Skin Stiffness Research Articles

Controlled surface wrinkling as a novel strategy for the compressibility-tunable PZT film-based energy harvesting system

Using a controlled surface wrinkling strategy, we designed a flexible energy harvesting system made from a compliant substrate, stiff skin layer, a thin PZT film, and an interdigitated electrode sandwich structure. This energy harvesting system, which operates under compressing and releasing operating modes that are common in nature and engineering, accommodates orders-of-magnitude increases in maximum compressive strain without fracture. This increased range allows the system to be used for more applications. We systematically explored the effects of different parameters on system compressibility and piezopotential output performance. These analytical results guide the design for enhancing compressibility or piezopotentials of the energy harvesting system.

Comparison of different MyotonPRO probes for skin stiffness evaluation in young women.

Stiffness of skin is widely used parameter in many research areas, for example cosmetic industry, dermatology or rheumatology for assessing of skin condition as well as changes occurring in skin. In this pioneering study, we conducted measurements of skin stiffness using MyotonPRO -novel tool, which was mainly used to evaluate biomechanical properties of muscles, ligaments and tendons. We expected that MyotonPRO , which shows great reproducibility in previous studies, will also be able to measure skin stiffness. Four replaceable probes designed by MyotonPRO (L-shape short and medium arm, standard cylindrical flat-end probe and the same standard probe with disc attachment ) were tested for measurement of skin stiffness in young women (30 healthy females) at three different locations (clavicula, volar forearm and shin). There was no significant difference between stiffness values obtained with L-shape short and L-shape medium arm probes in all investigated areas. Stiffness values recorded by regular probe and regular probe with disc attachment differ significantly from those collected with L-shape probes. There was also significant difference between values of stiffness obtained by standard with disc attachment and standard probes. Both L-shape probes show a great reliability for skin stiffness assessment. Therefore, MyotonPRO can be considered a reliable device for assessing skin stiffness.

Development of a Smartphone-Based Skin Simulation Model for Medical Education.

Teaching dermatology to medical students entails a series of lectures, pictures, and hands-on skin examinations to convey a sense of skin features and textures, often by use of simulated skin models. However, such methods can often lack accurate visual and tactile texture representation of skin lesions. To facilitate learning, we have developed a smartphone-based skin simulation model, which provides a configurable visual and tactile sense of a lesion by using the ubiquitous availability of smartphone-based mobile platforms. A polydimethylsiloxane (PDMS) overlay was used as a configurable translucent elastomer material to model the stiffness and texture of skin. A novel custom smartphone-based app was developed to capture images of various skin lesions, which were subsequently displayed on a tablet or second smartphone, over which the PDMS model skin elastomer was placed. Using the local Bluetooth connection between mobile devices, an iterative feedback algorithm corrected the visual distortion caused by the optical scattering of the translucent elastomer, enabling better virtual visualization of the lesion. The developed smartphone-based app corrected the distortion of images projected through the simulated skin elastomer. Surface topography of the developed PDMS elastomer provided a more accurate representation of skin texture. In this investigation, we developed a smartphone-based skin lesion visualization app with a simulated skin elastomer for training/education in not only dermatology but also all general medical specialties that examine the skin. This technique has the potential to advance the educational experience by giving students the ability to see, touch, and feel pragmatic skin textures and lesions.

TELOMERASE THERAPY REVERSES VASCULAR SENESCENCE IN HGPS

Hutchinson-Gilford Progeria Syndrome (HGPS) is characterized by accelerated aging due toa de novo mutation in the LMNA gene (c.1824C>T, G608G). The mutated LaminA (progerin) is permanently farnesylated, localizing to and distorting the nuclear envelope. HGPS children suffer from growth failure, loss of body fat and hair, aged- skin and joint stiffness. Progressive vascular aging causes death from heart attack or stroke in the teen years. Previously, we have demonstrated that in vitro treatment with human telomerase (hTERT) RNA of fibroblasts from HGPS children increased telomere length and reversed many functional and transcriptional changes associated with senescence.

The fibrillin microfibril/elastic fibre network: A critical extracellular supramolecular scaffold to balance skin homoeostasis.

