthesizes ECM and engages with adipocytes [5]. Notably, the lower
lineage was found to be largely responsible for dermal repair following wounding, explaining why scar tissue in
humans is particularly ECM-rich and lacks hair follicles [5].
In 2015, Rinkevich et al. described the discovery of a ‘scarring fibroblast’ lineage responsible for depositing
the vast majority of dorsal scar tissue in mice [6]. These cells are defined by lineage positivity for the homeobox
transcription factor EN1. The authors found that these same cells could be reliably identified via expression of the
marker CD26 and that ablation of these cells reduced scarring, although this also delayed wound healing. More
recently, Hu et al. found that PRRX1 demarcates the ventral lineage of murine scar-producing fibroblasts [7].
Novel insights into stem cell contributions to wound healing
In order to fully understand fibroblast heterogeneity, these cells’ lineages must be characterized. Plikus et al.showed
that during wound healing, adipoyctes can be generated from myofibroblasts (activated fibroblasts involved in
wound contraction), suggesting significant lineage plasticity in what were previously understood to be terminally
Regen. Med. (2018) 13(5), 491–495 ISSN 1746-0751 49110.2217/rme-2018-0073 C
2018 Future Medicine Ltd
Editorial desJardins-Park, Foster & Longaker
Topical application
of growth factors
(e.g., PDGF, EGF)
can increase
proliferation and
accelerate wound
Topical application
of cell-based skin
(e.g., Grax®) protect
the wound site
and provide
healing factors
Targeting broblast
decreases brosis in
Red blood cell Platelet Fibrin Neutrophil Cytokines
Macrophage Fibroblast ECM Adipocyte
Figure 1. Wound healing pathophysiology and novel therapeutics for wound healing. An overview of cutaneous
wound healing pathophysiology with a summary of recent wound healing therapeutics of note (discussed in depth in
the text). (A–C) A review of cutaneous wound healing pathophysiology.(A)During the rst stages of wound healing,
platelets are recruited to the open wound and deposit brin (which serves as a preliminary extracellular matrix) to
arrest bleeding. (B) During the next stages of wound healing, immune cells including neutrophils followed by
macrophages are recruited to the wound and clear dead tissue and debris in preparation for healing. New blood
vessels sprout around the site. Fibroblasts are recruited to the site in anticipation of scar formation. Keratinocytes
begin to migrate to cover the cutaneous wound surface. (C) Finally, during the remodeling phases of wound healing,
the keratinocytes have covered the site. Below the broblasts deposit new extracellular matrix replacing the brin
plug, which is then remodeled to form the nal scar. New blood vessels are pruned and nerves begin to regenerate to
the site. (D–F) Novel therapeutics for wound healing. (D) Growth factors such as PDGFs can be provided directly to the
wound to stimulate broblast proliferation and accelerate wound closure. (E) Cell-based skin substitutes
(e.g., Grax R
, Osiris Therapeutics, MD, USA) can be applied directly to the wound site to protect it and directly
provide factors including cells involved in wound healing. (F) Fibroblast mechanotransduction plays a role in
stimulating scar production. Treatments that target broblast mechanotransduction, such as modulation of the FAK
pathway, are being explored in the wound setting to decrease scar brosis and potentially improve cosmesis. Key for
cell types used in illustrations provided in box at bottom.
492 Regen. Med. (2018) 13(5) future science group
Fibroblasts & wound healing: an update Editorial
differentiated fibroblasts [8].Geet al. also demonstrated significant lineage infidelity among cells involved in wound
healing (including epidermal and hair follicle cells). They showed that this lineage infidelity is induced by stress-
response-related transcription factors and is transient in healing but persistent in the setting of cancer [9].Inthis
regard, cancer cells can co-opt regenerative mechanisms seen in healing.
Such examples of lineage plasticity are dismantling the concept of distinct populations of stem cells that supply
each cell type in a wound. For example, it is possible that under conditions of homeostasis, epidermal and hair
follicle fibroblast lineages are distinct but under stress conditions this distinction is blurred [9]. These findings might
explain why response to tissue injury can be highly variable across different individuals and pathological states.
Fibroblast heterogeneity across pathological wound healing states
Human wound healing may be viewed as a spectrum, with typical scar formation representing the ‘normal’
phenotype; chronic wounds at one extreme and hyperproliferative scarring and even keloids at the other. Previous
studies have begun to investigate mechanisms by which fibroblast dysfunction could contribute to pathological
wound healing states.
