Drug Delivery Research Articles

Advances in artificial cells based on microfluidic chips

One of the main goals of synthetic biology is to build artificial cells in a bottom-up manner, which not only facilitates the deep understanding of the origin of life and cell function but also plays a critical role in the research fields such as the development of artificial cell chassis, tissue models, engineering drug delivery systems, and drug screening tools. However, achieving this goal is extremely challenging. The complexity of cell structures and the miniaturization and diversity of basic modules pose high requirements for the construction methods. The microfluidic chip, as an advanced microanalysis system, serves as an effective tool for building artificial cells. It can accurately control the structure and local microenvironment of artificial cells, becoming the preferred approach for the current research on synthetic life. This article reviewed the methods of constructing, manipulating, and analyzed artificial cells based on microfluidic chips, emphasized the importance of the microenvironment for life systems and artificial self-sustaining systems. In addition, this article demonstrated the wide applications of artificial cells in multiple critical biomedical fields. Exploring the advantages, disadvantages, and application performance of different microfluidic methods can enrich our knowledge about artificial cell research. Finally, we made an outlook on the development of artificial cell research based on microfluidics, expecting that this field can achieve greater breakthroughs and progress.

Enhanced Skin Penetration and Efficacy: First and Second Generation Lipoidal Nanocarriers in Skin Cancer Therapy.

Skin carcinoma remains one of the most widespread forms of cancer, and its global impact continues to increase. Basal cell carcinoma, melanoma, and squamous cell carcinoma are three kinds of cutaneous carcinomas depending upon occurrence and severity. The invasive nature of skin cancer, the limited effectiveness of current therapy techniques, and constraints to efficient systems for drug delivery are difficulties linked with the treatment of skin carcinoma. In the present era, the delivery of drugs has found a new and exciting horizon in the realm of nanotechnology, which presents inventive solutions to the problems posed by traditional therapeutic procedures for skin cancer management. Lipid-based nanocarriers like solid lipid nanoparticles and nanostructured lipid carriers have attracted a substantial focusin recent years owing to their capability to improve the drug'ssite-specific delivery,enhancing systemic availability,and thus its effectiveness. Due to their distinct structural and functional characteristics, these nanocarriers can deliver a range of medications, such as peptides, nucleic acids, and chemotherapeutics, via different biological barriers, such as the skin. In this review, an effort was made to present the mechanism of lipid nanocarrier permeation via cancerous skin. In addition, recent research advances in lipid nanocarriers have also been discussed with the help of in vitro cell lines and preclinical studies. Being a nano size, their limitations and toxicity aspects in living systems have also been elaborated.

Comprehensive assessment of blood–brain barrier opening and sterile inflammatory response: unraveling the therapeutic window

Microbubbles (MBs) combined with focused ultrasound (FUS) has emerged as a promising noninvasive technique to permeabilize the blood–brain barrier (BBB) for drug delivery into the brain. However, the safety and biological consequences of BBB opening (BBBO) remain incompletely understood. This study aims to investigate the effects of two parameters mediating BBBO: microbubble volume dose (MVD) and mechanical index (MI). High-resolution MRI-guided FUS was employed in mouse brains to assess BBBO by manipulating these two parameters. Afterward, the sterile inflammatory response (SIR) was studied 6 h post-FUS treatment. Results demonstrated that both MVD and MI significantly influenced the extent of BBBO, with higher MVD and MI leading to increased permeability. Moreover, RNA sequencing revealed upregulation of major inflammatory pathways and immune cell infiltration after BBBO, indicating the presence and extent of SIR. Gene set enrichment analysis identified 12 gene sets associated with inflammatory responses that were significantly upregulated at higher MVD or MI. A therapeutic window was established between therapeutically relevant BBBO and the onset of SIR, providing operating regimes to avoid damage from stimulation of the NFκB pathway via TNFɑ signaling to apoptosis. These results contribute to the optimization and standardization of BBB opening parameters for safe and effective drug delivery to the brain and further elucidate the underlying molecular mechanisms driving sterile inflammation.

Biomaterials for non-invasive trans-tympanic drug delivery: requirements, recent advances and perspectives.

