Improved brachial skin hydration and appearance with hyperdiluted calcium hydroxylapatite.

INTRODUCTION: The search for minimally invasive treatments for areas not covered by clothing, such as the arms, has increased, particularly to combat flaccidity resulting from factors such as aging and weight loss. This study evaluated the efficacy of calcium hydroxyapatite (CaHA), an injectable biostimulator, in improving flaccidity and hydration of the skin of the arms. MATERIALS AND METHODS: Six women between 40 and 50 years old with visible signs of brachial flaccidity were selected. Calcium hydroxyapatite was injected into the arms in a 1:4 dilution (1.5 mL per side), with subjective evaluation based on the GAIS score and objective hydration analysis using corneometry. RESULTS: After a single application of CaHA, there was a significant increase in skin hydration (12.2%), objectively assessed by corneometry. Patient and physician satisfaction was high, evidenced by visible improvements in photographs and by the GAIS score. No significant adverse events were reported, demonstrating the safety of the procedure. DISCUSSION: Our clinical observations confirm the ability of CaHA to visibly improve arm flaccidity. In addition, hydration measures support previous histological studies demonstrating increases in dermal proteoglycans. Compared to other studies, the increase in skin hydration with CaHA was similar to those obtained with hyaluronic acid, suggesting comparable results with a more comfortable and less invasive technique. CONCLUSION: This study demonstrates the efficacy of CaHA in improving hydration of brachial skin after a single treatment. Despite the limitations of the sample size, the research contributes to the medical literature, highlighting the utility of the 3 mL CaHA presentation for brachial treatment with objective results in skin hydration.

A morphological analysis of calcium hydroxylapatite and poly-l-lactic acid biostimulator particles.

Injectable fillers, pivotal in aesthetic medicine, have evolved significantly with recent trends favoring biostimulators like calcium hydroxylapatite (CaHA-CMC; Radiesse, Merz Aesthetics, Raleigh, NC) and poly-l-lactic acid (PLLA; Sculptra Aesthetics, Galderma, Dallas, TX). This study aims to compare the particle morphology of these two injectables and examine its potential clinical implications. Utilizing advanced light and scanning electron microscopy techniques, the physical characteristics of CaHA-CMC and PLLA particles were analyzed, including shape, size, circularity, roundness, aspect ratio, and quantity of phagocytosable particles. The findings reveal several morphological contrasts: CaHA-CMC particles exhibited a smooth, homogenous, spherical morphology with diameters predominantly ranging between 20 and 45 µm, while PLLA particles varied considerably in shape and size, appearing as micro flakes ranging from 2 to 150 µm in major axis length. The circularity and roundness of CaHA-CMC particles were significantly higher compared to PLLA, indicating a more uniform shape. Aspect ratio analysis further underscored these differences, with CaHA-CMC particles showing a closer resemblance to circles, unlike the more oblong PLLA particles. Quantification of the phagocytosable content of both injectables revealed a higher percentage of phagocytosable particles in PLLA. These morphological distinctions may influence the tissue response to each treatment. CaHA-CMC's uniform, spherical particles may result in reduced inflammatory cell recruitment, whereas PLLA's heterogeneous particle morphology may evoke a more pronounced inflammatory response.

Successful Treatment of Noninflammatory CaHA Nodules Using Focused Mechanical Vibration.

Noninflammatory nodules arising from the injection of biostimulatory fillers persist as an unwanted complication. Pathologically, noninflammatory nodules may arise from superficial injection, accidental boluses, or incorrect concentration of microparticles contained within the filler. This case report introduces a method for reversing calcium hydroxylapatite (CaHA) using focused mechanical vibration. An in situ hyperdilution was created by injecting saline into the nodule core to prepare it for resuspension. Topical microneedling was subsequently applied to generate vibrations, aiming to disperse the accumulated CaHA particles. The outcome demonstrated a significant reduction in the size and visibility of the nodule. This combined saline-microneedling approach offers a potential noninvasive, nonpharmacologic solution for managing superficial CaHA nodules.