Multiple studies have shown that fibroblasts from chronic nonhealing wounds display abnormal phenotypes,
including decreased proliferation, early senescence and altered patterns of cytokine release [10], as well as abnormal
MMP and TIMP activity [11]. Conversely, keloid fibroblasts are known to exhibit increased proliferation and
decreased apoptosis [12], and it has been suggested that keloid fibroblasts induce an abnormal phenotype in
surrounding quiescent fibroblasts via paracrine signaling [13], explaining the observation that keloids outgrow the
initial wound boundaries. Early observations, such as that made by Wang et al. that hypertrophic scar fibroblasts
most closely resemble fibroblasts from deeper dermal layers [14], have alluded to the potential significance of different
fibroblast subgroups in pathological healing states. However, this complex biology and its clinical implications have
yet to be fully elucidated. We hope that research efforts will continue to explore these pathologies through the lens
of fibroblast heterogeneity in the skin, to shed new light on the mechanisms behind scarring disease.
Fibroblast-focused therapeutics
There have been many wound therapeutic innovations in scar modulation since our previous review. We will limit
our discussion to those most relevant to fibroblasts, including therapies involving the delivery of viable fibroblasts
to the wound site and manipulation of fibroblast behavior.
Growth factor therapies
Several growth factors, including PDGF, FGF and TGF-β, are known to stimulate fibroblast division, activity and/or
differentiation. But to date, only one growth factor, a recombinant human PDGF formulation (REGRANEX Gel,
Smith & Nephew, London, UK), has been approved for chronic wounds. Other growth factors including FGF and
TGF-βhave failed to robustly demonstrate improved wound healing in human patients [15,16]. The general failure
of growth factor therapies is likely due to multiple limitations including short half-life following delivery. While
attempts have been made to integrate biomaterials for controlled growth factor release [17], major breakthroughs
have yet to make their way into clinical practice.
Cell-based therapies
Effective wound treatments demand an agent that reflects the complex in vivo milieu of cell types and growth
factors. One approach has been to deliver viable allogeneic cells, including fibroblasts, to the wound site. These
cells do not persist indefinitely [18], but instead serve as a source of growth factors and cytokines to support the
function of the patient’s own cells.
Cell-based therapies are most often used for chronic wounds, perhaps because as previously mentioned these
patients’ own cells may be incompetent for wound healing. Cell-based therapies approved for use in wounds
incorporate a varying range of cells, from fibroblasts only to fibroblasts plus keratinocytes, or even fully cryopreserved
skin [19,20,21]. A more recent development in cell-based wound therapies, Grafix (Osiris Therapeutics, MD, USA),
consists of cryopreserved placental tissue including placental ECM and fibroblasts [22].
While all of these products are used clinically for a large variety of wound types, their full mechanism of
action remains unknown and in many cases their efficacy has not been robustly established in vivo [23].Increased
characterization of the different skin cell populations may enable the development of increasingly effective cell-based
future science group 493
Editorial desJardins-Park, Foster & Longaker
Novel directions: targeting regeneration & broblast mechanotransduction
In recent years, growing mechanistic understanding of fibroblast function has led to therapeutically promising
discoveries. Wnt signaling is known to be critical for skin differentiation and Wnt-responsive dermal fibroblasts
play a key role [24]. As such, Wnt-3a and FGF-9 (which triggers and amplifies Wnt expression and activation in
dermal fibroblasts) are being developed as therapies with the potential to achieve scarless healing with features of
regeneration [25,26,27].
It has also been established that mechanical forces play a role in the development of pathological scars [28].
Mechanotransduction in wound fibroblasts occurs via focal adhesion complexes, which link the ECM to the
intracellular cytoskeleton [29]. In 2011, Wong et al. demonstrated that FAK activation occurs following cutaneous
injury and that fibroblast-specific FAK inhibition decreases scarring in mice [30]. These results suggest that fibroblast
mechanotransduction may be a rich target for novel antiscarring wound therapies, and elucidating the molecular
pathways linking mechanotransduction and fibrosis is an active area of current research. Figure 1 illustrates the
stages of wound healing and fibroblast-related wound therapies.
