Skin Microenvironment Research Articles

TNIP1 Impacts Prognosis by Modulating the Immune Microenvironment in BRCA.

Breast invasive carcinoma (BRCA) affects women worldwide, and despite advancements in diagnosis, prevention, and treatment, outcomes remain suboptimal. TNIP1, a novel target involved in multiple immune signaling pathways, influences tumor development and survival. However, the connection between BRCA and TNIP1 remains unclear. Analysis of data from the TCGA, GEO, Sangerbox, and Ualcan databases revealed that TNIP1 is underexpressed in BRCA tissues. This finding was corroborated by RT-PCR and immunohistochemistry. Furthermore, data from the TCGA and GEPIA2 databases, along with Sangerbox, identified TNIP1 as a marker of poor prognosis in BRCA patients. TNIP1 expression shows significant positive correlations with the BRCA Tumor Microenvironment (TME) StromalScore (R = 0.22), ImmuneScore (R = 0.25), and ESTIMATEScore (R = 0.27). Various algorithms have demonstrated a strong association between TNIP1 expression and BRCA tumor-infiltrating immune cells (TIICs). Further analysis using EPIC, TIMER, MCPCounter, QUANTISEQ, xCell, and other computational tools revealed that elevated TNIP1 expression is significantly associated with increased immune cell scores. TNIP1 expression in BRCA tumor tissues also shows a strong correlation with immune checkpoint markers. Data from the HAP database indicate that TNIP1 expression is predominantly involved in the normal skin microenvironment. Subsequent analysis using the TISCH platform with the BRCA single-cell dataset demonstrated that TNIP1 exhibits higher expression levels in immune cells compared to non-immune cells in BRCA patients. This expression is significantly positively correlated with inflammation (R = 0.25) and differentiation (R = 0.28) within the TME, while showing negative correlations with BRCA stemness (R = -0.34) and invasion (R = -0.22). Consequently, TNIP1 is proposed as a potential prognostic marker and therapeutic target for BRCA.

D-mannose promotes diabetic wound healing through inhibiting advanced glycation end products formation in keratinocytes

BackgroundDiabetic chronic foot ulcers pose a significant therapeutic challenge around the world, resulting in adverse effects and complications in patients. D-mannose is enriched in cirtus peel and exerts beneficial effects among various diseases, especially against inflammation-related disorders.MethodsHere, we examined the potential effect of D-mannose during wound healing process in streptozotocin (STZ)-induced diabetes mice in vivo and by culturing keratinocytes under high glucose condition in vitro. The skin lesion healing was recorded in photos and evaluated by histochemical staining. What’s more, the advanced glycation end products (AGEs) concentration in blood and mice skin was quantified. Apoptotic cells were assessed by flow cytometry and Western blotting. Inflammatory cytokines and cellular differential gene expression levels were measured by real-time PCR. The expression of the AMPK/Nrf2/HO-1 signaling-related molecules was determined by Western blotting.ResultsWe first found that topical supplementation of D-mannose remarkably improved skin wound healing in diabetes mice. Furthermore, both in vivo and in vitro experiments demonstrated that D-mannose reduced the AGEs generation. Mechanistically, D-mannose inhibited AGEs, then upregulated AMPK/Nrf2/HO-1 signaling in the context of high glucose to maintain keratinocyte normal functions, which positively influenced macrophage and fibroblast to accelerate diabetic wound healing. Noteworthily, these protective effects of D-mannose were abolished by the pretreatment with inhibitors of AGEs or AMPK.ConclusionAs far as we know, this is the first study exploring the protective role of D-mannose on diabetic wound healing via topical supplementation. We find that D-mannose protects keratinocytes from high glucose stimulation via inhibition of AGEs formation as well as orchestrates inflammatory microenvironment in diabetic wounded skin, suggesting its supplementation as a potential therapy to promote refractory wound healing in diabetic patients.

Bidirectional Mendelian Randomization Analysis to Study the Relationship Between Human Skin Microbiota and Radiation-Induced Skin Toxicity.