Social Interest Data as a Proxy for Off-Label Performance-Enhancing Drug Use: Implications and Clinical Considerations.

Performance-enhancing drugs (PEDs) can be categorized into various classes based on the physiological mechanism of the compound, with the most popular being anabolic steroids, selective androgen receptor modulators, and growth hormones. Ancillary compounds, such as selective estrogen receptor modulators (SERMs) and selective estrogen receptor degraders, are commonly utilized alongside a PED to counterbalance any potential undesired side effects. With little clinically relevant data to support the use of these ancillary compounds, medical education and evidence-based approaches aimed at monitoring the potential adverse effects of PED use are sparse.This study aims to identify emerging trends in the interest of PEDs and related ancillary compounds, hypothesize the physiological effects of the continued respective behavior, and propose a proxy for use by clinicians to approximate off-label drug use and subsequently modify their practices accordingly. Several significant trends were identified for non-FDA-regulated compounds (i.e., selective androgen receptor modulators such as RAD-140) and off-label indications for FDA-regulated drugs (i.e., SERMs such as tamoxifen). A significant increase in interest regarding selective androgen receptor modulators, mirrored by anecdotal reports in clinical settings and online forums, is coupled with stagnant or decreasing interest in both post-cycle therapies and anabolic steroids. Ultimately, we propose a call to action for utilizing social data and/or prescription data as a proxy for clinicians to better understand trends in these compounds and thus refine their treatment protocols in a concordant manner.

A Structured Approach for Treating Calcium Hydroxylapatite Focal Accumulations.

BACKGROUND: Radiesse, a widely utilized calcium hydroxylapatite (CaHA) dermal filler, has shown effectiveness in soft tissue augmentation and regeneration. As with all dermal fillers, the potential for nodules may arise. Understanding the pathogenesis of these nodules and exploring effective treatment methodologies are crucial for optimizing patient outcomes. OBJECTIVES: A literature search was carried out to identify published literature documenting reversal of CaHA nodules. After identification, a consensus panel developed a structured approach, denoted by levels, for applying such reversal methods. METHODS: This concise review presents an algorithmic approach to addressing CaHA focal accumulations (noninflammatory nodules) based on invasiveness, cost, and potential risks based on published literature. RESULTS: Level 0 involves no intervention, relying on natural degradation for asymptomatic nodules. Level 1 interventions utilize mechanical dispersion techniques, including massage and in situ dispersion, which have demonstrated high success rates, cost effectiveness, and minimal invasiveness. Level 2 introduces alternative modalities such as pharmacological treatments with 5-fluorouracil and corticosteroids, lasers, and experimental approaches. Level 3 represents last-resort options, including calcium-chelating agents, manual removal, and surgical excision. CONCLUSIONS: The article offers a structured approach to managing CaHA focal accumulations.

Mechanically resilient hybrid aerogels containing fibers of dual-scale sizes and knotty networks for tissue regeneration.

The structure and design flexibility of aerogels make them promising for soft tissue engineering, though they tend to come with brittleness and low elasticity. While increasing crosslinking density may improve mechanics, it also imparts brittleness. In soft tissue engineering, resilience against mechanical loads from mobile tissues is paramount. We report a hybrid aerogel that consists of self-reinforcing networks of micro- and nanofibers. Nanofiber segments physically entangle microfiber pillars, allowing efficient stress distribution through the intertwined fiber networks. We show that optimized hybrid aerogels have high specific tensile moduli (~1961.3 MPa cm3 g-1) and fracture energies (~7448.8 J m-2), while exhibiting super-elastic properties with rapid shape recovery (~1.8 s). We demonstrate that these aerogels induce rapid tissue ingrowth, extracellular matrix deposition, and neovascularization after subcutaneous implants in rats. Furthermore, we can apply them for engineering soft tissues via minimally invasive procedures, and hybrid aerogels can extend their versatility to become magnetically responsive or electrically conductive, enabling pressure sensing and actuation.

Hierarchically Assembled Nanofiber Scaffolds with Dual Growth Factor Gradients Promote Skin Wound Healing Through Rapid Cell Recruitment.