Conclusion & future perspective
Understanding dermal fibroblast heterogeneity is a lofty but important goal. Major advancements have been made
in the last several years to expand our knowledge of the different populations, signaling pathways and cellular niches
of the diverse fibroblasts in mouse and human skin. Further work is needed to fully elucidate the contributions of
different dermal fibroblast lineages to wound healing, characterize the most specific markers for each cell population
and translate these populations from mice to humans. Increased comprehension of dermal fibroblast heterogeneity
may yield both mechanistic insights into existing therapies and inspiration for novel therapeutics targeting specific
cell populations in wound healing and scarring. We anticipate that in the near future, the field of wound healing
therapeutics will expand to mirror our growing understanding of the diversity of cells involved in this biology.
Financial & competing interests disclosure
MT Longaker is a co-founder of, has an equity position in, and serves on the board of Neodyne Biosciences, Inc., a startup company
which developed a device to reduce mechanical tension on wounds to minimize post-operative scarring. The authors have no other
relevant afliations or nancial involvement with any organization or entity with a nancial interest in or nancial conict with
the subject matter or materials discussed in the manuscript apart from those disclosed. This includes employment, consultancies,
honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.
No writing assistance was utilized in the production of this manuscript.
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... Fibroblasts: Fibroblasts can contract in addition to their main function in the creation of ECM, particularly in the granulation tissues of scars [7] . ...
... 12 Current thinking suggests a role for specific fibroblast populations as guides for the regenerative process, thus leading them to be taken into consideration for tissue engineering techniques. [13][14][15] In this sense, several properties are shared by MSCs and fibroblasts. For instance, numerous authors have already described the multilineage differentiation potential [16][17][18][19][20] and immune modulation [21][22][23] of fibroblast cells. ...
Scaffolds should provide structural support for tissue regeneration, allowing their gradual biodegradation and interacting with cells and bioactive molecules to promote remodeling. Thus, the scaffold's intrinsic properties affect cellular processes involved in tissue regeneration, including migration, proliferation, differentiation, and protein synthesis. In this sense, due to its biological effect and clinical potential, Platelet Rich Plasma (PRP) fibrin could be considered a successful scaffold. Given the high variability in commercial PRPs formulations, this research focused on assessing the influence of cellular composition on fibrin membrane stability and remodeling cell activity. The stability and biological effect were evaluated at different time points via D-dimer, type I collagen and elastase quantification in culture media conditioned by Plasma Rich in Growth Factors - Fraction 1 (PRGF-F1), Plasma Rich in Growth Factors - Whole Plasma (PRGF-WP) and Leukocyte-rich Platelet Rich Plasma (L-PRP) membranes, and by gingival fibroblast cells seeded on them, respectively. Ultrastructure of PRP membranes was also evaluated. Histological analyses were performed after 5 and 18 days. Additionally, the effect of fibrin membranes on cell proliferation was determined. According to the results, L-PRP fibrin membranes degradation was complete at the end of the study, while PRGF membranes remained practically unchanged. Considering fibroblast behavior, PRGF membranes, in contrast to L-PRP ones, promoted extracellular matrix biosynthesis at the same time as fibrinolysis and enhanced cell proliferation. In conclusion, leukocytes in PRP fibrin membranes drastically reduce scaffold stability and induce behavioral changes in fibroblasts by reducing their proliferation rate and remodeling ability.
... Epithelial cells at the wound's edge begin to proliferate and lay down the provisional matrix consisting of collagen [5][6][7]. Additionally, fibroblasts migrate into the wound area and deposit significant amounts of extracellular matrix (ECM) [8]. During the final stage of wound healing, collagen continues to be deposited and remodeled, and fibroblasts also secrete glycosaminoglycan and other proteins to support the new matrix [5][6][7]. ...
Chronic non-healing wounds are a significant healthcare challenge. Various biomaterials have been developed to treat chronic wounds but there are still opportunities for improvement of biomaterial therapeutics. This review discusses how fetal wound healing could be used as inspiration to develop pro-healing materials. Compared to adults, fetuses have enhanced wound healing outcomes and healing without scarring. Scarless fetal wound healing is associated with various key differences in several growth factors, cytokines, extracellular matrix components, and coagulation parameters. Mimicking the fetal wound healing environment through bioinspired materials could create improved therapeutics to treat chronic wounds. This review addresses the key differences between adult and fetal wound healing that allow for enhanced scarless fetal healing and discusses how these differences can be used to develop pro-healing materials.
