Epidermal Wound Healing Research Articles

Epidermal wound healing potentials of methanolic extract of Tetracapidium conophorum leaf on the limb of West African Dwarf goat

Epidermal wound healing potentials of methanolic extract of Tetracapidium conophorum leaf on the limb of West African Dwarf goat

Plakophilin 3 phosphorylation by ribosomal S6 kinases supports desmosome assembly.

Desmosome remodeling is crucial for epidermal regeneration, differentiation and wound healing. It is mediated by adapting the composition, and by post-translational modifications, of constituent proteins. We have previously demonstrated in mouse suprabasal keratinocytes that plakophilin (PKP) 1 mediates strong adhesion, which is negatively regulated by insulin-like growth factor 1 (IGF1) signaling. The importance of PKP3 for epidermal adhesion is incompletely understood. Here, we identify a major role of epidermal growth factor (EGF), but not IGF1, signaling in PKP3 recruitment to the plasma membrane to facilitate desmosome assembly. We find that ribosomal S6 kinases (RSKs) associate with and phosphorylate PKP3, which promotes PKP3 association with desmosomes downstream of the EGF receptor. Knockdown of RSKs as well as mutation of an RSK phosphorylation site in PKP3 interfered with desmosome formation, maturation and adhesion. Our findings implicate a coordinate action of distinct growth factors in the control of adhesive properties of desmosomes through modulation of PKPs in a context-dependent manner.

Inactivation of Zeb1 in GRHL2-deficient mouse embryos rescues mid-gestation viability and secondary palate closure

ABSTRACTCleft lip and palate are common birth defects resulting from failure of the facial processes to fuse during development. The mammalian grainyhead-like (Grhl1-3) genes play key roles in a number of tissue fusion processes including neurulation, epidermal wound healing and eyelid fusion. One family member, Grhl2, is expressed in the epithelial lining of the first pharyngeal arch in mice at embryonic day (E)10.5, prompting analysis of the role of this factor in palatogenesis. Grhl2-null mice die at E11.5 with neural tube defects and a cleft face phenotype, precluding analysis of palatal fusion at a later stage of development. However, in the first pharyngeal arch of Grhl2-null embryos, dysregulation of transcription factors that drive epithelial-mesenchymal transition (EMT) occurs. The aberrant expression of these genes is associated with a shift in RNA-splicing patterns that favours the generation of mesenchymal isoforms of numerous regulators. Driving the EMT perturbation is loss of expression of the EMT-suppressing transcription factors Ovol1 and Ovol2, which are direct GRHL2 targets. The expression of the miR-200 family of microRNAs, also GRHL2 targets, is similarly reduced, resulting in a 56-fold upregulation of Zeb1 expression, a major driver of mesenchymal cellular identity. The critical role of GRHL2 in mediating cleft palate in Zeb1−/− mice is evident, with rescue of both palatal and facial fusion seen in Grhl2−/−;Zeb1−/− embryos. These findings highlight the delicate balance between GRHL2/ZEB1 and epithelial/mesenchymal cellular identity that is essential for normal closure of the palate and face. Perturbation of this pathway may underlie cleft palate in some patients.

Phosphorylation of connexin 43 at MAPK, PKC or CK1 sites each distinctly alter the kinetics of epidermal wound repair

The gap junction protein connexin 43 (Cx43) is a key player in wound healing, and inhibitors of Cx43, which speed epidermal wound healing, are currently in clinical trials. Here, we provide direct in vivo evidence that specific phosphorylation events on Cx43 change the physiological response during wound healing. Blocking phosphorylation, through mutation of serine residues in Cx43 at the protein kinase C (PKC) or casein kinase 1 (CK1) sites, significantly slowed the rate of wound closure in vivo and in vitro and resulted in a thicker epidermal layer after reepithelialization. Conversely, preventing Cx43 phosphorylation by mitogen-activated protein kinases (MAPKs) through mutation significantly increased the rate of wound closure in vivo Defects in migration, but not proliferation, in all mutants were partially rescued in vitro by changing serine residues to aspartic or glutamic acid. These data prove that specific Cx43 phosphorylation events play an important role at different stages of wound healing. Thus, a clear physiological understanding of the spatiotemporal regulation of kinase activation and consequent effects on gap junctions could lead to a more targeted approach to modulating Cx43 expression during wound healing.