To address current challenges in effectively treating large skin defects caused by trauma in clinical medicine, the fabrication, and evaluation of a novel radially aligned nanofiber scaffold (RAS) with dual growth factor gradients is presented. These aligned nanofibers and the scaffold's spatial design provide many all-around "highways" for cell migration from the edge of the wound to the center area. Besides, the chemotaxis induced by two growth factor gradients further promotes cell migration. Incorporating epidermal growth factor (EGF) aids in the proliferation and differentiation of basal layer cells in the epidermis, augmenting the scaffold's ability to promote epidermal regeneration. Concurrently, the scaffold-bound vascular endothelial growth factor (VEGF) recruits vascular endothelial cells at the wound's center, resulting in angiogenesis and improving blood supply and nutrient delivery, which is critical for granulation tissue regeneration. The RAS+EGF+VEGF group demonstrates superior performance in wound immune regulation, wound closure, hair follicle regeneration, and ECM deposition and remodeling compared to other groups. This study highlights the promising potential of hierarchically assembled nanofiber scaffolds with dual growth factor gradients for wound repair and tissue regeneration applications.

Dilutional rheology of Radiesse: Implications for regeneration and vascular safety.

BACKGROUND: Calcium hydroxylapatite-carboxymethylcellulose (CaHA-CMC) injectables have emerged as dual-purpose fillers with bioregenerative and direct filling capabilities. AIMS: This study investigates the rheological properties of CaHA-CMC and its CMC carrier gel at various dilutions. METHODS: The storage modulus (G'), loss modulus (G″), complex viscosity (η*), loss factor (tan δ), cohesivity, and extrusion force were evaluated for a range of CaHA-CMC aqueous dilutions with an oscillatory rheometer, drop weight testing, and force analysis, respectively. RESULTS: Results revealed a significant decrease in G', η*, and increase in tan(δ) with increasing dilution, indicating a decline in the product's direct filling capabilities. Cohesivity decreased dramatically with dilution, potentially enhancing tissue biointegration and the product's biostimulatory effects. The CMC gel carrier displayed inelastic and non-resilient properties, with rheological changes differing from CaHA-CMC. Dilutional rheology was also correlated with previously published dilution-dependent biostimulatory data where hyperdiluted CaHA-CMC (>1:2) demonstrated a regenerative profile and diluted or hypodiluted mixtures retained meaningful filling properties and increased regeneration. CONCLUSIONS: These findings offer a continuum for tailoring the product's rheological profile to match specific tissue requirements. Customizable rheology allows CaHA-CMC to be tuned for either filling and contouring or optimal regenerative effects. Importantly, safety implications related to vascular occlusion suggest that dilutional rheomodulation decreases the risk of vascular events. In conclusion, this study highlights the significant impact of aqueous dilution on the rheological properties of CaHA-CMC and its carrier gel. The findings support the clinical application of tailored dilutions to achieve desired outcomes, providing versatility and safety for aesthetic applications.

Anti-Inflammatory Peptide-Conjugated Silk Fibroin/Cryogel Hybrid Dual Fiber Scaffold with Hierarchical Structure Promotes Healing of Chronic Wounds.

Chronic wounds resulting from diabetes, pressure, radiation therapy, and other factors continue to pose significant challenges in wound healing. To address this, this study introduces a novel hybrid fibroin fibrous scaffold (FFS) comprising randomly arranged fibroin fibers and vertically aligned cryogel fibers (CFs). The fibroin scaffold is efficiently degummed at room temperature and simultaneously formed a porous structure. The aligned CFs are produced via directional freeze-drying, achieved by controlling solution concentration and freezing polymerization temperature. The incorporation of aligned CFs into the expanded fibroin fiber scaffold leads to enhanced cell infiltration both in vitro and in vivo, further elevating the hybrid scaffold's tissue compatibility. The anti-inflammatory peptide 1 (AP-1) is also conjugated to the hybrid fibrous scaffold, effectively transforming the inflammatory status of chronic wounds from pro-inflammatory to pro-reparative. Consequently, the FFS-AP1+CF group demonstrates superior granulation tissue formation, angiogenesis, collagen deposition, and re-epithelialization during the proliferative phase compared to the commercial product PELNAC. Moreover, the FFS-AP1+CF group displays epidermis thickness, number of regenerated hair follicles, and collagen density closer to normal skin tissue. These findings highlight the potential of random fibroin fibers/aligned CFs hybrid fibrous scaffold as a promising approach for skin tissue filling and tissue regeneration.

