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Cryo-TEM micrographs of transfersomes obtained immediately after preparation (a, b) and after injection through the skin (c, d). Scale bars are 200 (a, c), 100 (d), and 50 (b) nm
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Needle-free liquid jet injectors are devices developed for the delivery of pharmaceutical solutions through the skin. In this paper, we investigated for the first time the ability of these devices to deliver intact lipid vesicles. Diclofenac sodium loaded phospholipid vesicles of two types, namely liposomes and transfersomes, were prepared and full...
Citations
... A pioneering study showed that fibroblast secretions were more effective in improving skin aging compared to stem cells [32]. It has been demonstrated that engineered EVs can be safely and effectively delivered to the dermis using a needle-free injector [33][34][35]. In this study, we used a needle-free injector to deliver engineered EVs to dermal fibroblasts, successfully achieving local homeostasis regulation function in mouse skin tissues. ...
Skin aging is characterized by the disruption of skin homeostasis and impaired skin injury repair. Treatment of aging skin has long been limited by the unclear intervention targets and delivery techniques. Engineering extracellular vesicles (EVs) as an upgraded version of natural EVs holds great potential in regenerative medicine. In this study, we found that the expression of the critical antioxidant and detoxification gene Gstm2 was significantly reduced in aging skin. Thus, we constructed the skin primary fibroblasts-derived EVs encapsulating Gstm2 mRNA (EVsGstm2), and found that EVsGstm2 could significantly improve skin homeostasis and accelerate wound healing in aged mice. Mechanistically, we found that EVsGstm2 alleviated oxidative stress damage of aging dermal fibroblasts by modulating mitochondrial oxidative phosphorylation, and promoted dermal fibroblasts to regulate skin epidermal cell function by paracrine secretion of Nascent Polypeptide-Associated Complex Alpha subunit (NACA). Furthermore, we confirmed that NACA is a novel skin epidermal cell protective molecule that regulates skin epidermal cell turnover through the ROS-ERK-ETS-Cyclin D pathway. Our findings demonstrate the feasibility and efficacy of EVs-mediated delivery of Gstm2 for aged skin treatment and unveil novel roles of GSTM2 and NACA for improving aging skin.
Graphical Abstract
... Thus, this route of administration is limited to a few compounds with defined physicochemical properties. However, several new physical, chemical and formulation technologies were developed during the last years [39][40][41][42] to improve drug penetration through the dermal barrier [43]. For testing chemical absorption in the skin, regulated methods are available. ...
Several ex vivo and in vitro skin models are available in the toolbox of dermatological and cosmetic research. Some of them are widely used in drug penetration testing. The excised skins show higher variability, while the in vitro skins provide more reproducible data. The aim of the current study was to compare the chemical composition of different skin models (excised rat skin, excised human skin and human-reconstructed epidermis) by measurement of ceramides, cholesterol, lactate, urea, protein and water at different depths of the tissues. The second goal was to compile a testing system, which includes a skin-on-a-chip diffusion setup and a confocal Raman spectroscopy for testing drug diffusion across the skin barrier and accumulation in the tissue models. A hydrophilic drug caffeine and the P-glycoprotein substrate quinidine were used in the study as topical cream formulations. The results indicate that although the transdermal diffusion of quinidine is lower, the skin accumulation was comparable for the two drugs. The various skin models showed different chemical compositions. The human skin was abundant in ceramides and cholesterol, while the reconstructed skin contained less water and more urea and protein. Based on these results, it can be concluded that skin-on-a-chip and confocal Raman microspectroscopy are suitable for testing drug penetration and distribution at different skin layers within an exposition window. Furthermore, obese human skin should be treated with caution for skin absorption testing due to its unbalanced composition.
... Cationic a-D-glucan nanoparticles 70-80 nm ID JI of the nanoparticles enhanced the immune response to a protein antigen (pigs, in vivo) [19] Exosomes 97 nm, 151 nm, 162 nm ID JI of exosomes caused less trauma than a conventional syringe, promoted collagen generation and dermal matrix thickening, and is suitable for cosmetic applications (mice, in vivo) [18] Liposomes Transfersomes 55 nm 46 nm Liposomes and transfersomes maintained their structural integrity, drug loading, and release properties upon JI (pig skin, in vitro) [17] Pharmaceutics 2022, 14, 1085 3 of 13 Injection volume, standoff distance, and particle size had an effect on the dispersion area and delivery efficiency, while particle shape and concentration did not influence these parameters (human skin, in vitro) [15] PLGA nanoparticles From 45 to 450 nm Nozzle diameter, injection pressure, and particle size influenced the penetration depth and the dispersion patterns (mouse skin + acrylamide gel, in vitro) [16] Cationic solid lipid nanoparticles 270 nm ID JI of pDNA-nanoparticles led to higher antibody titers than the immunization through subcutaneous (20 fold) and topical routes (65 fold) (mice, in vivo) [14] 2. Materials and Methods ...