On a curvature flow model for embryonic epidermal wound healing

The paper is a mathematical investigation of a curvature flow model for embryonic epidermal wound healing proposed by Ravasio et al. (2015). Under the flow we show that a closed, initially convex or close-to-convex curve shrinks to a round point in finite time. We also study the singularity, showing that the singularity profile after continuous rescaling is that of a circle. One of the key new results we require is a maximal time estimate, which is also of independent interest.

Reepithelialization in focus: Non-invasive monitoring of epidermal wound healing in vitro

Up to today, in vivo studies are the gold standard for testing of new therapeutics for cutaneous wound healing. Alternative in vitro studies are mostly limited to two-dimensional cell cultures and thus only poorly reflect the complex physiological wound situation. Here we present a new three-dimensional wound model based on a reconstructed human epidermis (RHE). We introduce impedance spectroscopy as a time-resolved test method to determine the efficacy of wound healing non-destructively by focusing on the barrier function of the RHE as a main feature of intact skin. We assessed the skin barrier quantitatively and qualitatively by calculating the transepithelial electrical resistance (TEER), by fitting an equivalent circuit and by analyzing the single characteristic frequency. Upon wounding using a 2 mm biopsy punch, the impedance dropped significantly to 3.5% of the initial value. Impedance spectroscopy thereby proved to be a sensitive tool to distinguish between wounds of different sizes. The glucose and lactate concentration in the medium revealed an acute stress reaction of the wounded RHE (wRHE) in the first days after wounding. During monitoring of reepithelialization over fourteen days, the barrier fully recovered. Microscopy and histology images correlate well with these findings, revealing an active wound closure mostly completed by day seven after wounding. These wounded epidermal models can now be applied in therapeutic screenings and with the help of rapid screening by impedance spectroscopy, expensive and time-consuming imaging and histological methods as well as the use of animal models can be reduced.

P73 regulates epidermal wound healing and induced keratinocyte programming.

p63 is a transcriptional regulator of ectodermal development that is required for basal cell proliferation and stem cell maintenance. p73 is a closely related p53 family member that is expressed in select p63-positive basal cells and can heterodimerize with p63. p73-/- mice lack multiciliated cells and have reduced numbers of basal epithelial cells in select tissues; however, the role of p73 in basal epithelial cells is unknown. Herein, we show that p73-deficient mice exhibit delayed wound healing despite morphologically normal-appearing skin. The delay in wound healing is accompanied by decreased proliferation and increased levels of biomarkers of the DNA damage response in basal keratinocytes at the epidermal wound edge. In wild-type mice, this same cell population exhibited increased p73 expression after wounding. Analyzing single-cell transcriptomic data, we found that p73 was expressed by epidermal and hair follicle stem cells, cell types required for wound healing. Moreover, we discovered that p73 isoforms expressed in the skin (ΔNp73) enhance p63-mediated expression of keratinocyte genes during cellular reprogramming from a mesenchymal to basal keratinocyte-like cell. We identified a set of 44 genes directly or indirectly regulated by ΔNp73 that are involved in skin development, cell junctions, cornification, proliferation, and wound healing. Our results establish a role for p73 in cutaneous wound healing through regulation of basal keratinocyte function.

Gelatin-Collagen Nonwoven Scaffold Provides an Alternative to Suprathel for Treatment of Superficial Skin Defects.