Various non-invasive delivery systems have recently been developed as an alternative to conventional injections. Local transdermal administration represents the most attractive method due to the low systemic side effects, excellent ease of administration, and persistent drug release. The tympanic membrane (TM), a major barrier between the outer and middle ear, has a similar structure of the stratum corneum compared to the surface of the skin. After several attempts, non-invasive trans-tympanic drug delivery has been regarded as a promising option in the treatment of middle and inner ear diseases. The round window membrane (RWM) was a possible non-invasive delivery approach from the middle to inner ear. The improved permeability of nanocarriers crossing the RWM is a current hotspot in therapeutics for inner ear diseases. In this review, we include the latest studies exploring non-invasive trans-tympanic delivery to treat middle and inner ear diseases. Both passive and active delivery systems are described. A summary of the benefits and disadvantages of various delivery systems in clinical practice and production procedures is introduced. Finally, future possible approaches for its effective application as a non-invasive middle and inner ear drug delivery system are characterised.

Hydrogels: a promising therapeutic platform for inflammatory skin diseases treatment.

Inflammatory skin diseases, such as psoriasis and atopic dermatitis, pose significant health challenges due to their long-lasting nature, potential for serious complications, and significant health risks, which requires treatments that are both effective and exhibit minimal side effects. Hydrogels offer an innovative solution due to their biocompatibility, tunability, controlled drug delivery capabilities, enhanced treatment adherence and minimized side effects risk. This review explores the mechanisms that guide the design of hydrogel therapeutic platforms from multiple perspectives, focusing on the components of hydrogels, their adjustable physical and chemical properties, and their interactions with cells and drugs to underscore their clinical potential. We also examine various therapeutic agents for psoriasis and atopic dermatitis that can be integrated into hydrogels, including traditional drugs, novel compounds targeting oxidative stress, small molecule drugs, biologics, and emerging therapies, offering insights into their mechanisms and advantages. Additionally, we review clinical trial data to evaluate the effectiveness and safety of hydrogel-based treatments in managing psoriasis and atopic dermatitis under complex disease conditions. Lastly, we discuss the current challenges and future opportunities for hydrogel therapeutics in treating psoriasis and atopic dermatitis, such as improving skin barrier penetration and developing multifunctional hydrogels, and highlight emerging opportunities to enhance long-term safety and stability.

A novel microfluidic tool for the evaluation of local drug delivery systems in simulated in vivo conditions.

A 3D-printed microfluidic tool for assessing local drug delivery systems (LDD) in simulated in vivo conditions was developed and evaluated. The device was designed considering the oral environment and dental applications, and it was fabricated with a high-precision resin 3D printer. Chitosan scaffolds loaded with different concentrations of doxycycline were used for evaluating our device. The concentration of the released drug was measured through in-line UV-VIS spectroscopy, and to verify the repeatability and accuracy of our measurements, comparisons with standard HPLC results were made (5% deviation). Cumulative drug release profiles in steady-state conditions were obtained and compared to the Weibull model. The behaviour of the LDD system in a dynamic environment was also evaluated during experiments where step changes in pH were introduced. It was demonstrated that under infection-like conditions, there is an immediate response from the polymer and a clear increase in the concentration of the released drug. Continuous flow and recirculation experiments were also conducted, revealing significant differences in the drug release profiles. Specifically, in the case of continuous flow, the quantity of the released drug is much higher due to the higher driving force for diffusion (concentration gradient). Overall, the proposed microfluidic tool proved to be ideal for evaluating LDD systems, as the in vivo microenvironment can be replicated in a better way than with currently used standard systems.

NIR Light and GSH Dual-Responsive Upconversion Nanoparticles Loaded with Multifunctional Platinum(IV) Prodrug and RGD Peptide for Precise Cancer Therapy.

Platinum(II) drugs as a first-line anticancer reagent are limited by side effects and drug resistance. Stimuli-responsive nanosystems hold promise for precise spatiotemporal manipulation of drug delivery, with the aim to promote bioavailability and minimize side effects. Herein, a multitargeting octahedral platinum(IV) prodrug with octadecyl aliphatic chain and histone deacetylase inhibitor (phenylbutyric acid, PHB) at axial positions to improve the therapeutic effect of cisplatin was loaded on the upconversion nanoparticles (UCNPs) through hydrophobic interaction. Followed attachment of DSPE-PEG2000 and arginine-glycine-aspartic (RGD) peptide endowed the nanovehicles with high biocompatibility and tumor specificity. The fabricated nanoparticles (UCNP/Pt(IV)-RGD) can be triggered by upconversion luminescence (UCL) irradiation and glutathione (GSH) reduction to controllably release Pt(II) species and PHB, inducing profound cytotoxicity. Both in vitro and in vivo experiments demonstrated that UCNP/Pt(IV)-RGD exhibited remarkable antitumor efficiency, high tumor-targeting specificity, and real-time UCL imaging capacity, presenting an intelligent platinum(IV) prodrug-loaded nanovehicle for UCL-guided dual-stimuli-responsive combination therapy.