Optimizing Skin Regenerative Response to Calcium Hydroxylapatite Microspheres Via Poly-Micronutrient Priming.

Regenerative aesthetics aims to restore the structure and function of aging skin. Two products, Radiesse (CaHA) and NCTF 135 HA (micronutrient mesotherapy) have been established as minimally invasive treatments that restore the structure and function of various skin components. It has been anecdotally observed by the authors, however, that some patients respond suboptimally to regenerative treatments without a clear indication as to why. It was hypothesized that micronutrient deficiencies in some patients may contribute to their lack of responsiveness and that a concurrent delivery of amino acids and co-enzymes may create a nutritional reservoir necessary for optimal protein synthesis. Noting that CaHA is known to drive the regeneration of extracellular matrix proteins, the aim of this case series was to investigate if “priming” the skin with NCTF 135 HA could lead to enhanced clinical effects of CaHA. The combination treatment resulted in improvements in panfacial aesthetics, skin laxity, wrinkle severity, skin luminosity, hyperpigmentation, and in skin and subcutis thicknesses in 100% of patients following a single treatment. This study is the first to introduce skin priming via diluting a regenerative biostimulator treatment with an amino acid-based diluent.  Citation: Theodorakopoulou  E, McCarthy A, Perico V, et al. Optimizing skin regenerative response to calcium hydroxylapatite microspheres via poly-micronutrient priming. J Drugs Dermatol. 2023;22(9):925-934. doi:10.36849/JDD.7405.

The Role of Calcium Hydroxylapatite (Radiesse) as a Regenerative Aesthetic Treatment: A Narrative Review.

For decades, a wide variety of natural and synthetic materials have been used to augment human tissue to improve aesthetic outcomes. Dermal fillers are some of the most widely used aesthetic treatments throughout the body. Initially, the primary function of dermal fillers was to restore depleted volume. As biomaterial research has advanced, however, a variety of biostimulatory fillers have become staples in aesthetic medicine. Such fillers often contain a carrying vehicle and a biostimulatory material that induces de novo synthesis of major structural components of the extracellular matrix. One such filler, Radiesse (Merz Aesthetics, Raleigh, NC), is composed of calcium hydroxylapatite microspheres suspended in a carboxymethylcellulose gel. In addition to immediate volumization, Radiesse treatment results in increases of collagen, elastin, vasculature, proteoglycans, and fibroblast populations via a cell-biomaterial-mediated interaction. When injected, Radiesse acts as a cell scaffold and clinically manifests as immediate restoration of depleted volume, improvements in skin quality and appearance, and regeneration of endogenous extracellular matrices. This narrative review contextualizes Radiesse as a regenerative aesthetic treatment, summarizes its unique use cases, reviews its rheological, material, and regenerative properties, and hypothesizes future combination treatments in the age of regenerative aesthetics.

Birt-Hogg-Dubé Syndrome: A Rare Genodermatosis Presenting as Skin Papillomas.

The authors present a rare case of Birt-Hogg-Dubé (BHD) syndrome that presented primarily as an aesthetic case. Previous providers failed to accurately diagnose BHD, despite the patient's history of pneumothoraces. This female patient complained of numerous recurrent, small skin-colored growths on the face and neck and patchy hypopigmentation from the multiple treatments she had to undergo for her "bumpy skin." She also suffered 4 spontaneous pneumothoraces. Following histopathologic and genetic testing, the patient was diagnosed with BHD. Computed tomography and ultrasound scans revealed multiple cysts in both lungs and an angiomyolipoma in both kidneys. This patient had undergone a variety of treatments to aesthetically remove and heal her skin bumps from several healthcare providers, all of whom had misdiagnosed her condition.

