Adipose Tissue-Derived Mesenchymal Stem Cell-Derived Exosomes Promote Wound Healing and Tissue Regeneration.

Wound healing is a complex process involving cell proliferation, migration, and extracellular matrix (ECM) remodeling. Extracellular vesicles (EVs) or exosomes derived from adipose tissue-derived stem cells (ASCs) are emerging as promising alternatives to cell therapy for advanced wound healing. Hyaluronic acid (HA), a major component of the skin ECM, is widely utilized in wound dressings and dermal fillers. This study aimed to investigate the effects of ASC-derived exosomes (ASC-EXOs) on human dermal fibroblasts (HDFs) and their potential combination with HA in in vivo wound healing and dermal filler models. In HDFs, ASC-EXOs increased cell proliferation and migration. ASC-EXOs also upregulated the expression of genes involved in cell proliferation and wound healing while stimulating collagen production in HDFs. In a porcine wound healing model, topical treatment with a combination of HA and ASC-EXOs led to higher wound closure rates compared to HA alone. Histological examination showed increased re-epithelialization and collagen type III deposition in wounds treated with the combination of HA and ASC-EXOs. In a mouse dermal filler model, tissues injected with the combination of HA and ASC-EXOs exhibited thicker tissue layers, increased vascularization, enhanced infiltration of myofibroblasts, and higher levels of collagen III and collagen fiber content compared to HA alone. These findings suggest that ASC-EXOs have beneficial effects on cell proliferation, migration, and gene expression related to wound healing, and they may accelerate wound closure and promote tissue regeneration. Furthermore, the combination of HA and ASC-EXOs may enhance wound healing and tissue remodeling, indicating its potential for both clinical and regenerative aesthetic applications in skin repair and regeneration.

MRI Visualization and Distribution Patterns of Foreign Modeling Agents: A Brief Pictorial Review for Clinicians.

Since the ancient Egyptians, people have always been worried about their physical appearance. Nowadays, for some cultures like Latin American, physical appearance depends on the context, and the concept of beauty is to have wider hips and more prominent buttocks. One way to achieve these goals is to inject foreign modelants that include some oils to modify certain body regions. Until today, the search continues to find a modelling agent that is nonteratogenic, noncarcinogenic, and not susceptible to infection and can stay at the spot where it was injected (not migration). This review is aimed at providing a brief, comprehensive assessment of the use of modeling agents and summarizes some key imaging features of filler-related complications. The topics of this review are historical data, epidemiology, classification of dermal fillers (xenografts, hyaluronic acid derivatives, autografts, homografts, synthetic materials), adverse reactions, imaging method used in the detection of injectable fillers, MRI patterns observed in complications of injectable fillers, and histological findings of immune response, treatment, and conclusions. We present several classifications of injectable fillers based on composition, degradation, and complications. Additionally, readers will find some representative cases of the most common locations of injectable fillers demonstrating their infiltrative MRI patterns.

Use of hyaluronidase in plastic surgery: A review.

Hyaluronidase is a family of enzymes that degrade hyaluronic acid (HA). It is found to increase vascular permeability and temporarily disrupt the extracellular matrix, promoting diffusion of substances through tissues. Alongside its applications in ophthalmology, obstetrics and gynaecology, musculoskeletal medicine, radiology and drug and fluid administration, hyaluronidase has a number of roles in the field of plastic surgery. The popularity of HA fillers in recent years has led to an increase in the usage of hyaluronidase in the treatment of filler-related complications. The purpose of this article is to review the current and future uses of hyaluronidase within the field of plastic surgery. Hyaluronidase is used as an adjunct to local anaesthetics in skin infiltration, skin graft harvesting, tumescent analgesia, managing complications of dermal fillers, treatment of extravasation injury, prevention and management of oedema, treatment of ganglion and management of scars. However, it has some limitations. Hyaluronidase is known to interact with a number of common medications. Several case reports also highlight the risk of allergic reaction to the substance. Although rare and usually mild, hyaluronidase has the potential to cause anaphylaxis. Other adverse effects include bruising and swelling. Overall, hyaluronidase appears to be a very safe, cheap and effective medication for a variety of uses in the field of plastic surgery and beyond.

CXCL12 loaded-dermal filler captures CXCR4 expressing melanoma circulating tumor cells.