Needle-free liquid jet injectors are medical devices used to administer pharmaceutical solutions through the skin. Jet injectors generate a high-speed stream of liquid medication that can puncture the skin and deliver the drug to the underlying tissues. In this work, we investigated the feasibility of using liquid jet injectors to administer nanosuspensions, assessing the impact of the jet injection on their pharmaceutical and physicochemical properties. For this purpose, the model drug diclofenac was used to prepare a set of nanosuspensions, stabilized by poloxamer 188, and equilibrated at different pHs. The hydrodynamic diameter and morphology of the nanocrystals were analyzed before and after the jet injection across porcine skin in vitro, together with the solubility and release kinetics of diclofenac in a simulated subcutaneous environment. The efficacy of the jet injection (i.e., the amount of drug delivered across the skin) was evaluated for the nanosuspension and for a solution, which was used as a control. Finally, the nanosuspension was administered to rats by jet injector, and the plasma profile of diclofenac was evaluated and compared to the one obtained by jet injecting a solution with an equal concentration. The nanosuspension features were maintained after the jet injection in vitro, suggesting that no structural changes occur upon high-speed impact with the skin. Accordingly, in vivo studies demonstrated the feasibility of jet injecting a nanosuspension, reaching relevant plasma concentration of the drug. Overall, needle-free jet injectors proved to be a suitable alternative to conventional syringes for the administration of nanosuspensions.
... 91 Even the intact phospholipid vesicles can be easily delivered across the skin. 92 Hu et al. used a needle-free device to pneumatically accelerate the penetration of exosome solution into the dermis of skin. 93 Administration of stem cell secretome by needle-free injection can overcome the physical injuries of needles and have better penetration or absorption. ...
... Thus, several skin penetration enhancement strategies have been investigated over the last decades. Besides the long-standing approach based on the use of chemical skin penetration enhancers, ionic liquids and physical methods for the perturbation of stratum corneum barrier [1], the use of nanotechnologies, alone or in combination with physical methods, has been investigated [2][3][4], and the number of publications is increasing exponentially. ...
The skin is the absorption site for drug substances intended to treat loco-regional diseases, although its barrier properties limit the permeation of drug molecules. The growing knowledge of the skin structure and its physiology have supported the design of innovative nanosystems (e.g. liposomal systems) to improve the absorption of poorly skin-permeable drugs. However, despite the dozens of clinical trials started, few topically applied liposomal systems have been authorized both in the EU and the USA. Indeed, the intrinsic complexity of the topically applied liposomal systems, the higher production costs, the lack of standardized methods and the more stringent guidelines for assessing their benefit/risk balance can be seen as causes of such inefficient translation. The present work aimed to provide an overview of the physicochemical and biopharmaceutical characterization methods that can be applied to topical liposomal systems intended to be marketed as medicinal products, and the current regulatory provisions. The discussion highlights how such methodologies can be relevant for defining the critical quality attributes of the final product, and they can be usefully applied based on the phase of the life cycle of a liposomal product: to guide the formulation studies in the early stages of development, to rationally design preclinical and clinical trials, to support the pharmaceutical quality control system and to sustain post-marketing variations. The provided information can help define harmonized quality standards able to overcome the case-by-case approach currently applied by regulatory agencies in assessing the benefit/risk of the topically applied liposomal systems.Graphical abstract
... In the meanwhile, the lack of needle can avert the stimulation of nervous tissue to prevent algesthesia, which is beneficial for the administration of growth hormone when injected daily or in pediatric patients. Furthermore, needle-free jet injection has been proved to be effective in delivering intact phospholipid vesicles and exosomes in recent years (Hu et al., 2019;Schlich et al., 2016). ...
The transdermal delivery of macromolecular drugs has become one of the focused topics in pharmaceutical research since it enables highly specific and effective delivery, while avoiding the pain and needle phobia associated with injection, or incidences like drug degradation and low bioavailability of oral administration. However, the passive absorption of macromolecular drugs via skin is highly restricted by the stratum corneum owing to high molecular weight. Therefore, various strategies have been extensively developed and conducted to facilitate the transdermal delivery of macromolecular drugs, among which, mechanical force-assisted techniques occupy dominant positions. Such techniques include ultrasound, needle-free jet injection, temporary pressure and microneedles. In this review, we focus on recent transdermal enhancing strategies utilizing mechanical force, and summarize their mechanisms, advantages, limitations and clinical applications respectively.