Nanodroplets Engineered with Folate Carbon Dots for Enhanced Cancer Cell Uptake toward Theranostic Application.

The research in nanotherapeutics is rapidly advancing, particularly in the realm of nanoconstructs for drug delivery. This study introduces folate-based carbon dot-decorated nanodroplets (f-Dnm), synthesized from a binary mixture of negatively charged folic acid carbon dots (f-CDs) and cationic-branched polyethylenimine (PEI). The uniformly spherical nanodroplets with an average diameter of 115 ± 15 nm exhibit notable photoluminescence. Surface potential analysis reveals a significant change upon coacervation, attributed to strong electrostatic interactions between f-CD and PEI. The engineered nanodroplets show excellent colloidal and photostability even after 6 months of storage at room temperature. The pH-dependent self-assembly and disassembly properties of f-Dnm are explored for drug loading and release studies using doxorubicin (DOX) as a model anticancer drug. Moreover, the f-Dnm nanocarrier demonstrates significantly higher drug loading capabilities (∼90%). In vitro release studies of doxorubicin-loaded f-Dnm [f-Dnm(DOX)] reveal 5 times higher drug release at lysosomal pH 5.4 compared to that at physiological blood pH 7.4. Cytocompatibility assessments using the MTT assay on HeLa, A549, and NIH-3T3 cells confirm the nontoxic nature of f-Dnm, even at high concentrations. Additionally, f-Dnm(DOX) exhibits higher cytotoxicity in HeLa cells compared to f-CD(DOX) at similar DOX concentrations. Cellular uptake studies show an increased uptake of f-Dnm in folate receptor-positive HeLa and MDA-MB 231 cells. Hemolysis assay validated the biocompatibility of the developed formulation. Overall, these engineered nanodroplets represent a class of nontoxic nanocarriers that offer promising potential as nanotherapeutics for folate receptor-positive cells.

Personalized Vascularized Models of Breast Cancer Desmoplasia Reveal Biomechanical Determinants of Drug Delivery to the Tumor.

Desmoplasia in breast cancer leads to heterogeneity in physical properties of the tissue, resulting in disparities in drug delivery and treatment efficacy among patients, thus contributing to high disease mortality. Personalized in vitro breast cancer models hold great promise for high-throughput testing of therapeutic strategies to normalize the aberrant microenvironment in a patient-specific manner. Here, tumoroids assembled from breast cancer cell lines (MCF7, SKBR3, and MDA-MB-468) and patient-derived breast tumor cells (TCs) cultured in microphysiological systems including perfusable microvasculature reproduce key aspects of stromal and vascular dysfunction causing impaired drug delivery. Models containing SKBR3 and MDA-MB-468 tumoroids show higher stromal hyaluronic acid (HA) deposition, vascular permeability, interstitial fluid pressure (IFP), and degradation of vascular HA relative to models containing MCF7 tumoroids or models without tumoroids. Interleukin 8 (IL8) secretion is found responsible for vascular dysfunction and loss of vascular HA. Interventions targeting IL8 or stromal HA normalize vascular permeability, perfusion, and IFP, and ultimately enhance drug delivery and TC death in response to perfusion with trastuzumab and cetuximab. Similar responses are observed in patient-derived models. These microphysiological systems can thus be personalized by using patient-derived cells and can be applied to discover new molecular therapies for the normalization of the tumor microenvironment.

Hyaluronic Acid Receptor-Mediated Nanomedicines and Targeted Therapy.