To evaluate the effect of a new biologic gelatin-collagen nonwoven scaffold compared with a more common synthetic wound dressing on the healing of superficial wounds. Three superficial wounds with a depth of 0.5 mm and a length of 2.4 cm were created on the flanks of six minipigs using a skin dermatome. One wound on each pig was treated with the new nonwoven scaffold, one with the more common synthetic wound dressing, and one functioned as an untreated control wound. All three wounds were then covered with a semipermeable, sterile, transparent film. After 7 days, complete wound closure of all wounds could be detected; epidermal thickness and the number of epidermal cells of all treated wounds were significantly increased compared with the control wounds. The nonwoven dressing showed slightly better results compared with the more common dressing. The nonwoven scaffold is an interesting and competitive material for promoting epidermal wound healing. Because it is a biologic dressing, it degenerates completely and does not have to be removed from the wound. Further research should be conducted to compare this new dressing with other currently available wound treatments.

Evaluation of Antibacterial Effect against Porphyromonas gingivalis and Biocompatibility of Essential Oil Extracted from the Gum of Pistacia atlantica Kurdica.

Objective This study investigates the antibacterial effect of essential oil extracted from the gum of Pistacia atlantica Kurdica against Porphyromonas gingivalis and histological evaluation of an experimental gel of the extract in wound healing in the back subcutaneous tissue of Wistar rats. Methods Clinical strains of bacteria obtained from subgingival plaque samples of individuals having periodontitis, isolation, and confirmation were done by conventional microbiological tests and molecular technique. Essential oil was extracted by using hydrodistillation method; antibacterial activity has been determined by two fold serial dilution method. Histological evaluation conducted on fifteen Wistar rats. Incisions were made on the dorsal surface of each animal for implanting of 3 polysilicone tubes (empty, tetracycline gel, and the experimental gel). After 1, 4, and 8 weeks, the animals were euthanized and the specimens were prepared histologically. Result The extract demonstrated antimicrobial effect and significant wound healing in the different study durations particularly our product showed progression in epidermal wound healing and decrease in cellularity and scoring of inflammatory cells. Conclusion The extract was able to pose inhibitory and bactericidal activity against P. gingivalis and the experimental gel was able to have a good wound healing that enable it to be considered as a compatible material.

The Type IV Collagenase Inhibitor, BiPS, Alters Keratin Expression in Sulfur Mustard Exposed Mouse Skin

Sulfur mustard (SM) is a potent chemical vesicant targeting many tissues including skin. The SM induced cutaneous toxicity is associated with edema, epidermal erosions, inflammation, and prolonged wound repair. Earlier studies have shown that overexpression of matrix metalloproteinase 9 (MMP9) degrades extracellular matrix proteins and leads to the separation of epidermis from dermis in skin exposed to SM. We have found that MMP9, a type IV collagenase, disrupts collagen IV (Col IV) a major component of the basement membrane (BM) zone in SM induced blisters. Col IV in the BM network has recently been reported to be a regulator of epidermal differentiation and keratin expression during wound repair. The type IV collagen (Col IV) BM network may regulate epidermal differentiation and keratin expression during development and wound repair. In this present study, we evaluated the MMP9 inhibitor BiPS [N‐hydroxy‐3‐phenyl‐2‐(4‐phenylbenzenesulfonamido) propanamide] in an epidermal wound healing model following SM exposure. Time course (24, 72, and 168 hrs post‐SM exposure) and compound evaluation studies (BiPS as a single pretreatment) were performed in a mouse ear vesicant model (MEVM) using histopathological changes, degree of hyperplasia and edema, and expression of type IV collagen, MMP9, keratin 10 (K10, differentiation marker), and keratin 6 (K6, wound‐inducible marker) for comparison. MMP9 mRNA and protein expression increased with time. Dual immunofluorescence studies using Col IV α1 and MMP9 antibodies showed BM zone breakdown of Col IV and apparent MMP9 expression in the epidermis and the adjacent dermal matrix of the SM injured skin. Dual immunofluorescent studies using K6 and K10 showed strong K6 and weak K10 expression in the hyperplastic epidermis. In the compound evaluation study, the BiPS pretreatment group demonstrated significant reduction in edema with 25% reduction of epidermal thickness, and improvement in overall tissue structure by 72 hr post‐SM exposure. mRNA expression of MMP9 was significantly downregulated in the BiPS treated group by 168 hr post exposure. Immunofluorescent studies showed that significant reduction of MMP9 expression in the skin and a continuous expression pattern of Col IV; similar to the unexposed control skin. Dual immunofluorescent studies show reduced K6 and increased K10 expression in hyperplastic epidermis when compared to SM treated samples. These results suggest that BiPS treatment may effectively improve BM integrity by the inhibition of MMP9 in SM exposed skin. This may in turn modulate the epidermal keratin expression and promote keratinocyte differentiation for wound repair. Targeting MMP9 for the restoration of BM may be an effective strategy for countering SM‐induced cutaneous injury.Support or Funding InformationGrant funding supported by ES005022, T32ES007148, and NIAMS U54AR055073.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Thyroid Hormone Receptors Regulate the Expression of microRNAs with Key Roles in Skin Homeostasis.