... Wound healing is a complicated and dynamic biological process, which is generally divided into four phases: hemostasis, inflammation, proliferation, and remodeling. [10][11][12][13] The process of wound healing was regulated by multiple signaling pathways, and the transforming growth factor-β1/Smad3 (TGF-β1/Smad3) signaling pathway has to be verified to play an essential role in regulating the process of wound healing. 14 Fibroblasts are present almost throughout the entire process of wound repair, especially in scar formation. ...
Full-text available
Exposure to microgravity can adversely affect the fitness of astronauts. The integrity of the skin plays a crucial role in protecting against mechanical forces and infections, fluid imbalance, and thermal dysregulation. In brief, the skin wound may cause unknown challenges to the implementation of space missions. Wound healing is a physiological process that relies on the synergistic action of inflammatory cells, extracellular matrix (ECM), and various growth factors to maintain the integrity of skin after trauma. Fibroblasts are present almost throughout the entire process of wound repair, especially in the scar formation at the endpoint of wound healing. However, there is limited knowledge about the extent to which fibroblasts are affected by the lack of gravity during wound healing. In this study, we utilized the rotary cell culture system, a ground-based facility that mimics the weightless condition, to study the alterations of L929 fibroblast cells under simulated microgravity (SMG). Our results demonstrated that the SM condition exerted negative influences on the proliferation and ECM formation of the L929 fibroblast. Whereas, the apoptosis of fibroblast was significantly upregulated upon exposure to SMG conditions. Moreover, the transforming growth factor-β1/Smad3 (TGF-β1/smad3) signaling pathway of L929 fibroblast related to wound repair was also altered significantly under a weightless environment. Overall, our study provided evidence that fibroblasts are strongly sensitive to SMG and elucidated the potential value of the TGF-β1/Smad3 signaling pathway modulating wound healing in the future practice of space medicine.
... Fibroblasts are cells regularly used for exploring biocompatibility on ECM-based material [33]. In our case, a marked induction in proliferation was observed after 48 h, maintaining this behavior until 72 h, which is the expected, since this behavior is key in this type of cell, as they are responsible for maintenance of the stroma by synthesizing growth factors and cytokines responsible for cell recruitment, essential for tissue regeneration [34]. Besides, recent cell therapies are based on the use of ECM, cryopreserved placental tissue, and fibroblasts to induce tissue regeneration [35]. ...
Background: The necessity to manufacture scaffolds with superior capabilities of biocompatibility and biodegradability has led to the production of extracellular matrix (ECM) scaffolds. Among their advantages, they allow better cell colonization, which enables its successful integration into the hosted tissue, surrounding the area to be repaired and their formulations facilitate placing it into irregular shapes. The ECM from porcine urinary bladder (pUBM) comprises proteins, proteoglycans and glycosaminoglycans which provide support and enable signals to the cells. These properties make it an excellent option to produce hydrogels that can be used in regenerative medicine. Objective: The goal of this study was to assess the biocompatibility of an ECM hydrogel derived from the porcine urinary bladder (pUBMh) in vitro using fibroblasts, macrophages, and adipose-derived mesenchymal stem cells (AD-MCSs), as well as biocompatibility in vivo using Wistar rats. Methods: Effects upon cells proliferation/viability was measured using MTT assay, cytotoxic effects were analyzed by quantifying lactate dehydrogenase release and the Live/Dead Cell Imaging assay. Macrophage activation was assessed by quantification of IL-6, IL-10, IL-12p70, MCP-1, and TNF-α using a microsphere-based cytometric bead array. For in vivo analysis, Wistar rats were inoculated into the dorsal sub-dermis with pUBMh. The specimens were sacrificed at 24 h after inoculation for histological study. Results: The pUBMh obtained showed good consistency and absence of cell debris. The biocompatibility tests in vitro revealed that the pUBMh promoted cell proliferation and it is not cytotoxic on the three tested cell lines and induces the production of pro-inflammatory cytokines on macrophages, mainly TNF-α and MCP-1. In vivo, pUBMh exhibited fibroblast-like cell recruitment, without tissue damage or inflammation. Conclusion: The results show that pUBMh allows cell proliferation without cytotoxic effects and can be considered an excellent biomaterial for tissue engineering.