Hyaluronic acid (HA) is a naturally occurring polysaccharide found in the extracellular matrix with broad applications in disease treatment. HA possesses good biocompatibility, biodegradability, and the ability to interact with various cell surface receptors. Its wide range of molecular weights and modifiable chemical groups make it an effective drug carrier for drug delivery. Additionally, the overexpression of specific receptors for HA on cell surfaces in many disease states enhances the accumulation of drugs at pathological sites through receptor binding. In this review, the modification of HA with drugs, major receptor proteins, and the latest advances in receptor-targeted nano drug delivery systems (DDS) for the treatment of tumors and inflammatory diseases are summarized. Furthermore, the functions of HA with varying molecular weights of HA in vivo and the selection of drug delivery methods for different diseases are discussed.

Tailoring Indocyanine Green J-Aggregates for Imaging, Cancer Phototherapy, and Drug Delivery: A Review.

Indocyanine green J-aggregates (ICG-Jagg) have emerged as a significant subject of interest in biomedical applications due to their unique optical properties, tunable size, and excellent biocompatibility. This comprehensive review aims to provide an in-depth exploration of ICG-Jagg, with a focus on elucidating the diverse facets of their preparation and the factors that influence the preparation process. Additionally, the review discusses their applications in biomedical diagnostics, such as imaging and contrast agents, as well as their utilization in drug delivery and various phototherapeutic interventions.

Advancing psoriasis drug delivery through topical liposomes.

Psoriasis, recognized as a chronic inflammatory skin disorder, disrupts immune system functionality. Global estimates by the World Psoriasis Day consortium indicate its impact on approximately 130 million people, constituting 4 to 5 percent of the worldwide population. Conventional drug delivery systems, mainly designed to alleviate psoriasis symptoms, fall short in achieving targeted action and optimal bioavailability due to inherent challenges such as the drug's brief half-life, instability, and a deficiency in ensuring both safety and efficacy. Liposomes, employed indrug delivery systems, emerge as highly promising carriers for augmenting the therapeutic efficacy of topically applied drugs. These small unilamellar vesicles demonstrate enhanced penetration capabilities, facilitating drug delivery through the stratum corneum layer of skin. This comprehensive review article illuminates diverse facets ofliposomes as a promising drug delivery system to treat psoriasis. Addressing various aspects such as formulation strategies, encapsulation techniques, and targeted delivery, the review underscores the potential of liposomes in enhancing the efficacy and specificity of psoriasis treatments.

3D-printed microrobots for biomedical applications.

Microrobots, which can perform tasks in difficult-to-reach parts of the human body under their own or external power supply, are potential tools for biomedical applications, such as drug delivery, microsurgery, imaging and monitoring, tissue engineering, and sensors and actuators. Compared with traditional fabrication methods for microrobots, recent improvements in 3D printers enable them to print high-precision microrobots, breaking through the limitations of traditional micromanufacturing technologies that require high skills for operators and greatly shortening the design-to-production cycle. Here, this review first introduces typical 3D printing technologies used in microrobot manufacturing. Then, the structures of microrobots with different functions and application scenarios are discussed. Next, we summarize the materials (body materials, propulsion materials and intelligent materials) used in 3D microrobot manufacturing to complete body construction and realize biomedical applications (e.g., drug delivery, imaging and monitoring). Finally, the challenges and future prospects of 3D printed microrobots in biomedical applications are discussed in terms of materials, manufacturing and advancement.

Multipocket Cage Enables the Binding of High-Order Bulky and Drug Guests Uncovered by MS Methodology.

Achieving high guest loading and multiguest-binding capacity holds crucial significance for advancement in separation, catalysis, and drug delivery with synthetic receptors; however, it remains a challenging bottleneck in characterization of high-stoichiometry guest-binding events. Herein, we describe a large-sized coordination cage (MOC-70-Zn8Pd6) possessing 12 peripheral pockets capable of accommodating multiple guests and a high-resolution electrospray ionization mass spectrometry (HR-ESI-MS)-based method to understand the solution host-guest chemistry. A diverse range of bulky guests, varying from drug molecules to rigid fullerenes as well as flexible host molecules of crown ethers and calixarenes, could be loaded into open pockets with high capacities. Notably, these hollow cage pockets provide multisites to capture different guests, showing heteroguest coloading behavior to capture binary, ternary, or even quaternary guests. Moreover, a pair of commercially applied drugs for the combination therapy of chronic lymphocytic leukemia (CLL) has been tested, highlighting its potential in multidrug delivery for combined treatment.

Decitabine enclosed biotin-zein conjugated nanoparticles: synthesis, characterization, in vitro and in vivo evaluation.