Super-Elastic Carbonized Mushroom Aerogel for Management of Uncontrolled Hemorrhage.

Uncontrolled hemorrhage is still the most common cause of potentially preventable death after trauma in prehospital settings. However, there rarely are hemostatic materials that can achieve safely and efficiently rapid hemostasis simultaneously. Here, new carbonized cellulose-based aerogel hemostatic material is developed for the management of noncompressible torso hemorrhage, the most intractable issue of uncontrolled hemorrhage. The carbonized cellulose aerogel is derived from the Agaricus bisporus after a series of processing, including cutting, carbonization, purification, and freeze-drying. In vitro, the carbonized cellulose aerogels with porous structure show improved hydrophilicity, good blood absorption, and coagulation ability, rapid shape recoverable ability under wet conditions. And in vivo, the carbonized aerogels show effective hemostatic ability in both small and big animal serious hemorrhage models. The amount of blood loss and the hemostatic time of carbonized aerogels are all better than the positive control group. Moreover, the mechanism studies reveal that the good hemostatic ability of the carbonized cellulose aerogel is associated with high hemoglobin binding efficiency, red blood cell absorption, and platelets absorption and activation. Together, the carbonized aerogel developed in this study could be promising for the management of uncontrolled hemorrhage.

Biomimetic natural biomaterials for tissue engineering and regenerative medicine: new biosynthesis methods, recent advances, and emerging applications.

Biomimetic materials have emerged as attractive and competitive alternatives for tissue engineering (TE) and regenerative medicine. In contrast to conventional biomaterials or synthetic materials, biomimetic scaffolds based on natural biomaterial can offer cells a broad spectrum of biochemical and biophysical cues that mimic the in vivo extracellular matrix (ECM). Additionally, such materials have mechanical adaptability, microstructure interconnectivity, and inherent bioactivity, making them ideal for the design of living implants for specific applications in TE and regenerative medicine. This paper provides an overview for recent progress of biomimetic natural biomaterials (BNBMs), including advances in their preparation, functionality, potential applications and future challenges. We highlight recent advances in the fabrication of BNBMs and outline general strategies for functionalizing and tailoring the BNBMs with various biological and physicochemical characteristics of native ECM. Moreover, we offer an overview of recent key advances in the functionalization and applications of versatile BNBMs for TE applications. Finally, we conclude by offering our perspective on open challenges and future developments in this rapidly-evolving field.

Nanofiber Aerogels with Precision Macrochannels and LL-37-Mimic Peptides Synergistically Promote Diabetic Wound Healing.

Fast healing of diabetic wounds remains a major clinical challenge. Herein, this work reports a strategy to combine nanofiber aerogels containing precision macrochannels and the LL-37-mimic peptide W379 for rapid diabetic wound healing. Nanofiber aerogels consisting of poly(glycolide-co-lactide) (PGLA 90:10)/gelatin and poly-p-dioxanone (PDO)/gelatin short electrospun fiber segments were prepared by partially anisotropic freeze-drying, crosslinking, and sacrificial templating with three-dimensional (3D)-printed meshes, exhibiting nanofibrous architecture and precision micro-/macrochannels. Like human cathelicidin LL-37, W379 peptide at a concentration of 3 µg/mL enhanced the migration and proliferation of keratinocytes and dermal fibroblasts in a cell scratch assay and a proliferation assay. In vivo studies show that nanofiber aerogels with precision macrochannels can greatly promote cell penetration compared to aerogels without macrochannels. Relative to control and aerogels with and without macrochannels, adding W379 peptides to aerogels with precision macrochannels shows the best efficacy in healing diabetic wounds in mice in terms of cell infiltration, neovascularization, and re-epithelialization. The fast re-epithelization could be due to upregulation of phospho-extracellular signal-regulated kinase (p38 MAPK) after treatment with W379. Together, the approach developed in this work could be promising for the treatment of diabetic wounds and other chronic wounds.

Extracellular Matrix Secretion Mechanically Reinforces Interlocking Interfaces.