Supramolecular networks composed of fibrillins (fibrillin-1 and fibrillin-2) and associated ligands form intricate cellular microenvironments which balance skin homoeostasis and direct remodelling. Fibrillins assemble into microfibrils which are not only indispensable for conferring elasticity to the skin, but also control the bioavailability of growth factors targeted to the extracellular matrix architecture. Fibrillin microfibrils (FMF) represent the core scaffolds for elastic fibre formation, and they also decorate the surface of elastic fibres and form independent networks. In normal dermis, elastic fibres are suspended in a three-dimensional basket-like lattice of FMF intersecting basement membranes at the dermal-epidermal junction and thus conferring pliability to the skin. The importance of FMF for skin homoeostasis is illustrated by the clinical features caused by mutations in the human fibrillin genes (FBN1, FBN2), summarized as "fibrillinopathies." In skin, fibrillin mutations result in phenotypes ranging from thick, stiff and fibrotic skin to thin, lax and hyperextensible skin. The most plausible explanation for this spectrum of phenotypic outcomes is that FMF regulate growth factor signalling essential for proper growth and homoeostasis of the skin. Here, we will give an overview about the current understanding of the underlying pathomechanisms leading to fibrillin-dependent fibrosis as well as forms of cutis laxa caused by mutational inactivation of FMF-associated ligands.

Quantifying Skin Stiffness in Graft-Versus-Host Disease, Morphea, and Systemic Sclerosis Using Acoustic Radiation Force Impulse Imaging and Shear Wave Elastography

There is a need for objective, sensitive, and reproducible methods of assessing skin sclerosis. We successfully adapted ultrasound-based, noninvasive methods for quantifying tissue stiffness for use on the skin: acoustic radiation force impulse (ARFI) imaging and shear wave elasticity imaging (SWEI) (Lee et al., 2015). ARFI imaging generates images of micron-scale tissue displacement, whereas SWEI measures the speed at which sound waves travel across target tissue (shear wave speed [SWS]) in meters per second (Palmeri and Nightingale, 2011).

Clinical presentation, sonographic features and treatment options of segmental stiff skin syndrome.

Segmental stiff skin syndrome is a rare genetic connective tissue disease, which is often misdiagnosed. High-frequency ultrasonography can represent a useful clinical adjunct in the differential diagnosis of this condition, in conjunction with the clinical and histopathological findings. Treatment options are limited and evidence is scarce. We present the clinical, sonographic and histological features of five paediatric patients diagnosed at our institution and discuss their response to treatment.

Anesthetic implications of a pediatric patient with stiff skin syndrome: A case report

Stiff skin syndrome is a rare genetic disorder that is present in infancy or early childhood. It is characterized by hard, inflexible skin and limited joint mobility making anesthetic management of these patients challenging. Their limited neck flexibility and chest wall rigidity make intubation and mask ventilation difficult. Intraoperative positioning can be challenging due to joint contractures and potential entrapment peripheral neuropathy. Even though peripheral intravenous access can be relatively easy, central venous cannulation may be problematic due to the hard skin overlying the entry sites. Our case report details the anesthetic management and considerations of a pediatric patient with stiff skin syndrome.

Ultrasound assessment of skin thickness and stiffness: the correlation with histology and clinical score in systemic sclerosis

sBackgroundUltrasound is a useful tool to evaluate and quantify skin lesions. Few studies have assessed the criterion validity of skin ultrasound in systemic sclerosis (SSc). The aims of the study were to investigate skin thickness and stiffness using ultrasound and shear wave elastography (SWE) in SSc and to validate skin ultrasound measurements against histological skin thickness.MethodsA total of 22 patients with diffuse cutaneous SSc (dcSSc), 22 with limited cutaneous SSc (lcSSc), and 22 age- and gender-matched healthy controls were enrolled. Skin thickness and stiffness were measured by B-mode ultrasound with SWE imaging on the bilateral fingers and hands. Additional ultrasound evaluation was carried out in 13 patients (9 dcSSc and 4 lcSSc) on their dorsal forearms, followed by skin biopsy conducted in the same skin areas. Correlations between ultrasound measurements and histological skin thickness and modified Rodnan skin score (mRSS) were investigated using Spearman’s correlation.ResultsCompared with controls, ultrasound-measured skin thickness and skin stiffness were significantly higher in patients with SSc (p < 0.001) and even higher in those with dcSSc. No clear correlation could be established between ultrasound-determined skin thickness and stiffness at the same site. Ultrasound-measured skin thickness correlated well with histological skin thickness (r = 0.6926, p = 0.009). A weaker association was also observed between histological skin thickness and local mRSS (r = 0.5867, p = 0.050).ConclusionsUltrasound is a reliable tool for quantifying skin involvement in SSc. Ultrasound-measured skin thickness showed good agreement with histological skin thickness.