MicroRNAs (miRNAs) play a unique role in posttranscriptional regulation of gene expression and control different aspects of skin development, homeostasis, and disease. Although it is generally accepted that thyroid hormone signaling is important in skin pathophysiology, the role of their nuclear receptors (TRs) in cutaneous miRNA expression has yet to be explored. RNAseq was used to compare the skin miRnome of wild-type mice and genetically modified mice lacking both TRα1 and TRβ, the main thyroid hormone binding isoforms. Changes in miRNAs with a crucial role in skin physiopathology were confirmed by stem-loop quantitative polymerase chain reaction in both total skin and isolated keratinocytes, and the levels of their target mRNAs were evaluated by real-time polymerase chain reaction. The skin of TRα1/TRβ knockout mice displays altered levels of >50 miRNAs. Among the downregulated species are several miRNAs, including miR-21, miR-31, miR-34, and miR-203, with crucial roles in skin homeostasis. TRα1 appears to be the main isoform responsible for their regulation. Increased levels of gene transcripts previously shown to be bona fide targets of these miRNAs are also found in the skin and keratinocytes of TR-deficient mice. This suggests that multiple miRNAs that are downregulated in the absence of TRs cooperate to regulate gene expression in the skin. The miRNAs reduced in TRα1/TRβ knockout mice are known to play crucial roles in epidermal proliferation, hair cycling, wound healing, stem-cell function, and tumor development, all processes altered in the absence of TRs. These results suggest that their regulation could contribute to the skin defects found in these mice and to the skin disorders associated with altered thyroid status in humans.

Hyaluronan metabolism enhanced during epidermal differentiation is suppressed by vitamin C.

Hyaluronan is a large, linear glycosaminoglycan present throughout the narrow extracellular space of the vital epidermis. Increased hyaluronan metabolism takes place in epidermal hypertrophy, wound healing and cancer. Hyaluronan is produced by hyaluronan synthases and catabolized by hyaluronidases, reactive oxygen species and KIAA1199. To investigate the changes in hyaluronan metabolism during epidermal stratification and maturation, and the impact of vitamin C on these events. Hyaluronan synthesis and expression of the hyaluronan-related genes were analysed during epidermal maturation from a simple epithelium to a fully differentiated epidermis in organotypic cultures of rat epidermal keratinocytes using quantitative reverse transcriptase polymerase chain reaction, immunostaining and Western blotting, in the presence and absence of vitamin C. With epidermal stratification, both the production and the degradation of hyaluronan were enhanced, resulting in an increase of hyaluronan fragments of various sizes. While the mRNA levels of Has3 and KIAA1199 remained stable during the maturation, Has1, Has2 and Hyal2 showed a transient upregulation during stratification, Hyal1 transcription remained permanently increased and transcription of the hyaluronan receptor, Cd44, decreased. At maturation, vitamin C downregulated Has2, Hyal2 and Cd44, whereas it increased high-molecular-mass hyaluronan in the epidermis, and reduced small fragments in the medium, suggesting stabilization of epidermal hyaluronan. Epidermal stratification and maturation is associated with enhanced hyaluronan turnover, and release of large amounts of hyaluronan fragments. The high turnover is suppressed by vitamin C, which is suggested to enhance normal epidermal differentiation in part through its effect on hyaluronan.