Radiation-induced skin toxicity, resulting from ionizing or nonionizing radiation, is a common skin disorder. However, the underlying relationship between skin microbiota and radiation-induced skin toxicity remains largely unexplored. Herein, we uncover the microbiota-skin interaction based on a genome-wide association study (GWAS) featuring 150 skin microbiota and three types of skin microenvironment. Summary datasets of human skin microbiota were extracted from the GWAS catalog database, and summary datasets of radiation-induced skin toxicity from the FinnGen biobank. Mendelian Randomization (MR) analysis was leveraged to sort out the causal link between skin microbiota and radiation-induced skin toxicity. We identified 33 causal connections between human skin microbiota and radiation-induced skin toxicity, including 19 positive and 14 negative causative directions. Among these potential associations, the genus Staphylococcus could serve as a common risk factor for radiation-induced skin toxicity, especially for radiodermatitis. And Streptococcus salivarius was identified as a potential protective factor against radiation-induced skin toxicity. Additional analysis indicated no pleiotropy, heterogeneity, or reverse causal relationship in the results. We comprehensively assessed potential associations of skin microbiota with radiation-induced skin toxicity and identified several suggestive links. Our results provide promising targets for the prevention and treatment of radiation-induced skin toxicity.

Advancements in Transdermal Drug Delivery Systems: Harnessing the Potential of Macromolecular Assisted Permeation Enhancement and Novel Techniques.

Transdermal drug delivery (TDD) represents a transformative paradigm in drug administration, offering advantages such as controlled drug release, enhanced patient adherence, and circumvention of hepatic first-pass metabolism. Despite these benefits, the inherent barrier function of the skin, primarily attributed to the stratum corneum, remains a significant impediment to the efficient permeation of therapeutic agents. Recent advancements have focused on macromolecular-assisted permeation enhancers, including carbohydrates, lipids, amino acids, nucleic acids, and cell-penetrating peptides, which modulate skin permeability by transiently altering its structural integrity. Concurrently, innovative methodologies such as iontophoresis, electroporation, microneedles, ultrasound, and sonophoresis have emerged as potent tools to enhance drug transport by creating transient microchannels or altering the skin's microenvironment. Among the novel approaches, the development of nanocarriers such as Liposome, niosomes, and transethosomes etc. has garnered substantial attention. These elastic vesicular systems, comprising lipids and edge activators, exhibit superior skin penetration owing to their deformability and enhanced payload delivery capabilities. Furthermore, the integration of nanocarriers with physical enhancement techniques demonstrates a synergistic potential, effectively addressing the limitations of conventional TDD systems. This comprehensive convergence of macromolecular-assisted enhancers, advanced physical techniques, and next-generation nanocarriers underscores the evolution of TDD, paving the way for optimized therapeutic outcomes.

Composite Nanofiber Membrane-Based Microfluidic Fluorescence Sensors for Sweat Analysis.

Microfluidic chips play a crucial role in wearable sensors for sweat collection. However, previously reported wearable microfluidic chips, such as those based on poly(dimethylsiloxane) (PDMS) and paper, encounter sweat accumulation at the skin-sensor interface in practical applications, which consequently affects both sensing stability and wearing comfort. Herein, we propose a composite nanofiber membrane (CNMF)-based microfluidic chip for in situ sweat collection. The CNMF with directional water transport capability was integrated with patterned PDMS to prepare microfluidic chips. On one hand, sweat can be automatically transported to the analysis area along the designed pathway. On the other hand, sweat transfers from the hydrophobic membrane close to the skin to the hydrophilic membrane, effectively avoiding sweat accumulation and facilitating a comfortable skin microenvironment. Subsequently, we constructed a CNMF-based microfluidic fluorescence sensor for the analysis of multiple targets in human sweat. A portable 3D-printed device was employed for the visual signal output. Results indicated that the microfluidic sensor exhibits excellent reliability for collecting and analyzing sweat. This work provides new insights into the construction of wearable microfluidic chips with enhanced wearing comfort.

Review on Hydrogel Based Systems and their use in Drug Delivery for Wound Healing & Wound Management