Aim: This study focuses on biotinylated nanocarriers designed to encapsulate amphiphilic molecules with self-biodegradable properties for enhanced drug delivery. Methods: Biotin-zein conjugated nanoparticles were synthesized and tested in C6 cell lines to evaluate their viability and cellular uptake. Optimization was achieved using a acentral composite design. The nanoparticles underwent thermogravimetric analysis, and their pharmacokinetics and biodistribution were also studied. Results: The optimized nanoparticles displayed 96.31% drug encapsulation efficiency, a particle size of 95.29nm and a zeta potential of -17.7mV. These nanoparticles showed increased cytotoxicity and improved cellular uptake compared with free drugs. Thermogravimetric analysis revealed that the drug-loaded nanocarriers provided better protection against drug degradation. Pharmacokinetic and biodistribution studies indicated that the formulation had an extended brain residence time, highlighting its effectiveness. Conclusion: The biotin-zein conjugated nanoparticles developed in this study offer a promising nano-vehicle for in vivo biodistribution and pharmacokinetic applications. Their high drug encapsulation efficiency, stability and extended brain residence time suggest they are effective for targeted drug delivery and therapeutic uses.

An instructional design strategy for optimization of GelMA hydrogels material properties

Gelatin methacryloyl (GelMA) hydrogels have become a key biomaterial in various biomedical fields, such as tissue regeneration engineering and drug delivery, due to their exceptional biocompatibility and customizable physical and chemical characteristics. The resemblance of GelMA to the extracellular matrix and its ability to be cured with light make it a popular choice for researchers. This research delves into how the material properties of GelMA hydrogels, specifically the density of the molecular network (DMN), impact their performance in different applications. By preparing GelMA hydrogels with different degrees of substitution (DS) and concentrations, and utilizing these attributes as key measurable parameters for determining DMN, we conducted a comprehensive evaluation of properties relevant to biological applications. We also suggest strategies for optimizing these properties. Through the application of the DMN theory, we show that precise control over material properties allows for tailored customization of GelMA hydrogels for specific tissue engineering and drug delivery purposes. This study offers valuable insights into the optimization of GelMA hydrogel properties to advance the field of tissue engineering and improve customization of cellular microenvironments.

Reactive oxygen species driven prodrug-based nanoscale carriers for transformative therapies.

Reactive oxygen species (ROS) drive processes in various pathological conditions serving as an attractive target for therapeutic strategies. This review highlights the development and use of ROS-dependent prodrug-based nanoscale carriers that has transformed many biomedical applications. Incorporating prodrugs into nanoscale carriers not only improves their stability and solubility but also enables site-specific drug delivery ultimately enhancing the therapeutic effectiveness of the nanoscale carriers. We critically examine recent advances in ROS-responsive nanoparticulate platforms, encompassing liposomes, polymeric nanoparticles, and inorganic nanocarriers. These platforms facilitate precise control over drug release upon encountering elevated ROS levels at disease sites, thereby minimizing off-target effects and maximizing therapeutic efficiency. Furthermore, we investigate the potential of combination therapies in which ROS-activated prodrugs are combined with other therapeutic agents and underscore their synergistic potential for treating multifaceted diseases. This comprehensive review highlights the immense potential of ROS-dependent prodrug-based nanoparticulate systems in revolutionizing biomedical applications; such nanoparticulate systems can facilitate selective and controlled drug delivery, reduce toxicity, and improve therapeutic outcomes for ROS-associated diseases.

Enhancing the sensing performance of Al-modified Graphene+ based sensor for anticancer medicinal molecules: a DFT study