1396 Impaired Aquaporin-3 protein expression in advanced glycation end products-treated human keratinocytes: A mechanism of impaired epidermal wound healing in diabetes?

1396 Impaired Aquaporin-3 protein expression in advanced glycation end products-treated human keratinocytes: A mechanism of impaired epidermal wound healing in diabetes?

Multiscale modeling of layer formation in epidermis.

The mammalian skin epidermis is a stratified epithelium composed of multiple layers of epithelial cells that exist in appropriate sizes and proportions, and with distinct boundaries separating each other. How the epidermis develops from a single layer of committed precursor cells to form a complex multilayered structure of multiple cell types remains elusive. Here, we construct stochastic, three-dimensional, and multiscale models consisting of a lineage of multiple cell types to study the control of epidermal development. Symmetric and asymmetric cell divisions, stochastic cell fate transitions within the lineage, extracellular morphogens, cell-to-cell adhesion forces, and cell signaling are included in model. A GPU algorithm was developed and implemented to accelerate the simulations. These simulations show that a balance between cell proliferation and differentiation during lineage progression is crucial for the development and maintenance of the epidermal tissue. We also find that selective intercellular adhesion is critical to sharpening the boundary between layers and to the formation of a highly ordered structure. The long-range action of a morphogen provides additional feedback regulations, enhancing the robustness of overall layer formation. Our model is built upon previous experimental findings revealing the role of Ovol transcription factors in regulating epidermal development. Direct comparisons of experimental and simulation perturbations show remarkable consistency. Taken together, our results highlight the major determinants of a well-stratified epidermis: balanced proliferation and differentiation, and a combination of both short- (symmetric/asymmetric division and selective cell adhesion) and long-range (morphogen) regulations. These underlying principles have broad implications for other developmental or regenerative processes leading to the formation of multilayered tissue structures, as well as for pathological processes such as epidermal wound healing.

VEGF, FGF-2 and TGFβ expression in the normal and regenerating epidermis of geckos: implications for epidermal homeostasis and wound healing in reptiles.

The skin is a bilayered organ that serves as a key barrier between an organism and its environment. In addition to protecting against microbial invasion, physical trauma and environmental damage, skin participates in maintaining homeostasis. Skin is also capable of spontaneous self-repair following injury. These functions are mediated by numerous pleiotrophic growth factors, including members of the vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF), and transforming growth factor β (TGFβ) families. Although growth factor expression has been well documented in mammals, particularly during wound healing, for groups such as reptiles less is known. Here, we investigate the spatio-temporal pattern of expression of multiple growth factors in normal skin and following a full-thickness cutaneous injury in the representative lizard Eublepharis macularius, the leopard gecko. Unlike mammals, leopard geckos can heal cutaneous wounds without scarring. We demonstrate that before, during and after injury, keratinocytes of the epidermis express a diverse panel of growth factor ligands and receptors, including: VEGF, VEGFR1, VEGFR2, and phosphorylated VEGFR2; FGF-2 and FGFR1; and phosphorylated SMAD2, TGFβ1, and activin βA. Unexpectedly, only the tyrosine kinase receptors VEGFR1 and FGFR1 were dynamically expressed, and only during the earliest phases of re-epithelization; otherwise all the proteins of interest were constitutively present. We propose that the ubiquitous pattern of growth factor expression by keratinocytes is associated with various roles during tissue homeostasis, including protection against ultraviolet photodamage and coordinated body-wide skin shedding.