Abstract: The largest organ of the human body, the skin, shields the body from the outside environment. Despite having a great capacity for regeneration, major skin abnormalities cannot heal on their own and must be covered with artificial skin. In recent years, significant advancements have been achieved in the area of skin tissue engineering to create novel skin replacements. Because of their porous as well as moisturized polymeric structural composition, hydrogels are one of the choices with the greatest ability to imitate the natural skin microenvironment. Naturally derived polymers, synthesized polymers, polymerizable synthetic monomolecules, as well as mixtures of natural and synthesized polymers, can all be used to create hydrogels. They can be used to assist in the regeneration as well as repair of the wounded dermis, epidermis or else both by dressing various wounds permanently or temporarily. Hydrogels possess distinct properties like lightweight, stretchable, biocompatible, and biodegradable; they have the potential to be incorporated as flexible solutions for the care of chronic wounds. Additionally, these characteristics make hydrogels appropriate for use in the pharmaceutical and medical industries. Physical, chemical, and hybrid bonding are all involved in the creation of hydrogels. Several processes, including solution casting, solution mixing, bulk crosslinking polymerization, the free radical mechanism, radiation therapy, and the development of interpenetrating networks, are used to create the bonding. This review primarily focuses on the type of wounds with phases in wound healing and the many kinds of hydrogels based on cross-linking, ionic charge, physical properties, source etc., and it also describes potential fabrication techniques for hydrogel design in biomedical applications, drug delivery as well as wound management hydrogel systems. Hydrogel-based systems for wound recovery and management are described, as well as current research & future prospective of hydrogel-based drug delivery systems in wound healing for topical applications.

Cell aggregation mediated by ACE2 deletion in Candida auris modulates fungal colonization and host immune responses in the skin.

Candida auris is an emerging multi-drug-resistant fungal pathogen that colonizes the skin and causes invasive infections in hospitalized patients. Multi-cellular aggregative phenotype is widely reported in the C. auris isolates, but its role in skin colonization and host immune response is not yet known. In this study, we generated aggregative phenotype by deleting the ACE2 gene in C. auris and determined the fungal colonization and host immune response using an intradermal mouse model of C. auris skin infection. Our results indicate that mice infected with ace2Δ strain had significantly lower fungal load after 3 and 14 days post-infections compared to the non-aggregative wild-type and the ACE2 reintegrated strain. The colonization of ace2Δ is associated with increased recruitment of CD11b+ Ly6G+ neutrophils and decreased accumulation of CD11b+ Ly6 Chi inflammatory monocytes and CD11b+ MHCII+ CD64+ macrophages. Furthermore, Th17 cells and type 3 innate lymphoid cells (ILCs) were significantly increased in the skin tissue of ace2Δ infected mice. Our findings suggest that aggregative phenotype mediated by ACE2 deletion in C. auris induces potent neutrophil and IL-17-mediated immune response and reduces fungal colonization in the skin.IMPORTANCEC. auris is a rapidly emerging fungal pathogen that can colonize hospitalized patients, especially in skin tissue, and cause invasive infections. C. auris isolates exhibit morphological heterogeneity, and the multicellular aggregative phenotype of C. auris is reported frequently in clinical settings. Understanding the role of fungal morphotypes in colonization, persistence, and immune response in the skin microenvironment will have potential applications in clinical diagnosis and novel preventive and therapeutic measures. Here, we utilized the murine model of intradermal infection and determined that the aggregative phenotype of C. auris as the result of ACE2 gene deletion elicits potential innate and adaptive immune responses in mice. These observations will help explain the differences in the skin colonization and immune responses of the aggregative morphotype of C. auris and open the door to developing novel antifungal therapeutics.

Protective Effects of Keratinocyte-Derived GCSF and CCL20 on UVB-Induced Melanocyte Damage.

The skin microenvironment created by keratinocytes (KC) influences the stress responses of melanocytes (MC) to UVB insults. This study employed RNA sequencing analysis as well as in vitro and in vivo models to elucidate the underlying mechanisms. Our RNA-Seq analysis revealed a statistically significant upregulation of GCSF and CCL20 genes in UVB-irradiated KC, correlating with the protective effects of KC on MC responses to UVB exposure. Recombinant GCSF and CCL20 exhibited the most pronounced modulation of UVB-induced MC responses. These effects included the attenuation of apoptosis and reduction of ROS formation, along with the upregulation of tyrosinase and tyrosinase-related protein-1, which are involved in the melanogenic pathway. ELISA was also used to confirm that UVB could induce the secretion of GCSF and CCL20 from KC. A similar correlation between GCSF and CCL20 expression in KC and tyrosinase levels in MC was observed in UVB-irradiated mouse skin. Our study provides novel insights into the protective role of GCSF and CCL20 in the paracrine effects of KC on UVB-induced MC damage through the modulation of stress response pathways, the MITF-tyrosinase axis, and the regulation of p53. These findings have implications for the development of pharmacological strategies targeting KC-derived paracrine factors for the prevention of skin photodamage.

