Comprehensive Evaluation of Injectability Attributes in OxiFree™ Dermal Fillers: MaiLi® Product Variants and Clinical Case Reports.

Dermal filler injectability is a critical factor for commercial product adoption by medical aesthetic professionals and for successful clinical administration. We have previously reported (in vitro and ex vivo) cross-linked hyaluronic acid (HA)-based dermal filler benchmarking in terms of manual and automated injectability requirements. To further enhance the function-oriented product characterization workflows and the clinical relevance of dermal filler injectability assessments, the aim of this study was to perform in vivo evaluations. Therefore, several variants of the MaiLi® product range (OxiFree™ technology) were characterized in vitro and in vivo in terms of injectability attributes, with a focus on hydrogel system homogeneity and ease of injection. Firstly, standardized in vitro assays were performed in SimSkin® cutaneous equivalents, with variations of the clinical injector, injection site, and injection technique. Then, automated injections in SimSkin® cutaneous equivalents were comparatively performed in a texture analysis setup to obtain fine-granulometry injection force profile results. Finally, five female participants were recruited for the in vivo arm of the study (case reports), with variations of the clinical injector, injection site, and injection technique. Generally, the obtained quantitative force values and injection force profiles were critically appraised from a translational viewpoint, based on discussions around the OxiFree™ manufacturing technology and on in-use specialized clinician feedback. Overall, the present study outlined a notable level of homogeneity across the MaiLi® product range in terms of injectability attributes, as well as consistently high ease of administration by medical aesthetic clinicians.

Finite element analysis of biomechanical interactions of a subcutaneous suspension suture and human face soft-tissue: a cadaver study.

In order to study the local interactions between facial soft-tissues and a Silhouette Soft® suspension suture, a CE marked medical device designed for the repositioning of soft tissues in the face and the neck, Finite element simulations were run, in which a model of the suture was embedded in a three-layer Finite Element structure that accounts for the local mechanical organization of human facial soft tissues. A 2D axisymmetric model of the local interactions was designed in ANSYS, in which the geometry of the tissue, the boundary conditions and the applied loadings were considered to locally mimic those of human face soft tissue constrained by the suture in facial tissue repositioning. The Silhouette Soft suture is composed of a knotted thread and sliding cones that are anchored in the tissue. Hence, simulating these interactions requires special attention for an accurate modelling of contact mechanics. As tissue is modelled as a hyper-elastic material, the displacement of the facial soft tissue changes in a nonlinear way with the intensity of stress induced by the suture and the number of the cones. Our simulations show that for a 4-cone suture a displacement of 4.35 mm for a 2.0 N external loading and of 7.6 mm for 4.0 N. Increasing the number of cones led to the decrease in the equivalent local strain (around 20%) and stress (around 60%) applied to the tissue. The simulated displacements are in general agreement with experimental observations.

Collagen Stimulators in Body Applications: A Review Focused on Poly-L-Lactic Acid (PLLA).

The number of aesthetic procedures performed worldwide continues to grow together with an increase in the population seeking the restoration or preservation of a youthful appearance. Requests for non-surgical body rejuvenation are increasing. Patients are looking for safe and effective minimally invasive aesthetic procedures. Soft-tissue dermal fillers can meet these expectations. Based on the beneficial outcomes of these treatments in many facial areas, a new trend is developing to target body areas. Different dermal fillers are available and include collagen stimulators initially developed to restore facial volume. Furthermore, they are associated with long-lasting efficiency, a high level of patient satisfaction and a good safety profile, with mainly minor adverse events reported. In appropriate conditions of use, they are now used for body rejuvenation in clinical practice. Their use is expanding and allows addressing various issues including volume loss, skin laxity, cellulite, striae distensae and wrinkles. This review focuses on poly-L-lactic acid (PLLA), used in the first collagen stimulator and one of the most investigated in facial and in off-facial body applications. The available published data, although still limited, are presented by body area, neck and chest, buttocks, abdomen, upper arms, thighs, knees, and hands. Key features of the concerned zones and the main clinical signs affecting the body part as well as the injection modalities are provided along with the aesthetic results. This represents the state of the art on which to base further developments necessary for optimal and safe outcomes of treatment with the PLLA-based collagen stimulators and others in this class for body rejuvenation.

European Multicenter Prospective Study Evaluating Long-Term Safety and Efficacy of the Polycaprolactone-Based Dermal Filler in Nasolabial Fold Correction.