Development of distant metastasis relies on interactions between cancer and stromal cells. CXCL12, also known as stromal-derived factor 1α (SDF-1α), is a major chemokine constitutively secreted in bone marrow, lymph nodes, liver and lung, playing a critical role in the migration and seeding of neoplastic cells. CXCL12 activates the CXCR4 receptor that is overexpressed in several human cancer cells. Recent evidence reveals that tumors induce pre-metastatic niches in target organ producing tumor-derived factors. Pre-metastatic niches represent a tumor growth-favoring microenvironment in absence of cancer cells. A commercially available dermal filler, hyaluronic acid (HA) -based gel, loaded with CXCL12 (CLG) reproduced a "fake" pre-metastatic niche. In vitro, B16-hCXCR4-GFP, human cxcr4 expressing murine melanoma cells efficiently migrated toward CLG. In vivo, CLGs and empty gels (EGs) were subcutaneously injected into C57BL/6 mice and 5 days later B16-hCXCR4-GFP cells were intravenously inoculated. CLGs were able to recruit a significantly higher number of B16-hCXCR4-GFP cells as compared to EGs, with reduced lung metastasis in mice carrying CLG. CLG were infiltrated by higher number of CD45-positive leukocytes, mainly neutrophils CD11b+Ly6G+ cells, myeloid CD11b+Ly6G- and macrophages F4/80. CLG recovered cells recapitulated the features of B16-hCXCR4-GFP (epithelial, melanin rich, MELAN A/ S100/ c-Kit/CXCR4 pos; α-SMA neg). Thus a HA-based dermal filler loaded with CXCL12 can attract and trap CXCR4+tumor cells. The CLG trapped cells can be recovered and biologically characterized. As a corollary, a reduction in CXCR4 dependent lung metastasis was detected.

Standardized in vitro analysis of the degradability of hyaluronic acid fillers by hyaluronidase.

BACKGROUND: Hyaluronidase is a hyaluronic acid (HA) metabolizing enzyme, which is approved as an adjuvant for infiltration anesthesia. The "off-label" use of hyaluronidase is regarded as gold standard for the management of HA-filler-associated complications. Yet, up to date there are only few studies that have systematically assessed the degradability of different HA-fillers by hyaluronidase. OBJECTIVE: To analyze the interactions of HA-fillers and hyaluronidase in a time-dependent manner using a novel standardized in vitro approach. METHODS: Comparable HA-fillers, Belotero Balance Lidocaine (BEL; Merz), Emervel classic (EMV; Galderma) and Juvederm Ultra 3 (JUV; Allergan), were incubated with a fluorescent dye and bovine hyaluronidase (HYAL; Hylase "Dessau", Riemser) or control (NaCl) and monitored by time-lapse videomicroscopy. The degradation of HA-fillers was assessed as decrease in fluorescence intensity of HA-filler plus hyaluronidase vs. HA-filler plus control, quantified by computer-assisted image analysis (ImageJ). RESULTS: Hyaluronidase showed a significant degradation of the HA-fillers BEL and EMV. Degradation was measurable at 5 h (BEL) and 7 h (EMV), respectively; significance was reached at 14 h (BEL) and 13 h (EMV). No effect of hyaluronidase was observed for JUV. CONCLUSION: Time-lapse microscopy enables systematically, standardized, comparative in vitro analyses of the interactions of hyaluronidase and HA-fillers.

Biochemistry, Physiology, and Tissue Interactions of Contemporary Biodegradable Injectable Dermal Fillers.

BACKGROUND: Injectable dermal fillers are becoming increasingly popular for soft tissue augmentation and rejuvenation. Most contemporary biodegradable products are derived from hyaluronic acid, calcium hydroxylapatite, or poly-L-lactic acid. Achievement of desired cosmetic outcomes is largely dependent on selection of the optimal injectable product based on the chemical composition, the physiologic interactions with surrounding tissue, product longevity, and a thorough understanding of potential adverse reactions. OBJECTIVE: To review and describe the biochemistry, physiology, and tissue interactions of the most commonly used contemporary biodegradable dermal fillers. METHODS: A thorough review of the literature was performed with additional review of pertinent clinical cases and corresponding histopathology. RESULTS: This article provides a comprehensive review of the biochemistry, physiology, and potential tissue interactions of the most commonly used biodegradable dermal fillers. The underlying biochemical properties of each product and how they contribute to specific physiologic and adverse tissue reactions is described. CONCLUSION: Understanding of the innate differences in the physical properties, and physiologic responses to soft tissue fillers allows clinicians to achieve desired aesthetic outcomes with fewer adverse events.

Physical properties of a novel small-particle hyaluronic acid filler: In vitro, in vivo, and clinical studies.

BACKGROUND: Infraorbital region is one of the most important regions that show the signs of aging. In recent years, hyaluronic acid (HA) fillers have been used to correct this region for esthetic treatments. Although HA fillers with various physical properties are used, limited research has been performed to compare their efficacy. OBJECTIVE: We aimed to compare three HA fillers to determine which is the most appropriate filler for the correction of the infraorbital region and evaluate the correction of such by performing a clinical test using CLEVIEL Fine. METHODS: We performed in vitro and in vivo tests using one new HA filler and two other commercial HA fillers. We compared the rheological properties, resistance to degradation, and in vivo duration test results of the three fillers. Nine patients participated in the clinical test using CLEVIEL Fine for 24 weeks. RESULTS: CLEVIEL Fine showed good rheological and physical characteristics for the infraorbital region. It had a low elasticity and cohesiveness, low incidence of postinjection swelling, high tanδ, narrow particle distribution, and small particle size. Further, it showed better resistance to the enzymes and radicals in the in vitro test than the other two HA fillers and a similar duration in the mouse test. In the clinical test, all patients showed good elasticity and hydration in the infraorbital region for 24 weeks. CONCLUSIONS: CLEVIEL Fine was proven to be safe and effective based on the in vitro, in vivo, and clinical study results.