Characterization of macrophages associated with human skin models exposed to UV radiation.

Skin macrophages play important roles in the response to external stimuli. Human skin equivalents (HSEs) incorporating the human monocytic cell line THP-1 were fabricated to generate immunocompetent human skin models. These HSEs were used to investigate the influence of the skin microenvironment and ultraviolet A (UVA) on macrophages. Transcriptomic analysis revealed that THP-1 cells in HSEs were enriched in extracellular matrix interaction hallmark but downregulated in DNA replication hallmark. Upon UVA exposure, immunocompetent HSEs presented epidermal distortion and increased DNA double-strand breaks (DSBs). The genes associated with oxidative stress and the inflammatory response were significantly upregulated in THP-1 cells. When the photoprotective agent mycosporine-2-glycine from cyanobacteria was applied to HSEs, the incidence of UVA-induced DSBs was significantly lower, and inflammatory and UV response hallmarks were downregulated in THP-1 cells. Taken together, these results suggest that immunocompetent HSEs can be used to investigate the responses of skin-resident macrophages to external stimuli.

Acne and rosacea: similarities and differences. A review

Acne and rosacea are frequently encountered in the clinical practice of a dermatologist. These diseases can develop simultaneously in the same patient. Most often, the erythematous form of rosacea is combined with acne. Because of the similarity of clinical manifestations with acne, the diagnosis of rosacea can be easily missed. Common pathogenetic factors in the 2 diseases are thought to be genetics, alterations in the microbiome, immune disorders, and skin barrier dysfunction. There are few works addressing the relationship between acne and rosacea. A recent study identified a number of common differentially expressed genes, including interleukin-1B and matrix metalloproteinase 9, and showed that gamma delta T cells may play an important role in the development of both diseases. Despite the common pathogenesis and the similarity of some clinical manifestations (papules and pustules), acne and rosacea must be distinguished. In rosacea, there is persistent facial erythema induced by vasoregulatory neutropeptides, whereas in acne, the inflammatory process is due to excess sebum and changes in the skin microbiome. Isotretinoin is used for systemic therapy of both diseases. The drug affects the level of some cytokines, including inhibiting the expression of matrix metalloproteinase 9. In addition, it reduces sebum production in acne, and due to its ability to alter the skin microenvironment, it can reduce Propionibacterium acnes in acne and Demodex folliculorum in rosacea. Daily and cumulative doses for rosacea and acne will differ, as will topical therapy for these conditions. For acne, the combination of clindamycin and benzoyl peroxide is well established for the treatment of acne, allowing rapid meaningful clinical effect. In rosacea, metronidazole in cream form, which has better tolerability, is recommended as a topical agent. In patients suffering from both diseases simultaneously, a combination of clindamycin and benzoyl peroxide should be used to relieve acute inflammation, after which it is possible to switch to metronidazole.

Activation and Targetability of TYMP-IL-6-TF Axis in the Skin Microenvironment in Patients with Uremic Calciphylaxis

Activation and Targetability of TYMP-IL-6-TF Axis in the Skin Microenvironment in Patients with Uremic Calciphylaxis

Causal Relationship of Skin Microbiota on Psoriasis: A Mendelian Randomization Study.

Epidemiological investigations have indicated an association between skin microbiota imbalance and psoriasis, however, the causal relationship has not been confirmed through Mendelian randomization (MR). MR employed genetic instrumental variables (IVs) to evaluate the causal relationship between skin microbiota and psoriasis, providing new insights for potential treatments. Summary statistics for psoriasis and related traits were available from FinnGen R10 and United Kingdom Biobank (UKB) consortium. The genome-wide association studies (GWAS) on skin microbiota in three skin microenvironments came from two population-based German cohorts. Several selection processes were used to determine the optimal instrumental variables. Five MR methods were performed and different sensitivity analyses approaches yield robustness evidence under different assumptions. 449 SNPs were employed as IVs for 53 bacterial genera, with F-statistics between 20.18 and 42.44, indicating no evidence of weak instrument bias. Bacteroides was associated with psoriasis from UKB in IVW (OR, 95% CI: 0.914, 0.869-0.961; P < 0.001, PB-H = 0.007). The taxon was also associated with psoriasis vulgaris (IVW: OR, 95% CI, 0.918, 0.872-0.967; P = 0.001, P B-H = 0.054) and psoriasis and related disorders (IVW: OR, 95% CI, 0.915, 0.875-0.957; P < 0.001, P B-H = 0.008). Consistent causal estimates were identified in terms of both magnitude and direction, indicating a protective effect of Bacteroides. The MR study found that Bacteroides in the antecubital fossa may protect against psoriasis, offering genetic proof that skin microbiota helps prevent the condition.