BACKGROUND: Age-related changes affecting facial areas can be corrected using minimally invasive dermal fillers. The use of polycaprolactone-dermal filler (PCL-filler) in aesthetics is increasing. OBJECTIVE: To evaluate the long-term safety and efficacy of the PCL-filler, in a European, multicenter, prospective study. MATERIALS AND METHODS: Subjects (n = 90) with moderate/severe nasolabial folds (Wrinkle Severity Rating Scale [WSRS]: 3 to 4) were treated on Day 0 with a single injection of similar volume on each side; safety and efficacy assessments were performed over an 18-month period. In 1 of the 3 study centers, safety was evaluated at 30 months. RESULTS: At Month 12 (M12; primary endpoint), 84% of subjects showed a ≥1-point improvement on the WSRS (M6: 92%; M18: 64%). From the investigator/subject's evaluation, from Day 7 to M12, Global Aesthetic Improvement was reported for >90% of subjects, with the effect maintained for up to 18 months in >80% of patients. Subjects/investigators reported high satisfaction and skin quality improvement. Most of the immediate injection-site reactions disappeared after 2 to 4 days. No severe or unexpected adverse events were reported. CONCLUSION: This study demonstrated the long-term safety and efficacy of the PCL-filler, with safety confirmed for up to 30 months.

Polycaprolactone-based dermal filler complications: A retrospective study of 1111 treatments.

BACKGROUND: Aging signs can be corrected through volume restoration in multiple soft tissue layers and in the supraperiosteal plane using hyaluronic acid (HA) or nonhyaluronic acid (non-HA) fillers. The non-HA bioresorbable polycaprolactone (PCL)-based filler with collagen-stimulating properties has a proven safety profile, but rare potential complications such as nodules and granuloma can occur. Furthermore, PCL-based fillers cannot be immediately removed by injection of an enzyme. These potential drawbacks have yet to be described in the literature. AIMS: The author performed 1111 treatments between 2015 and 2018. This study aims to review and analyze these treatments to ascertain the complication rates of the PCL-based filler. Suggestions for complication prevention and management are also discussed. METHODS: 780 patients treated with the PCL-based filler were reviewed by the physician between April 2015 and May 2018. During this period, 5595 syringes were used in 1111 treatments. All complication data were acquired by phone interviews, reports by patients, or observation at follow-up visits. Complications were subdivided into early-onset (occurring up to 2 weeks after treatment) and late-onset events (occurring more than 2 weeks to years after treatment). RESULTS: Among the 1111 treatments, there were 50 cases (4.5%) of edema that lasted longer than 2 weeks, 30 cases (2.7%) of bruising, 8 cases (0.72%) of malar edema, 5 cases (0.45%) of temporarily palpable lumps and 2 cases (0.18%) of discoloration. There were no cases of intravascular injection, nodules/granulomas, or infection. CONCLUSION: The complication rate of the PCL-based filler was found to be low, and there were no cases of intravascular injection, nodules, and/or granulomas during the 3-year observation. Longer-lasting edema was associated with a higher injection volume and malar edema was related to lymphatic compression.

Polycaprolactone: How a Well-Known and Futuristic Polymer Has Become an Innovative Collagen-Stimulator in Esthetics.

Compared to other domains, tissue engineering and esthetics have dramatically expanded in recent years, leading to both major biomedical advances and futuristic perspectives. The two share a common approach based on biomaterials, especially polymers. This paper illustrates this with the example of polycaprolactone (PCL), a polymer synthesized in the early 1930s, and one of its most recent applications, a PCL-based collagen stimulator, a filler used in esthetics. PCL is biocompatible and biodegradable. Its specific physicochemical and mechanical properties, viscoelasticity and ease of shaping led to the production of PCL-based products with various shapes and durations dependent on its biodegradation kinetics. PCL has been safely used in the biomedical field for more than 70 years, from sutures to tissue and organ replacement by 3D printing. The PCL-based collagen stimulator is composed of PCL microspheres suspended in a carboxymethyl-cellulose gel carrier providing immediate and sustained volumizing effects when injected; the morphology, the biocompatibility of the PCL microspheres embedded with the collagen fibers produced all contribute to the creation of a unique 3D scaffold for a sustained effect. Its safety has been investigated in clinical studies and vigilance surveys. Recently published experts' recommendations on injection modalities and techniques should help further optimize treatment outcome and safety. This paper also integrates reviews and recommendations on the prevention and management of adverse events related to dermal and subdermal fillers including the PCL-based collagen stimulator. In addition, in terms of efficacy and safety, this product benefits from its daily clinical use in esthetics worldwide and continuous extensive fundamental and clinical research, both on it and the PCL polymer. Forthcoming data from further investigations will reinforce knowledge of the product and procedures in the field.