It is recently reported that a new pure carbon-based structure graphene+ (G+) exhibits more excellent properties such as buckling structure similar to penta-graphene and Dirac cones like graphene. In this work, a comprehensive exploration and comparison of the adsorption behaviors and sensing performances of optimal Al-doped G+ (Al_G+) and pristine G+ are explored by combing density functional theory with non-equilibrium Green’s function for anticancer drugs molecules, namely Cisplatin (CP), Hydroxyurea (HU), 5-fluorouracil (5-FU) and 6-Mercaptopurine (6-MP). Firstly, the stable and optimal structure of Al_G+ is obtained by sequentially substituting three distinct carbon atoms with Al atom. Moreover, it is found that the introduction of Al atom leads to the disappearance of the Dirac cones, resulting in a transition from semi-metallic to metallic. Subsequently, CP and HU exhibit physical adsorption, 5-FU and 6-MP are chemically adsorbed on the surface of G+ by high adsorption energy. However, the adsorption energy of Al_G+ for both CP and HU all increased by about 1.5eV compared with G+. 5-FU and 6-MP are chemically adsorbed on Al_G+ by appropriate adsorption energies. Finally, the G+/Al_G+-based sensor is constructed to investigate the sensitivity of medicinal molecules according to chemisorption. It is seen that the sensitivity of the G+ to 5-FU and 6-MP is all less than 22%. Although the Al_G+ has the sensitivity below 22% for CP, HU and 5-FU, which has up to 62% for 6-MP, more than 40% higher than other medicinal molecules. Further, the high sensitivity and selectivity of Al_G+ towards 6-MP are elucidated through scattering states and transmission spectra of sensors. Upon the results, it suggests that Al_G+ has broad application prospects in multiple fields such as drug delivery and medicinal molecular detection especially for 6-MP.

SUPERPARAMAGNETIC HYDROPHILIC MOLECULARLY IMPRINTED NANOPARTICLES FOR AN EFFICIENT AND SELECTIVE REMOVAL OF TETRACYCLINE FROM WATER

In this work, a novel superparamagnetic hydrophilic molecularly imprinted nanomaterial for the removal of tetracycline (TC) was synthesized utilizing magnetite (Fe3O4) as the magnetic core, TC as the template molecule, 3-aminopropyltriethoxysilane (APTES) as the functional monomer, and tetraethoxysilane (TEOS) as the cross-linker. Initially, Fe3O4 magnetic nanoparticles (MNP) coated with SiO2 (MNP@SiO2) were synthesized, followed by TC molecular imprinting on the nanoparticles. Initially, Fe3O4 MNP coated with SiO2 (MNP@SiO2) were synthesized, followed by TC molecular imprinting on the nanoparticles. The synthesis method for MNP@SiO2 was optimized, and DLS analysis of 10 replicates showed a nanoparticle size of 70.1 ± 5.8 nm, indicating high method reproducibility. The MNP@SiO2, as well as the imprinted (MNP@SiO2-MIP) and non-imprinted (MNP@SiO2-NIP) nanomaterials, were characterized by FTIR, TEM, VSM, XRD, DLS, Z potential, and BET analysis. The saturation magnetization (Ms) values were 43 emu/g for MNP@SiO2 and 32 emu/g for both MNP@SiO2-MIP and MNP@SiO2-NIP, confirming suitability for magnetic separation using external magnets. Batch binding experiments conducted in water and methanol assessed adsorption isotherms and binding kinetics, with data fitting the Langmuir isotherm model better than the Freundlich model. The developed MIP exhibited significant selectivity against other molecules with similar functional groups and size. In water, the adsorption capacity of the MNP@SiO2-MIP was 23 mg/g, with an imprinting factor of 2.2. Furthermore, the MIP demonstrated good regeneration performance. The material was tested on TC-spiked tap water samples, achieving 80.1% TC removal with high reproducibility (3.2%, n=3). Combining hydrophilic superparamagnetic nanoparticles with molecular imprinting enhances their potential applications in environmental remediation, antibiotic purification, and drug delivery.

PAMAM dendrimers as mediators of dermal and transdermal drug delivery: a review.

Poly(amidoamine) dendrimers have been widely investigated as potential nanomaterials that can enhance the skin permeation of topically applied drugs. This article reviews the studies that have used dendrimers as penetration enhancers and examines the mechanisms by which enhancement is claimed. A wide range of studies have demonstrated that, in certain circumstances and for certain drugs, the incorporation of dendrimers into a topically applied formulation can significantly increase the amount of drug passing into and through the skin. In some cases, dendrimers offered little or no enhancement of skin permeation, suggesting that the drug-dendrimer interaction and the selection of a specific dendrimer were central to ensuring optimal enhancement of skin permeation. Significant interactions between dendrimers and other formulation components were also reported in some cases. Dendrimers offer substantial potential for enhancing drug delivery into and across the skin, putatively by mechanisms that include occlusion and changes to surface tension. However, most of these studies are conducted in vitro and limited progress has been made beyond such laboratory studies, some of which are conducted using membranes of limited relevance to humans, such as rodent skin. Thus, the outcomes and claims of such studies should be treated with caution.