Skin corrosion test: a comparison between reconstructed human epidermis and full thickness skin models

Currently, there is a strong global trend towards the development of in vitro models to replace the use of animals in safety evaluation tests. Reconstructed Human Epidermis (RHE) models have been employed as an alternative method to animal testing of skin corrosion and irritation potential of chemical compounds. However, the consequences of an absence of the dermal compartment in these models should be considered since the cross-talk between fibroblasts and keratinocytes is fundamental for promoting proper epidermal stratification, homeostasis, inflammatory response and wound healing. In this study, we compare in-house developed models of Reconstructed Human Epidermis (i.e. USP-RHE) and full thickness skin (i.e. USP-FTS) regarding their response when submitted to skin corrosion assays, based on Guideline 431 (OECD). The results show that both models correctly classified the four substances tested (2-phenylethyl bromide, benzylacetone, lactic acid, octanoic acid) as corrosive or non-corrosive. Furthermore, we have demonstrated higher cell viability of the USP-FTS model compared to the USP-RHE model, a sign of its improved barrier function, following the exposure to the substances test on the corrosion assay. This emphasizes the importance of employing in vitro models that are more physiologically relevant and that better mimic the in vivo situation for the toxicological screening of substances.

Crawling wounded: molecular genetic insights into wound healing from Drosophila larvae.

For animals, injury is inevitable. Because of this, organisms possess efficient wound healing mechanisms that can repair damaged tissues. However, the molecular and genetic mechanisms by which epidermal repair is accomplished remain poorly defined. Drosophila has become a valuable model to study epidermal wound healing because of the comprehensive genetic toolkit available in this organism and the similarities of wound healing processes between Drosophila and vertebrates. Other reviews in this Special Issue cover wound healing assays and pathways in Drosophila embryos, pupae and adults, as well as regenerative processes that occur in tissues such as imaginal discs and the gut. In this review, we will focus on the molecular/genetic control of wound-induced cellular processes such as inflammation, cell migration and epithelial cell-cell fusion in Drosophila larvae. We will give a brief overview of the three wounding assays, pinch, puncture, and laser ablation, and the cellular responses that ensue following wounding. We will highlight the actin regulators, signaling pathways and transcriptional mediators found so far to be involved in larval epidermal wound closure and what is known about how they act. We will also discuss wound-induced epidermal cell-cell fusion and possible directions for future research in this exciting system.

Regulation of the Glycerol Transporter, Aquaporin-3, by Histone Deacetylase-3 and p53 in Keratinocytes

Aquaporin- (AQP) 3, a water and glycerol channel, plays an important role in epidermal function, with studies showing its involvement in keratinocyte proliferation, differentiation, and migration and in epidermal wound healing and barrier repair. Increasing speculation about the use of histone deacetylase (HDAC) inhibitors to treat skin diseases led us to investigate HDAC's role in the regulation of AQP3. The broad-spectrum HDAC inhibitor suberoylanilide hydroxamic acid induced AQP3 mRNA and protein expression in a dose- and time-dependent manner in normal keratinocytes. The SAHA-induced increase in AQP3 levels resulted in enhanced [3H]glycerol uptake in normal but not in AQP3-knockout keratinocytes, confirming that the expressed AQP3 was functional. Use of HDAC inhibitors with different specificities limited our exploration of the responsible HDAC member to HDAC1, HDAC2, or HDAC3. Cre-recombinase-mediated knockdown and overexpression of HDAC3 suggested a role for HDAC3 in suppressing AQP3 expression basally. Further investigation implicated p53 as a transcription factor involved in regulating HDAC inhibitor-induced AQP3 expression. Thus, our study supports the regulation of AQP3 expression by HDAC3 and p53. Because suberoylanilide hydroxamic acid is already approved to treat cutaneous T-cell lymphoma, it could potentially be used as a therapy for skin diseases like psoriasis, where AQP3 is abnormally expressed.