Unlabelled: Emerging evidence indicates that fibroblasts play pivotal roles in immunoregulation by producing various proteins under health and disease states. In the present study, for the first time, we compared the proteomes of serum-starved human skin fibroblasts and peripheral blood mononuclear cells (PBMCs) using Nano-LC-ESI-tandem mass spectrometry. This analysis contributes to a better understanding of the underlying molecular mechanisms of chronic inflammation and cancer, which are intrinsically accompanied by growth factor deficiency.The proteomes of starved fibroblasts and PBMCs consisted of 307 and 294 proteins, respectively, which are involved in lymphocyte migration, complement activation, inflammation, acute phase response, and immune regulation. Starved fibroblasts predominantly produced extracellular matrix-related proteins such as collagen/collagenase, while PBMCs produced focal adhesion-related proteins like beta-parvin and vinculin which are involved in lymphocyte migration. PBMCs produced a more diverse set of inflammatory molecules like heat shock proteins, while fibroblasts produced human leukocytes antigen-G and -E that are known as main immunomodulatory molecules. Fifty-four proteins were commonly found in both proteomes, including serum albumin, amyloid-beta, heat shock cognate 71 kDa, and complement C3. GeneMANIA bioinformatic tool predicted 418 functions for PBMCs, including reactive oxygen species metabolic processes and 241 functions for starved fibroblasts such as antigen processing and presentation including non-classical MHC -Ib pathway, and negative regulation of the immune response. Protein-protein interactions network analysis indicated the immunosuppressive function for starved fibroblasts-derived human leucocytes antigen-G and -E. Moreover, in an in vitro model of allogeneic transplantation, the immunosuppressive activity of starved fibroblasts was experimentally documented. Conclusion: Under serum starvation-induced metabolic stress, both PBMCs and fibroblasts produced molecules like heat shock proteins and amyloid-beta, which can have pathogenic roles in auto-inflammatory diseases such as rheumatoid arthritis, type 1 diabetes mellitus, systemic lupus erythematosus, aging, and cancer. However, starved fibroblasts showed immunosuppressive activity in an in vitro model of allogeneic transplantation, suggesting their potential to modify such adverse reactions by down-regulating the immune system.
Millions of people die each year from cancer, which is caused by a combination of lifestyle and hereditary factors. It is characterized by unregulated cell division and proliferation. Mohs micrographic surgery, which involves tissue excision followed by H&E staining, is the most common procedure for cancer diagnosis. However, this procedure is time-consuming, necessitates the use of qualified professionals, and there is a considerable risk of misdiagnosis, resulting in ineffective treatment. Cancer cells have different optical characteristics than healthy tissues due to their abnormal nature. Polarization-resolved techniques can take advantage of this feature for faster, more accurate, and non-invasive disease diagnosis. The principles and applications of several polarization-enabled cancer detection approaches are described in this chapter. The techniques outlined include fluorescence spectroscopy, near-infrared (NIR) spectroscopy, hyperspectral spectroscopy, Raman spectroscopy, fluorescence microscopy, confocal microscopy, two-photon (2p) fluorescence microscopy, second-harmonic generation (SHG), third-harmonic generation (THG), coherent anti-stokes Raman scattering (CARS), stimulated Raman scattering (SRS) microscopy, surface-enhanced Raman scattering (SERS), and optical coherence tomography (OCT).KeywordsPolarizationMicroscopySpectroscopyCancer diagnosisTumor
Chronic and acute wounds pose a huge burden on patients and health care systems. Early diagnosis and prompt treatment is essential in preventing further complications such as limb amputation and infection. Recent progress in our understanding of different wounds’ pathophysiology, has resulted in developing different drug delivery vehicles to target different phases of wound healing. During the past decade, microspheres and nanospheres have gained significant attention in drug delivering wound dressings. These vehicles have gained popularity largely due their biocompatibility, biodegradability, their high capacity to deliver various drug types, and long term sustained release profile. In the current review, we will discuss the challenges and prospects of microsphere and nanosphere-based drug delivery systems in wound healing.