Hyaluronic Acid in Dermatology.

Hyaluronic acid (HA) is a major component of the extracellular matrix of the skin and plays an important role in the metabolism of the dermis. It has a key position in wound healing and tissue repair processes owing to its ability to maintain a humid environment favorable to healing and the stimulation of growth factors, cellular constituents, and the migration of various cells essential for healing. This review aims to describe briefly the physical, chemical, and biologic properties of HA, together with some details of the dermatologic indications of this unique molecule.

Preparation and characterization of a novel polysialic acid-hyaluronan graft copolymer potential as dermal filler.

Polysialic acid (PSA) and hyaluronan (HA) are non-immunogenic and biodegradable natural polysaccharides, but HA belongs to glycosaminoglycans and can be immediately degraded by human enzymes. In this study, we synthesized a novel PSA-HA draft copolymer to improve HA stability in vivo. This draft copolymer was characterized by SEM, element analysis and Zeta potential. Cytotoxicity assays, as well as pyrogen and hemolysis tests, were also conducted to test its biological functions further. Results showed that PSA-HA draft copolymer satisfies the medical requirement for biomaterials. In vivo degradation test proved that this copolymer can reduce the irritation rate and prolong the duration of cross-linked HA in skin. These results indicated that PSA-HA draft copolymer can be potentially used as an alternative for free HA in dermal filler (dual-phase cross-linked HA system).

Visual, Ultrasonographic, and Microscopic Study on Hyaluronic Acid-Based Gel.

BACKGROUND: Hyaluronic acid (HA) fillers are commonly used for enhancement of lips, and for softening fine lines and correcting skin depressions. OBJECTIVE: This study sought to investigate whether the Vycross™ technology used for Volbella™ gel resulted in a cohesive gel, as documented in our previous studies with three other HA fillers (Restylane® NASHA™ [Q-MED, Uppsala, Sweden], Esthélis® Basic CPM™ [Anteis SA, Geneva, Switzerland], and Juvéderm® Ultra 3 using Hylacross technology [Allergan, Irvine, CA, USA]).
METHOD: The "resistance traction test" and "cohesiveness test" were conducted according to standard methods. Juvéderm® Volbella™ gel was injected into the buttock area, both in the superficial reticular and mid-reticular dermis. Tissue samples were analyzed at days 0, 15, and 90 by histology and immunohistochemistry, and visualized using electron microscopy. For Volbella™ gel, the same ultrasound devices as previously used were employed.
RESULTS: Prior to staining, Volbella™ gel presented resistance to spreading, suggesting a certain degree of cohesiveness. When smeared between two slides and following toluidine blue staining, the gel was visible through the microscope in the form of multiple tiny discrete particles, possibly resulting from gel desintegration. At 1/3 dilution with saline serum, Volbella™ gel disintegrated into several lumps, whereas at 1/1 dilution, Volbella gel appeared more cohesive. Yet when adding one drop 70% ethanol, the gel resembled a poorly defined magma, with numerous small lumps. On ultrasound, Volbella™ gel was found to leak in the hypodermis. On histological analysis, Volbella™ gel was visible as pools of variables sizes, particularly in the superficial and mid-reticular dermis, but also hypodermis.
CONCLUSION: Juvéderm Volbella™ gel appears to be a gel characterized by low-medium cohesiveness. The study findings, combined with our previous work, show that HA fillers using Vycross™ technology are not ideally suited for superficial use, unlike HA fillers using CPM technology™.

J Drugs Dermatol. 2016;15(9):1092-1098.

The biological basis for poly-L-lactic acid-induced augmentation.

BACKGROUND: Granulomatous reactions to poly-L-lactic acid (PLLA)-based filler have been described previously. Neither the biological background of these partly late-onset reactions or the desired augmenting effect of PLLA has been studied to date. Histological studies have revealed foreign body reactions and foreign body giant cell formation. OBJECTIVE: The aim of this study was to increase our knowledge about the biological mechanisms behind the augmenting effect of PLLA-based filler. METHODS: We characterised the cell infiltrate and collagen type of PLLA-treated tissue by immunofluorescence staining. The expression of genes related to collagen metabolism was determined. RESULTS: CD68(+) macrophages were found next to PLLA. CD90(+) fibroblasts were found alongside. αSMA-positive structures indicated myofibroblasts and neovascularisation. Substantial collagen type III deposition was detected next to PLLA particles and collagen type I was found at the periphery of PLLA encapsulations. mRNA expression for collagen type I and III transcripts, as well as for TGFß1 and TIMP1, was upregulated significantly. CONCLUSION: PLLA-induced augmentation is most likely based on capsule formation orchestrating macrophages, (myo-)fibroblasts, and collagen type I and III fibres. We observed considerably slower degradation of PLLA particles than described previously. Thus PLLA particles were still retrievable 28 months after subcutaneous application.