Metabolism of Anethole Dithiolethione by Rat and Human Liver Microsomes: Formation of Various Products Deriving from Its O-Demethylation and S-Oxidation. Involvement of Cytochromes P450 and Flavin Monooxygenases in These Pathways.

A study of the metabolism of anethole dithiolethione (ADT, 5-(p-methoxyphenyl)-3H-1,2-dithiole-3-thione) by rat and human liver microsomes showed the formation of the corresponding S-oxide and the S-oxide of desmethyl-ADT (dmADT, 5-(p-hydroxyphenyl)-3H-1,2-dithiole-3-thione), and of p-methoxy-acetophenone (pMA) and p-hydroxy-acetophenone (pHA), in addition to the previously described metabolites, dmADT, anethole dithiolone (ADO, 5-(p-methoxyphenyl)-3H-1,2-dithiole-3-one) and its demethylated derivative dmADO [5-(p-hydroxyphenyl)-3H-1,2-dithiole-3-one]. The microsomal metabolism of ADO under identical conditions led to dmADO and to pMA and pHA. The metabolites of ADT derive from two competing oxidative pathways: an O-demethylation catalyzed by cytochromes P450 and an S-oxidation mainly catalyzed by flavin-dependent monooxygenases (FMO) and, to a minor extent, by CYP enzymes. The most active human CYP enzymes for ADT demethylation appeared to be CYP1A1, 1A2, 1B1, 2C9, 2C19, and 2E1. ADT S-oxidation is catalyzed by FMO 1 and 3, and to a minor extent by CYP enzymes such as CYP3A4.

Recommendations for volume augmentation and rejuvenation of the face and hands with the new generation polycaprolactone-based collagen stimulator (Ellansé®).

BACKGROUND: The range of fillers currently available for soft-tissue augmentation is constantly expanding. The latest advances in filler technology include collagen biostimulators that exert their esthetic effect by promoting neocollagenesis. One such product is the next-generation collagen biostimulator (Ellansé®) that demonstrates properties as yet unseen in soft-tissue fillers. It is composed of polycaprolactone (PCL) microspheres in an aqueous carboxymethylcellulose gel carrier. Given its specific characteristics and the number of areas that can be treated with this innovative product, experts' recommendations were deemed necessary and are therefore presented in this paper with a specific focus on the indications, treatment areas and procedures as well as injection techniques. METHODS: A multinational, multidisciplinary group of plastic surgeons and dermatologists convened to develop recommendations with a worldwide perspective. This publication provides information on the specific characteristics of the product and focuses on the recommendations on the injection techniques. RESULTS: Recommendations on injection techniques are provided for the upper face, mid-face and lower face and zone by zone for each of these areas, as well as hands. Based on the particular anatomy of each area, the focus is on the techniques and devices of injection and the volume and depth of injection. The information is tabulated, and photos are presented for illustration. CONCLUSION: These recommendations provide a guideline for physicians who wish to perform safe and efficacious treatment with the PCL collagen stimulator for face and rejuvenation with volume augmentation.

Safety of poly-L-lactic acid (New-Fill®) in the treatment of facial lipoatrophy: a large observational study among HIV-positive patients.

BACKGROUND: Facial lipoatrophy is a frequently reported condition associated with use of antiretroviral (ARV) drugs. Poly-L-lactic acid (PLLA) acid has been used to correct facial lipoatrophy in people with HIV since 2004 both in Europe and the United States. The objective of this study was to establish, in real life conditions and in a large sample, the safety of PLLA (New Fill®, Valeant US, Sinclair Pharma Paris, France) to correct facial lipoatrophy among HIV-positive patients. METHODS: A longitudinal study was conducted between 2005 and 2008 in France. Data from 4,112 treatment courses (n = 4,112 patients) and 15,665 injections sessions (1 to 5 injection sessions per treatment course) were gathered by 200 physicians trained in the use of PLLA. RESULTS: The average age of patients (88.3% males) treated for lipoatrophy was 47.1 ± 8.1 years (Mean ± SD); 91.2% of patients had been receiving ARV treatment for 10.9 (±4.2) years; CD4 T-cell count was 535 ± 266 cells/mm3. The duration of facial lipoatrophy was 5 ± 2.8 years and the severity was such that 47.3% of patients required five injection sessions of PLLA and 81.9% of the sessions required two vials of the preparation. The final visit, scheduled two months after the last injection session, was attended by 66.0% of patients (n = 2,713). 48 treatment courses (2.8%) were discontinued due to adverse events (AEs). The overall incidence of AEs per course was 18.8%. Immediate AEs, bleeding (3.4%), bruising (2.3%), pain (2.0%), redness at injection site (1.6%), and swelling of the face (0.7%), occurred in 15.4% of courses and 7.0% of sessions (usually during the first session). Non-immediate AEs, mainly nodules (5.7%), inflammation (0.7%), granuloma (0.3%), discolouration (0.2%), and skin hypertrophy (0.1%), occurred in 6.7% of courses. Non-immediate AEs occurred within a time ranging from 21 days (inflammation) to 101 days (granuloma) and all but three of the 13 cases of granuloma resolved. Product efficacy was rated satisfactory by 95% of the patients and physicians. CONCLUSIONS: This study demonstrated, in real-life conditions and on a large sample, that PLLA injections were feasible, efficient, and safe when performed by trained physicians.