Yorkie regulates epidermal wound healing in Drosophila larvae independently of cell proliferation and apoptosis

Yorkie (Yki), the transcriptional co-activator of the Hippo signaling pathway, has well-characterized roles in balancing apoptosis and cell division during organ growth control. Yki is also required in diverse tissue regenerative contexts. In most cases this requirement reflects its well-characterized roles in balancing apoptosis and cell division. Whether Yki has repair functions outside of the control of cell proliferation, death, and growth is not clear. Here we show that Yki and Scalloped (Sd) are required for epidermal wound closure in the Drosophila larval epidermis. Using a GFP-tagged Yki transgene we show that Yki transiently translocates to some epidermal nuclei upon wounding. Genetic analysis strongly suggests that Yki interacts with the known wound healing pathway, Jun N-terminal kinase (JNK), but not with Platelet Derived Growth Factor/Vascular-Endothelial Growth Factor receptor (Pvr). Yki likely acts downstream of or parallel to JNK signaling and does not appear to regulate either proliferation or apoptosis in the larval epidermis during wound repair. Analysis of actin structures after wounding suggests that Yki and Sd promote wound closure through actin regulation. In sum, we found that Yki regulates an epithelial tissue repair process independently of its previously documented roles in balancing proliferation and apoptosis.

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Enzymatically crosslinked microporous hydrogel scaffolds that form in situ promote dermal healing Evaluation of: Griffin DR, Weaver WM, Scumpia PO, DiCarlo D, Segura T. Accelerated wound healing by injectable microporous gel scaffolds assembled from annealed building blocks. Nat. Mater. 14, 737–744 (2015). Tunable scaffolds that respond to environmental factors could enable enhanced tissue integration and wound healing. To achieve this goal, scaffold designs have incorporated biomimetic functionality, including thrombin-activated factor XIII (FXIIIa) crosslinking [1], matrix metalloproteinase responsiveness [2] and mechanical matching [3]. Scaffolds that can alter their properties in situ in response to environmental stimuli are desired to achieve changes in stiffness, shape, release and degradation that can lead to improved tissue regeneration. In this study, Griffin et al. describe a bottom-up strategy to fabricating scaffolds that accelerate wound healing [4]. They use a microfluidic approach to form hydrogel microparticle (microgel) building blocks that can establish interconnected network structures upon FXIIIa-mediated crosslinking. These microporous annealed particles (MAPs) incorporate reactive multiarmed poly(ethylene)glycol-vinyl sulfone, the commonly used RGD cell adhesion peptide and the K and Q noncanonical transglutaminase peptide substrates with cysteine-terminated matrix metalloproteinase-sensitive peptides that allow for cell-controlled material degradation. Scaffolds are annealed by FXIIIa addition and can be injected into wound sites for in situ solidification and shape-conformation. These MAPs are mechanically robust and can be tuned to achieve storage moduli from 10 to 1000 Pa, which fall within the stiffness range of soft tissues. In vitro studies demonstrate that MAP scaffolds enable 3D cellular network formation and cell proliferation and survival after 6 days. In vivo studies in SKH1-HR and Balb/c epidermal wound healing models demonstrate integration of MAP scaffolds after 24 h, significant wound closure as compared with nonporous chemically matched controls after 5 days or physically matched control scaffolds up to 7 days. 5 days following injection of MAP scaffolds, keratin-5, keratin-14 and CD49f staining revealed re-epithelialization, and PECAM-1, NG2 and PDGFR-β staining indicated that the scaffolds promoted complex vascular development. MAP scaffolds were also able to sustain normal hair follicle formation when compared with normal tissue. The scaffolds promoted less CD11b cell infiltration as compared with nonporous controls after 5 days, which suggests that MAP scaffolds cause a lower immune response. Taken together, MAP scaffolds promote accelerated wound healing by utilizing natural enzymatic mechanisms and mimicking favorable mechanical and degradation properties to facilitate cell infiltration and proliferation. The study may have benefited from evaluating wound closure, dermal regeneration and Our panel of experts highlight the most important research articles across the spectrum of topics relevant to the field of regenerative medicine