... Microneedles with different needle lengths, from 20 to 2000 micron, are commercially available and used both for cosmetic and therapeutic purposes [17]. The combination of nanotechnology with advanced, minimally invasive devices -such as microneedles or needle-free jet injectors-might further improve the local delivery of therapeutics [18,19]. In the present work, the combination of nanocrystal technology with the use of a microneedle roller was investigated as a potential method to enhance DCF delivery to the skin. ...
Topical application of the anti-inflammatory drug diclofenac (DCF) reduces the severity of systemic unwanted effects compared to its oral administration. A number of transdermal formulations are available on the market and routinely used in clinical and home-care settings. However, the amount of DCF delivered across the skin remains limited and often insufficient, thus making the oral route still necessary for achieving sufficient drug concentration at the inflamed site. In attempting to improve the transdermal penetration, we explored the combined use of DCF nanosuspensions with a microneedle roller. Firstly, DCF nanosuspensions were prepared by a top-down media milling method and characterized by spectroscopic, thermal and electron microscopy analyses. Secondly, the pore-forming action of microneedle rollers on skin specimens (ex vivo) was described by imaging at different scales. Finally, DCF nanosuspensions were applied on newborn pig skin (in vitro) in combination with microneedles roller treatment, assessing the DCF penetration and distribution in the different skin layers. The relative contribution of microneedle length, nanosuspension stabilizer and application sequence could be identified by systemically varying these parameters.
... Physical approaches utilise electric currents, ultrasounds, or microneedles. Investigations into the use of chemical and physical methods in combination with nanoparticles have identified new approaches that utilise nanocarriers with chemical permeation enhancers and nanocrystals/nanoparticles with penjet or microneedles (El Maghraby et al., 2006;Schlich et al., 2016;Tham et al., 2018). ...
Over the last three decades, research in the field of phospholipid nanocarriers as tools to improve dermal and transdermal drug delivery has grown substantially. In particular, liposomes have been the target of studies aimed at reformulating vesicles with a greater ability to deliver drugs trans-dermally. A number of additives with varied physicochemical properties have been combined with traditional components of liposomes. These novel modification processes have produced new classes of vesicles with the potential to enhance the treatment of both dermatological disorders and systemic pathologies. Development of the first deformable and elastic phospholipid vesicles has highlighted the key role of vesicle composition in promoting release of vesicle content into and through the skin. This paper discusses the key vesicle properties and mechanisms of delivery by which newly developed phospholipid vesicles can improve percutaneous drug delivery.
... Moreover, the modulation of the injector parameters also showed an effect, with higher pressures and wider nozzles being correlated with deeper penetration and smaller dispersion area. Given the substantial differences in terms of composition, stiffness, and surface properties between polymeric and lipidic nanocarriers, our group evaluated the feasibility of jet injecting intact phospholipid vesicles across the skin [82]. This study aimed at proving that liposomes could bear the pressure generated by the plunger and the high velocity impact with the skin without any damage (Figure 9.3). ...
Needle‐free jet injectors are medical devices used for the delivery of liquid medications across the skin as a high‐speed stream of fluid, without the use of a needle. The absence of a needle abolishes the risk of needle‐stick injuries, frequent among healthcare providers, and increases the compliance to injections in needle‐phobic patients. Through the modulation of several parameters of the jet injectors, the liquid medication can be delivered to different sites within or below the skin, thus allowing the use of such devices for both local and systemic therapies in a multitude of disorders. In the present chapter, after a brief historical overview, the functioning principles and the rationale behind the use of needle‐free jet injectors are presented. Moreover, preclinical and clinical studies where jet injectors have been employed for the systemic or local delivery of therapeutics are reviewed. Finally, in the last section, the potential of such devices for the administration of nano‐ and micro‐particulate drug delivery systems is discussed.
... The best fitting parameters obtained from this modeling were z H = 19.0 Å and σ H = 3.0 Å, resulting in a double layer thickness (d B ) of 50 Å, a value in good agreement with others reported for similar systems (Carboni et al., 2013;Pabst et al., 2003;Schlich et al., 2016). ...
The use of adrenaline in cardiopulmonary resuscitation is a long-standing medical procedure, recommended by several international guidelines. However, its unspecific action on adrenergic receptors and the need for repeated administrations pose serious concerns about its safety, the balance between benefits and risks being still under debate. To address this issue, a sustained release nano-formulation of adrenaline was developed. Adrenaline was encapsulated into PEGylated, anionic liposomes by a pH-driven loading technique. Particular attention was devoted to the prevention of oxidation of adrenaline by optimizing the preparative process and including an optimal amount of antioxidants in the formulation. The vesicles obtained were then characterized for size, zeta-potential, and lamellarity, while their morphology was described by cryo-TEM. The controlled release properties were confirmed by two different in vitro release-testing methods, and the biocompatibility was assayed on human endothelial cells in vitro.