Distribution pattern of tachykinin NK2 receptors in human colon: involvement in the regulation of intestinal motility.

Although a number of pharmacological studies have shown the involvement of tachykinin type 2 receptors (NK2r) in the regulation of human colonic motility, few data are available so far on their pattern of expression. In this study this pattern was investigated in the myenteric plexuses, the longitudinal and circular muscle layers (external muscular layers), and the interstitial cells of Cajal (ICCs) using confocal microscopy immunofluorescence methods. NK2r immunoreactivity (NK2r-IR) was detected in the soma of myenteric neurons and in nerve varicosities located in myenteric plexuses as well as in external muscular layers. Colocalization analysis of NK2r-IR and synaptophysin-IR, showed significant regional differences in the distribution of NK2r-expressing nerve varicosities, the rate of occurrence was found to be 56.08% +/- 3% (mean +/- SE) in the external muscular layers and 30.22% +/- 1% (mean +/- SE) in the myenteric plexuses. NK2r-IR was found in membranes of most muscle cells previously incubated with a selective NK2r agonist, [beta-Ala(8)] neurokinin A fragment 4-10, at 4 degrees C, and then mainly relocated in the cytoplasm when heated to 37 degrees C. A number of NK2r-IR nerve varicosities were close to NK2r-expressing neurons and muscle cells. Some of NK2r-expressing neurons and nerves were tachykinin-IR. No NK2r-IR was detected in ICCs. The present data indicate that presynaptic and postsynaptic neuroneuronal and neuromuscular regulatory processes mediated by tachykinins via NK2r may occur for modulating human colonic motility.

Expression of the neurokinin type 1 receptor in the human colon.

The distribution of the neurokinin type 1 receptor (NK1r) in human intestine, mapped in a few immunohistochemical investigations in the antrum and the duodenum, is comparable to that widely studied in rodents. Importantly, despite pharmacological evidence of their presence in mammalian intestinal muscle, their immunohistochemical visualization in smooth muscle cells remains to be determined in human digestive tract. In the present work, we studied the distribution of NK1r in the human colon, with a particular view to visualize their expression in muscle cells. With this aim, part of colonic segments were incubated with nicardipine and TTX in order to induce accumulation of the NK1r on cell membrane. NK1r were visualized by using immunohistochemistry combined with fluorescence and confocal microscopy. Without incubation, NK1r-IR was clearly observed on the membrane and the cytoplasm of myenteric and submucous neurons and interstitial cells of Cajal, but could not be clearly determined in the longitudinal and circular muscle. NK1r-IR-expressing neurons and interstitial cells were closely surrounded by substance P (SP) immunoreactive nerves. Incubation of colonic segments with nicardipine and TTX at 4 degrees C for 1 h with SP allowed to reveal a strong NK1r-IR at the surface of muscle cells. Incubation with SP (10(-6) M) at 37 degrees C for 1 min induced a relocation of NK1r-IR into the cytoplasm of muscle. This is interpreted as an internalization of NK1r induced by the binding of SP on muscular NK1r. The present data contribute to emphasize the role of NK1r in tachykinin-mediated neuronal processes regulating intestinal motility.

Cardiovascular and survival effects of sympatho-inhibitors in adriamycin-induced cardiomyopathy in rats.