Cellulose acetate hierarchical porous coated textile with passive daytime radiative cooling, flexibility and durability

Passive daytime radiative cooling technology is a highly efficient cooling technology with zero energy consumption. When utilized for personal thermal management, radiative cooling textiles are capable of finely regulating the temperature of the human skin microenvironment. This study presents a cellulose acetate (CA) hierarchical porous coated textile that accomplishes high reflectance of sunlight over the full wavelength range, with a low cost and scalability, and a simple preparation procedure. With a high reflectance of 0.91 in the solar wavelength band and a high emissivity of 0.95 in the atmospheric window wavelength band, the CA hierarchical porous coated textile offers exceptional spectrally selective performances. It manifests a subambient cooling temperature of up to 19.0 °C and a skin overheating prevention effect of up to 4.2 °C. Furthermore, the coated textile possesses promising abrasion resistance, acid-alkali corrosion resistance, and mechanical properties. The present work provides a facile path for the development of green-based radiative cooling coated textiles.

What lies behind melasma: a review of the related skin microenvironment.

Melasma is an acquired chronic pigmentary disorder affecting millions of individuals worldwide. However, the pathogenesis of melasma remains unclear. This article provides a comprehensive review of the pathophysiological changes occurring in the skin microenvironment of melasma lesions, which can be summarized as follows: (1) skin barrier dysfunction and abnormal synthesis, transport, and intracellular distribution of melanin in the epidermis; (2) basement membrane damage; (3) solar elastosis, vascular changes, senescent fibroblasts, mast cell infiltration, and sebocyte participation in the dermis; and (4) systemic factors such as sex hormones and oxidative stress. Furthermore, potential therapeutic strategies are introduced to provide novel perspectives for fundamental and clinical research related to melasma.

ZnO nanoparticles induce melanoma-like lesions via recruiting dermal dendritic cells in barrier-damaged skin in mice

ZnO nanoparticles (NPs) are used in skin treatments and cosmetics, the toxicity of long-term and continuous exposure to ZnO NPs is unknown. Mice with epidermal barrier dysfunction revealed melanoma-like lesions after continuous exposure to ZnO NPs. However, the effects of metallic NPs on the skin microenvironment and immune system remain poorly understood. Mice with epidermal barrier failure were given continuous exposure to ZnO NPs for 7 weeks. The malignant transformation of melanocytes was induced with ZnO NPs 2.5 μg/ml for 72 h exposure. The supernatant of the culture medium from dendritic cells after being exposed to 10 μg/ml ZnO NPs for 24 h was applied to melanocytes to explore the effect of recruitment of DCs. The expressure of ZnO NPs resulted in a tendency of malignant transformation of melanocytes, the recruitment of DCs induces this process by produce inflammatory factors such as TNF-α. These DC-produced inflammatory factors, which were induced by ZnO NP exposure, increased the production of matrix metalloproteinases in melanocytes and expedited the malignant transformation process. Our findings revealed that the disrupted cutaneous microenvironment by ZnO NPs penetrated directly promoted the malignant transformation of melanocytes, which process also indirectly enhanced by the TNF-αsecreted from the recruited DCs.

A multiplex microbial profiling system for the identification of the source of body fluid and skin samples

Determining the source of body fluids is crucial in forensic investigations, as it provides valuable information about suspects and the nature of the crime. Microbial markers that trace the source of tissues and body fluids based on site specificity and temporal stability are often used effectively for this purpose. In this study, a multiplex system comprising seven microbial markers (Finegoldia magna, Corynebacterium tuberculostearicum, Cutibacterium acnes, Haemophilus parainfluenzae, Streptococcus oralis, Prevotella melaninogenica and Faecalibacterium prausnitzii) was developed to distinguish between skin, saliva, and feces samples. Based on these markers, the system produces electropherograms that are specific for each sample type. We collected 492 samples from six different skin sites (palm, antecubital crease, inguinal crease, cheek, upper back, and toe web space), the buccal mucosa, and stool were collected to further test the system. Beta diversity analysis revealed distinct clustering among the three sample groups. Additionally, skin microenvironment cluster analysis was used to identify skin sites accurately. This analysis classified skin samples into four distinct microenvironments: dry, moist, oily, and foot. Finally, we established a machine learning prediction model based on random forest regression to identify the skin microenvironment, achieving an overall prediction accuracy of 79 %. The multiplex system developed in this study accurately identifies the sources of body fluids, and the skin microenvironment. These findings offer new insights into the application of microbial markers in forensic science.