Inspired by the growth characteristic of leaf epidermis cell walls: A bio-ITCLC core for supporting a flexible skin with combined morphing applications

Inspired by low transverse and high vertical stiffness characteristics of leaf epidermis cell walls, a biomimetic Isosceles Trapezoid Corrugated Lattice Cellular (bio-ITCLC) core is designed and fabricated. The constitutive model of the bio-ITCLC sandwich panel under out-of-plane compression is built to demonstrate great potential of the bio-ITCLC core for decoupling the mutual restriction of small tangential and large normal stiffness of a flexible skin. After that, the variable stiffness, equating to the continually changing stiffness characteristic of epidermis cell walls, is introduced in the above constitutive model to capture the growth behavior of a leaf shape via epidermis cell divisions to study morphing mechanisms of a flexible skin. On this basis, by the supporting effect of self-adaption units in the bio-ITCLC core, with new circumstances, is proposed to be one promising approach for designing a flexible skin with the small tangential and large normal stiffness for multi-morphing applications.

Effect of Finger Sliding Direction on Tactile Perception, Friction and Dynamics

Human beings use certain styles when perceiving physical characteristics of objects with fingers. Sliding direction of finger contact is among the aforementioned styles. Thus, understanding the effect of sliding direction on tactile perception is essential. This study investigated the perception and identification of the roughness of sandpapers in two different sliding directions: proximal and distal. Furthermore, the corresponding tribological and dynamical properties of finger contact were examined using a custom setup. It was observed that the sliding direction and sliding speed influenced subjective judgment. The interaction between these two factors was also considered. A macroscopically continuous movement with a series of local collisions among the contact asperities enhanced the tactile perception in the proximal sliding. While in the distal direction, stick–slip occurred and interrupted the collision process, and reduced the tactile perception. The stick–slip phenomenon is modulated by various factors, including the external force and variations in the skin stiffness, which is influenced by the fingernail as well as the different friction properties in the two sliding directions.

Pro-Fibrotic Phenotype in a Patient with Segmental Stiff Skin Syndrome via TGF-β Signaling Overactivation

Transforming growth factor β (TGF-β) superfamily signaling pathways are ubiquitous and essential for several cellular and physiological processes. The overexpression of TGF-β results in excessive fibrosis in multiple human disorders. Among them, stiff skin syndrome (SSS) is an ultrarare and untreatable condition characterized by the progressive thickening and hardening of the dermis, and acquired joint limitations. SSS is distinct in a widespread form, caused by recurrent germline variants of FBN1 encoding a key molecule of the TGF-β signaling, and a segmental form with unknown molecular basis. Here, we report a 12-year-old female with segmental SSS, affecting the right upper limb with acquired thickening of the dermis evident at the magnetic resonance imaging, and progressive limitation of the elbow and shoulder. To better explore the molecular and cellular mechanisms that drive segmental SSS, several functional studies on patient’s fibroblasts were employed. We hypothesized an impairment of TGF-β signaling and, consequently, a dysregulation of the associated downstream signaling. Lesional fibroblast studies showed a higher phosphorylation level of extracellular signal-regulated kinase 1/2 (ERK1/2), increased levels of nuclear factor-kB (NFkB), and a nuclear accumulation of phosphorylated Smad2 via Western blot and microscopy analyses. Quantitative PCR expression analysis of genes encoding key extracellular matrix proteins revealed increased levels of COL1A1, COL3A1, AGT, LTBP and ITGB1, while zymography assay reported a reduced metalloproteinase 2 enzymatic activity. In vitro exposure of patient’s fibroblasts to losartan led to the partial restoration of normal transforming growth factor β (TGF-β) marker protein levels. Taken together, these data demonstrate that in our patient, segmental SSS is characterized by the overactivation of multiple TGF-β signaling pathways, which likely results in altered extracellular matrix composition and fibroblast homeostasis. Our results for the first time reported that aberrant TGF-β signaling may drive the pathogenesis of segmental SSS and might open the way to novel therapeutic approaches.