Adriamycin (ADR) is a widely used drug for the treatments of cancers. This study evaluates the effects of moxonidine and metoprolol on cardiac hemodynamics and survival in ADR-induced left ventricular dysfunction (total dose of 20 mg/kg in a 4-week regimen). Rats were treated with the centrally acting I(1)R agonist sympatho-inhibitor, moxonidine, or with the non-selective beta-adrenergic antagonist, metoprolol, during 1 month or until death. Treatments began 1 week after the onset of the ADR administration. Low doses (0.5 and 1 mg/kg/day) of moxonidine and metoprolol (10 mg/kg/day) improved cardiovascular function. High doses of moxonidine (3 mg/kg/day) and metoprolol (150 mg/kg/day) were cardiodepressive. Moxonidine and metoprolol both failed to improve survival. These data indicate that a treatment with these sympatho-inhibitors can reduce the left ventricular dysfunction induced by ADR. Moreover, these cardioprotective effects where obtained even when ADR was used at a dose regimen usually employed for its antineoplastic effects in rodents. Nevertheless, in this particular cardiomyopathy, we did not find any association between improvements of functional parameters and survival whatever the drug and the dose used. This problem points out the difficulty to prevent, at least with sympatho-inhibitory drugs alone, the mortality linked to the chronic cardiotoxicity of ADR.

Studies of congenic lines in the Brown Norway rat model of Th2-mediated immunopathological disorders show that the aurothiopropanol sulfonate-induced immunological disorder (Aiid3) locus on chromosome 9 plays a major role compared to Aiid2 on chromosome 10.

Brown Norway (BN) rats treated with aurothiopropanol-sulfonate (Atps) constitute a model of Th2-mediated immunological disorders associated with elevated IgE responses and renal IgG deposits. Using F(2) offspring between Atps-susceptible BN and Atps-resistant Lewis rats, we had previously mapped three quantitative trait loci on chromosomes 9, 10, and 20 for which BN alleles increased susceptibility to Atps-induced immunological disorders (Aiid). In this study we have used congenic lines for the latter two quantitative trait loci, formerly called Atps2 and Atps3 and now named Aiid2 (chromosome 10) and Aiid3 (chromosome 9), for fine mapping and characterization of their impact on Atps-triggered reactions. In Aiid2 congenic lines, the gene(s) controlling part of the IgE response to Atps was mapped to an approximately 7-cM region, which includes the IL-4 cytokine gene cluster. Two congenic lines in which the introgressed segments shared only a portion of this 7-cM region, showed an intermediate IgE response, indicating the involvement of several genes within this region. Results from BN rats congenic for the Lewis Aiid3 locus, which we mapped to a 1.2-cM interval, showed a stronger effect of this region. In this congenic line, the Atps-triggered IgE response was 10-fold lower than in the BN parental strain, and glomerular IgG deposits were either absent or dramatically reduced. Further genetic and functional dissections of these loci should provide insights into pathways that lead to Th2-adverse reactions.

A randomized phase IIb trial of anethole dithiolethione in smokers with bronchial dysplasia.

BACKGROUND: Results from preclinical studies have suggested that the organosulfur compound anethole dithiolethione (ADT) may be an effective chemopreventive agent for lung cancer. We conducted a phase IIb study to determine the effects of ADT in smokers with bronchial dysplasia. METHODS: One hundred twelve current and former smokers with a smoking history of at least 30 pack-years and at least one site of bronchial dysplasia identified by an autofluorescence bronchoscopy-directed biopsy were randomly assigned to receive placebo or ADT at 25 mg orally thrice daily for 6 months. Each subject then underwent a follow-up bronchoscopy-directed biopsy. We used changes in histopathologic grade and nuclear morphometry index (MI) as the primary and secondary end point biomarkers, respectively. Chi-square tests with continuity correction were used to compare response rates on a lesion- and person-specific basis between the two study groups. All statistical tests were two-sided. RESULTS: One hundred one subjects had a follow-up bronchoscopy. In the lesion-specific analysis, progression rate of pre-existing dysplastic lesions by two or more grades and/or the appearance of new lesions was statistically significantly lower in the ADT group (8%) than in the placebo group (17%) (P<.001; difference = 9%, 95% confidence interval [CI] = 4% to 15%). In the person-specific analysis, the disease progression rate was statistically significantly lower in the ADT group (32%) than in the placebo group (59%) (P =.013; difference = 27%, 95% CI = 6% to 48%). The two treatment groups did not differ statistically significantly in terms of nuclear MI. Among individuals with an abnormal nuclear MI before treatment (29 in the ADT group and 25 in the placebo group), the progression rate in the ADT group (41%) was substantially lower than that in the placebo group (60%), although the difference was not statistically significant (P =.28; difference = 19%, 95% CI = -11% to 49%). Adverse events were mostly minor gastrointestinal symptoms that resolved with dose reduction or discontinuation of the medication. CONCLUSION: Our results suggest that, in smokers, ADT is a potentially efficacious chemoprevention agent for lung cancer.