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New findings: What is the topic of this review? Wound healing is a general response of the body to injury and can be divided into three phases: inflammation, inflammation resolution and repair. In this review, we compare the wound-healing response of the skin after an injury and the wound-healing response of the heart after a myocardial infarction. What advances does it highlight? We highlight differences and similarities between skin and cardiac wound healing and summarize how skin can be used to provide information about the heart. Abstract: Wound healing is a general response of the body to injury. All organs share in common three response elements to wound healing: inflammation to prevent infection and stimulate the removal of dead cells, active anti-inflammatory signalling to turn off the inflammatory response, and a repair phase characterized by extracellular matrix scar formation. The extent of scar formed depends on the ability of endogenous cells that populate each organ to regenerate. The skin has keratinocytes that have regenerative capacity, and in general, wounds are fully re-epithelialized. Heart, in contrast, has cardiac myocytes that have little to no regenerative capacity, and necrotic myocytes are entirely replaced by scars. Despite differences in tissue regeneration, the skin and heart share many wound-healing properties that can be exploited to predict the cardiac response to pathology. We summarize in this review article our current understanding of how the response of the skin to a wounding event can inform us about the ability of the myocardium to respond to a myocardial infarction.
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Chronic wounds affect over 4 million individuals and pose a significant burden to the US healthcare system. Diabetes, venous stasis, radiation or paralysis are common risk factors for chronic wounds. Unfortunately, the current standard of care (SOC) has a high relapse rate and these wounds continue to adversely affect patients' quality of life. Fortunately, advances in tissue engineering have allowed for the development of cell-based wound dressings that promote wound healing by improving cell migration and differentiation. As the available options continue to increase in quantity and quality, it is important for physicians to have an easy to use guide to understand the optimal dressing to use in each given situation. The objective of this review is to identify the currently available biologic dressings, describe their indications, and provide a framework for integration into clinical practice. This review included 53 studies consisting of prospective and retrospective cohorts as well as several randomized control trials. Three general categories of cell-based biologic dressings were identified and nine brands were included. Cell-based biologic dressings have shown efficacy in a broad range of scenarios, and studies examining their efficacy have improved our understanding of the pathophysiology of chronic wounds. Amniotic and placental membranes have the widest scope and can be used to treat all subtypes of chronic wounds. Human skin allografts and bioengineered skin substitutes can be used for chronic ulcers but generally require a vascularized wound bed. Autologous platelet rich plasma (PRP) has shown promise in venous stasis ulcers and decubitus ulcers that have failed conventional treatment. Overall, more research is necessary to determine if these novel therapeutic options will change the current SOC, but current studies demonstrate encouraging results in the treatment of chronic wounds.
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Over centuries, the field of regenerative skin tissue engineering has had several advancements to facilitate faster wound healing and thereby restoration of skin. Skin tissue regeneration is mainly based on the use of suitable scaffold matrices. There are several scaffold types, such as porous, fibrous, microsphere, hydrogel, composite and acellular, etc., with discrete advantages and disadvantages. These scaffolds are either made up of highly biocompatible natural biomaterials, such as collagen, chitosan, etc., or synthetic materials, such as polycaprolactone (PCL), and poly-ethylene-glycol (PEG), etc. Composite scaffolds, which are a combination of natural or synthetic biomaterials, are highly biocompatible with improved tensile strength for effective skin tissue regeneration. Appropriate knowledge of the properties, advantages and disadvantages of various biomaterials and scaffolds will accelerate the production of suitable scaffolds for skin tissue regeneration applications. At the same time, emphasis on some of the leading challenges in the field of skin tissue engineering, such as cell interaction with scaffolds, faster cellular proliferation/differentiation, and vascularization of engineered tissues, is inevitable. In this review, we discuss various types of scaffolding approaches and biomaterials used in the field of skin tissue engineering and more importantly their future prospects in skin tissue regeneration efforts.
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Objective: To discuss the use of Grafix®, a commercially available, cryopreserved placental membrane, for the treatment of chronic/stalled wounds of different etiologies. Approach: To describe the unique composition of Grafix, to provide an overview of the existing clinical evidence supporting the benefits of Grafix for wound treatment, and to share the experience of the South Shore Hospital Center for Wound Healing (Weymouth, MA) with Grafix for the treatment of nonhealing wounds. Results: Clinical evidence supports the safety and efficacy of Grafix for the treatment of chronic/stalled wounds, including those that have failed other advanced treatment modalities. Innovation: Grafix is a cryopreserved placental membrane manufactured utilizing a novel technology that enables the preservation of all placental membrane components in their native state. Placental membranes have a unique composition of extracellular matrix, growth factors, and cells (including mesenchymal stem cells), which makes this tissue unique among other advanced biological wound treatment modalities. Conclusion: Clinical evidences support the benefits of Grafix for head-to-toe wound treatment.