Quantitative assessment of temporal skin elasticity using shear wave elastography in pediatric cochlear implant users

ObjectiveTo evaluate temporal skin thicknesses and stiffness values using shear wave elastography (SWE) in asymptomatic pediatric patients who underwent cochlear implantation. Subjects and methodsSixty-four deafened pediatric patients with unilateral cochlear implant (CI) who had no complications were enrolled. The age, sex, weight, height, body mass index (BMI), CI side, duration of CI use and CI device brand of all participants were noted. Temporal skin thickness and stiffness values were measured from implanted and contralateral unimplanted sides using SWE. ResultsThe mean skin thickness measurements of implanted and unimplanted sides were 11.87 ± 3.42 and 5.34 ± 1.56 mm, respectively. The mean skin stiffness measurements of implanted and unimplanted sides were 3.08 ± 0.7 and 1.29 ± 0.26 m/s, respectively. There were statistically significant differences in skin thickness and stiffness between implanted and unimplanted sides (P < .001, P < .001). The mean skin thickness and stiffness measurements did not differ among types of CI devices (P = .948, P = .362). Age had positive correlation with implanted (P < .001, P = .019) and unimplanted sides (P < .001, P < .001) skin thickness and stiffness. BMI had positive correlation with implanted (P < .001, P = .023) and unimplanted sides (P < .001, P < .001) skin thickness and stiffness. Duration of CI use had positive correlation with implanted side skin thickness (P < .001) and stiffness (P = .031). ConclusionTemporal skin thickness and stiffness increase after CI surgery. SWE has the potential to improve diagnostic accuracy, and our results may provide important data for evaluation of clinical entities that affect temporal skin structures.

Effect of fullerene nanoemulsion on the repair of wrinkles induced by UVB radiation: A c57bl6 mice model.

The effect of fullerene nanoemulsion on skin wrinkle repair in an animal model was evaluated using ultrasonic images processing. Wrinkles were created in C57BL6 mice during 35days of UVB radiation. Then, to investigate the therapeutic effect of fullerene nanoemulsions, mice were divided into three groups of control, UVB radiation, and treatment with fullerene nanoemulsion. Stable fullerene nanoemulsions were prepared using shear equalization. The therapeutic effect of fullerene nanoemulsion was investigated by extracting the skin thickness and mechanical parameters. Histology studies were performed to confirm the reliability of the treatment. A significant decrease was observed in the thickness of the epidermis and dermis layers (43% and 36%), Young modulus (27%), and the shear modulus (20%) of the skin on day 28 of the fullerene nanoemulsion treatment. Skin stiffness obtained by tensiometry on day 28 of the treatment showed a 48% reduction in the treatment group compared with the control group. Histological results confirmed the effect of fullerene nanoemulsions on wrinkle repair. The healing effect of fullerene nanoemulsion in wrinkle repair was confirmed. To study the skin repair, parameters including Young modulus, the shear modulus, and skin layer thickness can be calculated using ultrasonic images processing.

Calf Pain-Brazilian Jujitsu Fighter

HISTORY: 29 yo male Brazilian jujitsu fighter with a history of Henoch-Schonlein purpura and eczema presents to clinic for 6 months of right anterolateral calf pain without a clear injury. He reports constant, dull, aching pain, worse with dorsiflexion and resisted plantar flexion. He notes associated pitting edema, dry leathery skin, hypopigmentation, and hyperesthesia that began 3-4 months ago. He has stopped jujitsu due to symptoms. Tib-fib xrays and venous duplex were negative. He tried acetaminophen, ibuprofen, physical therapy, topical clobetasol, and oral prednisone with short-term improvement. PHYSICAL EXAMINATION: Skin of the anterolateral calf is indurated with hair loss, a leathery appearance, and areas of depigmentation. The distal lateral calf is warm and erythematous, with swelling posterior to the lateral malleolus. Tinel’s sign is negative at the fibular head. Pulses are normal bilaterally with ankle plantar and dorsiflexion. Ankle ROM is full. Light touch sensation is intact in L2-S2 dermatomes and strength is 5/5 in lower extremities. DIFFERENTIAL DIAGNOSIS: Complex regional pain syndrome, Cellulitis, Scleroderma, Eosinophilic fasciitis, Chronic exertional compartment syndrome, Vascular insufficiency TEST AND RESULTS: Lab work: inflammatory markers and rheumatologic labs negative except for elevated CK (356) of unknown significance. EMG/NCS: low amplitude right vs left sural sensory nerve suggesting sural neuropathy although within normal limits; no fibular neuropathy or radiculopathy. MRI right leg: nonspecific skin thickening of anterolateral shin with fascial edema and mild fibularis longus myositis. Skin biopsy: linear morphea versus eosinophilic fasciitis FINAL WORKING DIAGNOSIS: Segmental Linear Morphea (localized scleroderma) TREATMENT AND OUTCOMES: Dermatology referral led to biopsy; subsequently, treatment with PO methotrexate (MTX), high dose IV methylprednisolone for three cycles, and topical clobetasol ointment BID. UVA1 phototherapy was also started due to extensive disease and ankle and knee joint involvement. Subjective improvement in ROM, skin stiffness, and strength per patient after 2 cycles of methylprednisolone. Switched to SQ MTX for better absorption and lower cost. Patient continues to improve as he remains on the above treatment protocol.