Drawing inspiration for biomaterials from biological systems has led to many biomedical innovations. One notable bioinspired device, Velcro, consists of two substrates with interlocking ability. Generating reversibly interlocking biomaterials is an area of investigation, as such devices can allow for modular tissue engineering, reversibly interlocking biomaterial interfaces, or friction-based coupling devices. Here, a biaxially interlocking interface generated using electrostatic flocking is reported. Two electrostatically flocked substrates are mechanically and reversibly interlocked with the ability to resist shearing and compression forces. An initial high-throughput screen of polyamide flock fibers with varying diameters and fiber lengths is conducted to elucidate the roles of different fiber parameters on scaffold mechanical properties. After determining the most desirable parameters via weight scoring, polylactic acid (PLA) fibers are used to emulate the ideal scaffold for in vitro use. PLA flocked scaffolds are populated with osteoblasts and interlocked. Interlocked flocked scaffolds improved cell survivorship under mechanical compression and sustained cell viability and proliferation. Additionally, the compression and shearing resistance of cell-seeded interlocking interfaces increased with increasing extracellular matrix deposition. The introduction of extracellular matrix-reinforced interlocking interfaces may serve as binders for modular tissue engineering, act as scaffolds for engineering tissue interfaces, or enable friction-based couplers for biomedical applications.

Electrospun Nanofibers for Wound Management.

Electrospun nanofibers show great potential in biomedical applications. This mini review article traces the recent advances in electrospun nanofibers for wound management via various approaches. Initially, we provide a short note on the four phases of wound healing, including hemostasis, inflammation, proliferation, and remodeling. Then, we state how the nanofiber dressings can stop bleeding and reduce the pain. Following that, we discuss the delivery of therapeutics and cells using different types of nanofibers for enhancing cell migration, angiogenesis, and re-epithelialization, resulting in the promotion of wound healing. Finally, we present the conclusions and future perspectives regarding the use of electrospun nanofibers for wound management.

Nanofiber capsules for minimally invasive sampling of biological specimens from gastrointestinal tract.

Accurate and rapid point-of-care tissue and microbiome sampling is critical for early detection of cancers and infectious diseases and often result in effective early intervention and prevention of disease spread. In particular, the low prevalence of Barrett's and gastric premalignancy in the Western world makes population-based endoscopic screening unfeasible and cost-ineffective. Herein, we report a method that may be useful for prescreening the general population in a minimally invasive way using a swallowable, re-expandable, ultra-absorbable, and retrievable nanofiber cuboid and sphere produced by electrospinning, gas-foaming, coating, and crosslinking. The water absorption capacity of the cuboid- and sphere-shaped nanofiber objects is shown ∼6000% and ∼2000% of their dry mass. In contrast, unexpanded semicircular and square nanofiber membranes showed <500% of their dry mass. Moreover, the swallowable sphere and cuboid were able to collect and release more bacteria, viruses, and cells/tissues from solutions as compared with unexpanded scaffolds. In addition to that, an expanded sphere shows higher cell collection capacity from the esophagus inner wall as compared with the unexpanded nanofiber membrane. Taken together, the nanofiber capsules developed in this study could provide a minimally invasive method of collecting biological samples from the duodenal, gastric, esophagus, and oropharyngeal sites, potentially leading to timely and accurate diagnosis of many diseases. STATEMENT OF SIGNIFICANCE: Recently, minimally invasive technologies have gained much attention in tissue engineering and disease diagnosis. In this study, we engineered a swallowable and retrievable electrospun nanofiber capsule serving as collection device to collect specimens from internal organs in a minimally invasive manner. The sample collection device could be an alternative endoscopy to collect the samples from internal organs like jejunum, stomach, esophagus, and oropharynx without any sedation. The newly engineered nanofiber capsule could be used to collect, bacteria, virus, fluids, and cells from the abovementioned internal organs. In addition, the biocompatible and biodegradable nanofiber capsule on a string could exhibit a great sample collection capacity for the primary screening of Barret Esophagus, acid reflux, SARS-COVID-19, Helicobacter pylori, and gastric cancer.