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Fibroblasts in fibrosis Excess fibrous connective tissue, similar to scarring, forms during the repair of injuries. Fibroblasts are known to be involved, but their role is poorly characterized. Rinkevich et al. identify two lineages of dermal fibroblasts in the dorsal skin of mice (see the Perspective by Sennett and Rendl). A fibrogenic lineage, defined by embryonic expression of Engrailed-1 , plays a central role in dermal development, wound healing, radiation-induced fibrosis, and cancer stroma formation. Targeted inhibition of this lineage results in reduced melanoma growth and scar formation, with no effect on the structural integrity of the healed skin, thus indicating therapeutic approaches for treating fibrotic disease. Science , this issue 10.1126/science.aaa2151 ; see also p. 284
Tissue stem cells contribute to tissue regeneration and wound repair through cellular programs that can be hijacked by cancer cells. Here, we investigate such a phenomenon in skin, where during homeostasis, stem cells of the epidermis and hair follicle fuel their respective tissues. We find that breakdown of stem cell lineage confinement—granting privileges associated with both fates—is not only hallmark but also functional in cancer development. We show that lineage plasticity is critical in wound repair, where it operates transiently to redirect fates. Investigating mechanism, we discover that irrespective of cellular origin, lineage infidelity occurs in wounding when stress-responsive enhancers become activated and override homeostatic enhancers that govern lineage specificity. In cancer, stress-responsive transcription factor levels rise, causing lineage commanders to reach excess. When lineage and stress factors collaborate, they activate oncogenic enhancers that distinguish cancers from wounds.
Hair follicles: Secret to prevent scars? Although some animals easily regenerate limbs and heal broken flesh, mammals are generally not so gifted. Wounding can leave scars, which are characterized by a lack of hair follicles and cutaneous fat. Plikus et al. now show that hair follicles in both mice and humans can convert myofibroblasts, the predominant dermal cell in a wound, into adipocytes (see the Perspective by Chan and Longaker). The hair follicles activated the bone morphogenetic protein (BMP) signaling pathway and adipocyte transcription factors in the myofibroblast. Thus, it may be possible to reduce scar formation after wounding by adding BMP. Science , this issue p. 748 ; see also p. 693
Objective: The purpose of this study was to examine the characteristics of a cryopreserved split-thickness skin allograft produced from donated human skin and compare it with fresh, unprocessed human split-thickness skin. Background: Cutaneous wound healing is a complex and organized process, where the body re-establishes the integrity of the injured tissue. However, chronic wounds, such as diabetic or venous stasis ulcers, are difficult to manage and often require advanced biologics to facilitate healing. An ideal wound care product is able to directly influence wound healing by introducing biocompatible extracellular matrices, growth factors, and viable cells to the wound bed. Materials and methods: TheraSkin (processed by LifeNet Health, Virginia Beach, Virginia, and distributed by Soluble Systems, Newport News, Virginia) is a minimally manipulated, cryopreserved split-thickness human skin allograft, which contains natural extracellular matrices, native growth factors, and viable cells. The authors characterized TheraSkin in terms of the collagen and growth factor composition using ELISA, percentage of apoptotic cells using TUNEL analysis, and cellular viability using alamarBlue assay (Thermo Fisher Scientific, Waltham, Massachusetts), and compared these characteristics with fresh, unprocessed human split-thickness skin. Results: It was found that the amount of the type I and type III collagen, as well as the ratio of type I to type III collagen in TheraSkin, is equivalent to fresh unprocessed human split-thickness skin. Similar quantities of vascular endothelial growth factor, insulinlike growth factor 1, fibroblast growth factor 2, and transforming growth factor β1 were detected in TheraSkin and fresh human skin. The average percent of apoptotic cells was 34.3% and 3.1% for TheraSkin and fresh skin, respectively. Conclusions: Cellular viability was demonstrated in both TheraSkin and fresh skin.
Deciding whether to treat a scar or leave it alone depends on accurate diagnosis of scar type and scar site, symptoms, severity, and stigma