188 scRNA-seq and RNA-seq for Stiff Skin Syndrome identify pericytes as a key pathogenic cell population and avenue for therapeutic targeting

Stiff skin syndrome (SSS) is a rare (<100 reported cases), slowly progressive skin condition, caused by genetic mutation in the FBN1gene. It is characterized by thickened skin associated with muscle weakness and limited joint mobility. Currently there is no known treatment. While SSS is considered as scleroderma (Sc)-like disorder, there has not been any molecular study conducted to investigate the potential differences or similarities between the two diseases. Here, we report molecular profiling for the skin biopsies of 3 stiff skin syndrome and 3 scleroderma patients using bulk RNA-seq and single cell RNA-seq (scRNA-seq) techniques. We revealed >4,000 genes being differentially expressed in SSS skin that are highly correlated with genes dysregulated in scleroderma (Sc) skin. In stark contrast to scleroderma, which showed enrichment of myofibroblasts, there was marked enrichment of pericytes (distinguished by the expression of RGS5) in the dermal layer of SSS (10% in Sc versus >30% in SSS), confirmed by IHC. We also demonstrate expression of the therapeutically targetable adrenergic receptors (i.e. ADRA1D,ADRA2B) in pericytes, and ABCA1in fibroblasts in SSS. Previous work has suggested ADRA signaling as a promoter of fibroblast differentiation in smooth muscle. When restricting to SSS-dysregulated genes that are not differentially expressed in Sc, we identified fibroblast-expressing FGFR4(fibroblast growth factor receptor 4) as the most significantly up-regulated gene (FC=6.2; p=1.2x10-15). Our transcriptomic study illustrates the largely similar but subtle molecular differences between SSS and Sc and demonstrates that identification of dysregulated disease specific pathways can potentially facilitate the identification of therapeutic targets.

Validation of the suction device Nimble for the assessment of skin fibrosis in systemic sclerosis

ObjectivesSkin fibrosis is a main hallmark of systemic sclerosis (SSc). Clinical assessment is done semi-quantitatively using the modified Rodnan skin score (mRSS). Objective measurements for quantifying skin fibrosis could complement the mRSS to achieve higher reproducibility. The aim of this study was to explore the potential of suction measurements to detect structural changes in the skin that are associated with skin fibrosis.MethodsThis clinical trial included 30 SSc patients and 30 healthy volunteers (HC). We validated a novel suction device—the Nimble—to quantify skin stiffness in comparison to the Cutometer using the OMERACT filter.ResultsA significant difference (p < 0.05) between the skin stiffness of HC and SSc patient groups was found for each location measured. The correlation between the measurements of forearm skin stiffness and the mRSS values was high for the Nimble (r = 0.82) and moderate for the Cutometer (r = 0.58). A ROC analysis showed good ability for the Nimble to distinguish between SSc patients with and without skin involvement (AUC = 0.82). Both suction devices provided excellent reliability in all measurements on HC and SSc patients and proved face validity and feasibility.ConclusionSuction devices assessing skin stiffness, such as the Nimble, show clear potential to objectively quantify skin fibrosis in SSc patients and might be promising outcome measures complementing established methods such as the mRSS.Trial registrationClinicaltrials.gov, NCT03644225, Registered 23 August 2018—Retrospectively registered, http://www.clinicaltrials.gov

The bioengineering theory of the key modes of action of a cyanoacrylate liquid skin protectant.