Causal roles of skin microbiota in skin cancers suggested by genetic study.

There is evidence from observational studies that skin microbiota is linked to skin cancers. Nevertheless, the causal association between skin microbiota and skin cancers is yet to be fully clarified. A bidirectional two-sample Mendelian randomization (MR) was performed to determine the causal relationship between skin microbiota and skin cancers. A total of 294 skin microbial taxa were identified from the first genome-wide association study across three skin microenvironments of two German population cohorts. Summary data of three skin cancers (malignant melanoma, squamous cell carcinoma, and basal cell carcinoma) were obtained from the FinnGen consortium. Moreover, sensitivity analysis examined horizontal pleiotropy and heterogeneity, and microenvironment-based meta-analysis confirmed the reliability of the results. We identified 65 nominal causalities and 5 strong causal associations between skin microbiota and skin cancers. Among them, the class Bacilli revealed a bidirectional positive relationship with malignant melanoma. The class Betaproteobacteria and class Gammaproteobacteria demonstrated a causal association with an elevated risk of malignant melanoma and basal cell carcinoma, respectively. In the reverse MR analysis, malignant melanoma was associated with a lower abundance of phylum Bacteroidetes. There were no indications of significant heterogeneity in instrumental variables or evidence of horizontal pleiotropy. Our MR analysis indicated bidirectional causal associations between skin microbiota and skin cancers, and had the potential to offer novel perspectives on the mechanistic of microbiota-facilitated carcinogenesis.

Aged Human Dermal Extracellular Matrix as an Innovative Scaffold for Aging on Chip Model

Currently, there is a growing demand for developing innovative biomaterials that represent skin microenvironment more realistically. Here, we present an optimised protocol to extract and characterize an innovative human adult dermal extracellular matrix scaffold to represent the dermal layer in advanced 3D skin models.

Biofabrication and Monitoring of a 3D Printed Skin Model for Melanoma.

There is an unmet need for in vitro cancer models that emulate the complexity of human tissues. 3D-printed solid tumor micromodels based on decellularized extracellular matrices (dECMs) recreate the biomolecule-rich matrix of native tissue. Herein a 3D in vitro metastatic melanoma model that is amenable for drug screening purposes and recapitulates features of both the tumor and the skin microenvironment is described. Epidermal, basement membrane, and dermal biocompatible inks are prepared by means of combined chemical, mechanical, and enzymatic processes. Bioink printability is confirmed by rheological assessment and bioprinting, and bioinks are subsequently combined with melanoma cells and dermal fibroblasts to build complex 3D melanoma models. Cells are tracked by confocal microscopy and surface-enhanced Raman spectroscopy (SERS) mapping. Printed dECMs and cell tracking allow modeling of the initial steps of metastatic disease, and may be used to better understand melanoma cell behavior and response to drugs.

Viscoelastic Supramolecular Hyaluronan-Peptide Cross-Linked Hydrogels.

Viscoelasticity plays a key role in hydrogel design. We designed a physically cross-linked hydrogel with tunable viscoelasticity, comprising supramolecular-assembled peptides coupled to hyaluronan (HA), a native extracellular matrix component. We then explored the structural and molecular mechanisms underlying the mechanical properties of a series of these HA-peptide hydrogels. By modifying the peptide sequence, we modulated both long- and short-time stress relaxation rates as a way to target viscoelasticity with limited impact on stiffness, leading to gels that relax up to 60% of stress in 10 min. Gels with the highest viscoelasticity exhibited large mesh sizes and β-sheet secondary structures. The stiffness of the gel correlated with hydrogen bonding between the peptide chains. These gels are cytocompatible: highly viscoelastic gels that mimic the native skin microenvironment promote dermal fibroblast cell spreading. Moreover, HA-peptide gels enabled cell encapsulation, as shown with primary human T cells. Overall, these physically-cross-linked hydrogels enable tunable viscoelasticity that can be used to modulate cell morphology.