Application of microfluidic chips in skin field research

Microfluidics has a wide range of applications in the fields of drug delivery, immediate detection, cell sorting and organ microarrays.

Droplet microfluidic chips, sensitive sensing chips, and organoids capable of manipulating cells and cellular microenvironments offer new opportunities for the preparation of controlled and homogeneous micro- or nano-formulations, health monitoring, and in vitro simulation of skin conditions.

As the third major drug delivery system after oral and injection, transdermal drug delivery avoids the degradation of oral drugs and the pain problems associated with injection; however, it also faces the challenges of a narrow range of drug choices, poor transdermal effect and low bioavailability.

Application of microfluidic chips in transdermal drug delivery

Preparation of drug carriers

In transdermal drug delivery systems, particle size and formulation stability directly affect whether the drug can reach the local tissues through the skin or enter the blood circulation, thus exerting the drug effect.

Conventional methods such as stirring and oscillation lack precise control over the mixing process, which can easily lead to problems such as particle aggregation, uneven particle size distribution, and large batch-to-batch variation.

Microfluidics, on the other hand, has significant advantages in precisely regulating particle size, improving particle dispersion and enhancing formulation stability. Therefore, droplet microfluidic chips are increasingly used to prepare transdermal drug carriers.

microemulsion

Microemulsion is a transparent or translucent thermodynamically stable system with strong skin delivery capability. However, at present, microemulsions are mainly prepared by traditional methods such as manual mixing and vortex mixing, which are unable to precisely control the droplet size and its distribution.

Indeed, the production of single and multiple emulsion carriers can be achieved by a combination of microfluidic cross-flow, flow focusing and co-axial flow. Droplets can be formed by utilizing the interaction of shear stress and interfacial tension between immiscible fluids.

It has been reported that microemulsions produced using a microreactor were observed to have droplets of 20-40 nm in different batches and the dermal flux of the resulting gel was much higher than that of commercially available cream preparations.

Polymer particles

Biodegradable microsphere polymers are receiving increasing attention as injectable carriers. Researchers have utilized microfluidic devices to fabricate microspheres with excellent morphological characteristics that significantly reduce adverse reactions after subcutaneous injection.

PCL microspheres with particle sizes ranging from 26.6-161 μm have been successfully prepared by a flow-focused microfluidic device, and these microspheres are not only of excellent morphology, but also effective in mitigating adverse reactions after subcutaneous injection.

In addition, nanoparticles with small size, narrow particle size distribution and long-term stability were prepared by microfluidic chip combined with 3D printing technology. The results of tests using rabbits and rats as models show that these nanoparticles do not cause irritating reactions such as skin erythema and can effectively treat acne.

liposome

Liposomes are nano-vesicular structures composed of biocompatible and biodegradable lipids capable of encapsulating hydrophilic, lipophilic, and amphiphilic drugs, which have great potential for topical delivery in the skin.

However, the liposomes prepared by conventional methods have large and inhomogeneous particle sizes, leading to poor stability. Microfluidic technology platforms have overcome these drawbacks and thus have received widespread attention.

Vitamin-containing liposomes suitable for the pharmaceutical field can be produced using microfluidic devices with high encapsulation rates and drug loading capacity. Liposomes show significant advantages in in vitro skin permeation tests, with a skin permeation capacity dozens of times higher than that of solutions.

microneedle

In addition to creating complex drug carriers, microfluidic chips can deliver active molecules directly to the target site, increasing the local availability of the drug and reducing adverse effects.

Microneedles are more widely used in carrier-free transdermal drug delivery platforms developed using microfluidic chips. The reservoir of the device contains an interface for releasing or withdrawing fluids, and the length of the microneedle is designed to penetrate the epidermis without touching the nociceptive nerve, which facilitates drug penetration and avoids pain at the injection site.

A multilayered microfluidic chip driven by pulsations from the wearer's arteries has been developed using soft lithography and 3D printing techniques and combined with a 3D printed microneedle array to enable painless drug delivery.

Application of microfluidic chips in transdermal testing

Elastomers and modified polymer materials are flexible and able to return to their original state after stress relief, so they are commonly used in micro-valves, micro-mixers, and micro-separators for rigid micro-channels.

With the development of material science and electronic technology, flexible microfluidic chips are widely used, especially in skin-wearable microfluidic chips for biofluid monitoring, which has made significant progress.

Biological fluids are typically derived from blood, sweat, interstitial fluids, saliva and tears, with sweat being the most commonly analyzed. By monitoring changes in the concentration of nutrients and metabolites in sweat, microfluidic chips can also assess clinical risk.

Microfluidic Skin Chip

The development of drug discovery and precision medicine relies on advances in drug testing technology. However, model animals for preclinical testing do not fully represent the complexity of the human body and there are ethical and regulatory issues associated with animal testing, so there is an urgent need to establish in vitro alternatives to mimic the human skin system.

However, the complexity of the skin has hindered the development of many in vitro models.2D cell culture techniques have a long history of simplicity and ease of manipulation, but are unable to mimic cell-to-cell or cell-to-matrix interactions and signaling pathways due to their monolayer growth format and lack of extracellular matrix.

3D cell culture bridges these gaps and enhances physiological relevance, but still does not highly mimic the dynamic transport of molecules, angiogenesis, and the complexity of human tissues.

Currently, microfluidic skin-on-a-chip (SoC) is considered a promising alternative to in vitro skin for several reasons:

① It drives fluid perfusion, removes waste produced by the cells and provides fresh media, thereby extending the life of cells in vitro;

② The cyclic tensile and shear stresses generated by fluid flow and the stiffness of the controllable substrate can mimic the physiologically relevant mechanical forces to which cells are subjected;

③ Perfused blood vessels can be introduced to further enhance the complexity and realism of the model.

SoC Platforms for Drug Development

SoC platforms for detection are typically created by introducing skin biopsy samples or human skin equivalents (HSEs) into the chip, or by generating skin models directly in the chip.

Some laboratories have cultured human fibroblasts and keratin-forming cells in microfluidic chips for examining the adverse effects of sorafenib on the skin as well as the pharmacodynamic effects of coenzyme Q10, and the results of the obtained tests are consistent with the clinical pharmacological activity of the drug. Although SoC platforms are not yet widely adopted, their application in drug development is being explored and developed.

Dermatology Modeling

The cutaneous vascular system not only influences percutaneous penetration of substances and response to irritants, but is also involved in a variety of pathological responses, including acute or chronic inflammatory diseases, tumor growth, malignant melanoma metastasis, and wound healing.

Therefore, generating a cutaneous vascular system is important for modeling the pathological and physiological conditions of the skin. Although dermatological modeling using microfluidic SoC platforms is still in its infancy, success has been achieved in fabricating vascularized skin models and testing skin irritation.