The objective of this article is to formulate a new bioengineering theoretical framework for modelling the biomechanical efficacy of cyanoacrylate skin protectants, with specific focus on the Marathon technology (Medline Industries, Inc., Northfield, Illinois) and its modes of action. This work details the bioengineering and mathematical formulations of the theory, which is based on the classic engineering theories of flexural stiffness of coated elements and deformation friction. Based on the relevant skin anatomy and physiology, this paper demonstrates: (a) the contribution of the polymerised cyanoacrylate coating to flexural skin stiffness, which facilitates protection from non-axial (eg, compressive) localised mechanical forces; and (b) the contribution of the aforementioned coating to reduction in frictional forces and surface shear stresses applied by contacting objects such as medical devices. The present theoretical framework establishes that application of the cyanoacrylate coating provides considerable biomechanical protection to skin and subdermally, by shielding skin from both compressive and frictional (shearing) forces. Moreover, these analyses indicate that the prophylactic effects of the studied cyanoacrylate coating become particularly strong where the skin is thin or fragile (typically less than ~0.7 mm thick), which is characteristic to old age, post-neural injuries, neuromuscular diseases, and in disuse-induced tissue atrophy conditions.

Stress Analysis of a Flange Stiffened FRP Composite Panel with Varying Stacking Sequence

Large panel structures made of composites are common building units in aerospace industries. In order to increase the stiffness of such structures, the panel or skin is adhered to a flange and supported by a web. Such a stiffened panel is modeled as an arrangement of web, flange and panel with an interface between the flange and the panel. In this paper, three dimensional stress analysis of one such stiffened panel has been carried out using the finite element analysis. The geometric non-linearity has been assumed in the analysis. The effect of material anisotropy and the laminate stacking sequence on the stress components has been studied. Material Graphite Fiber Reinforced Polymeric (GFRP) composite has been used and, two different configurations were considered while the unidirectional prepregs were laid up in quasi-isotropic [0/0/0/0]2 and cross-ply [0/90/90/0]2. Subsequently, the coupled stress failure criterion has been used to predict the critical location of damage onset. When component damage indicator attained the value of 1.0, the component was considered to lose stiffness and structural integrity.

Systemic Sclerosis Dermal Fibroblasts Induce Cutaneous Fibrosis Through Lysyl Oxidase-like 4: New Evidence From Three-Dimensional Skin-like Tissues.

Systemic sclerosis (SSc) is a clinically heterogeneous disease characterized by increased collagen accumulation and skin stiffness. Our previous work has demonstrated that transforming growth factor β (TGFβ) induces extracellular matrix (ECM) modifications through lysyl oxidase-like 4 (LOXL-4), a collagen crosslinking enzyme, in bioengineered human skin equivalents (HSEs) and self-assembled stromal tissues (SAS). We undertook this study to investigate cutaneous fibrosis and the role of LOXL-4 in SSc pathogenesis using HSEs and SAS. SSc-derived dermal fibroblasts (SScDFs; n = 8) and normal dermal fibroblasts (NDFs; n = 6) were incorporated into HSEs and SAS. These 3-dimensional skin-like microenvironments were used to study the effects of dysregulated LOXL-4 on ECM remodeling, fibroblast activation, and response to TGFβ stimulation. SScDF-containing SAS showed increased stromal thickness, collagen deposition, and interleukin-6 secretion compared to NDF-containing SAS (P < 0.05). In HSE, SScDFs altered collagen as seen by a more mature and aligned fibrillar structure (P < 0.05). With SScDFs, enhanced stromal rigidity with increased collagen crosslinking (P < 0.05), up-regulation of LOXL4 expression (P < 0.01), and innate immune signaling genes were observed in both tissue models. Conversely, knockdown of LOXL4 suppressed rigidity, contraction, and α-smooth muscle actin expression in SScDFs in HSE, and TGFβ-induced ECM aggregation and collagen crosslinking in SAS. A limitation to the development of effective therapeutics in SSc is the lack of in vitro human model systems that replicate human skin. Our findings demonstrate that SAS and HSE can serve as complementary in vitro skin-like models for investigation of the mechanisms and mediators that drive fibrosis in SSc and implicate a pivotal role for LOXL-4 in SSc pathogenesis.