How Advances in Bioimpedance Spectroscopy Are Driving Portable Device Innovation

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Bioimpedance spectroscopy is a technique that allows scientists and physicians to monitor the effectiveness and pharmacokinetic properties of transdermal drug delivery. This article provides a detailed introduction to the technique from the perspective of the basic principles and characteristics of human dermal tissue, and describes the technology that can be used to implement portable monitoring devices.

What is Bioimpedance Spectroscopy?

Impedance spectroscopy is a measurement technique used to characterize the electrical properties of various dielectrics. It measures the impedance or resistance of a dielectric in the presence of an alternating current. This impedance varies with frequency, and by analyzing this variation, we can quickly and cost-effectively understand material properties that are usually difficult to evaluate. Impedance measurements are based on the ratio of two measurable quantities, voltage and current. In order to measure impedance, the system needs to be perturbed by applying an electric potential. There are two ways to achieve this perturbation: (a) using an AC excitation voltage and measuring the AC current response; (b) using an AC excitation current and measuring the AC voltage response. If the applied voltage or current is a small signal, the system can be considered linear. The response signal has no frequency shift. This means that all alternating quantities can be linearly related and can be described by amplitude and phase alone, so these quantities are well represented in the frequency domain by complex numbers.

Some physical systems can be characterized by their impedance patterns, a measurement method generally defined as electrochemical impedance spectroscopy (EIS). EIS is applicable to a variety of use cases, including electrochemical cell (battery) measurements, gas or liquid detection, and biological tissue analysis. When used for biological tissue analysis, EIS is often referred to as bioimpedance spectroscopy, which describes the response of a living organism or part of it to an externally applied electric current.

In the past decade, bioimpedance spectroscopy has become popular in some traditional applications, such as body composition analysis, hydration measurement, galvanic skin response (GSR) or electrodermal activity (EDA). In addition, a group of emerging innovative technologies also applies the bioimpedance concept to pharmacodynamics. In this trendy application field, a promising research direction is drug delivery analysis.

生物阻抗谱在药效动力学领域的一个显著用途是无创实时监测透皮给药后药物的生物利用度1。

What is TMD?

TMD stands for Transdermal medicine delivery, which is a drug delivery method that administers a drug mixture through intact skin. This method has many advantages over other conventional drug delivery routes. It is non-invasive, painless, and systemic, avoiding needle sticks or more invasive biopsy methods that require local anesthesia. TMD applies local negative pressure to a large area of ​​healthy skin surface, disrupting the epidermal-dermal junction and forming blisters that gradually fill with interstitial fluid and serum. The drug penetrates the layers of the epidermis, passing through the outermost layer of the skin (the stratum corneum) to reach the inner tissue without accumulating in any intermediate layers. Once the drug reaches the inner dermis, it triggers systemic absorption and is transported to the whole body through the dermal microcirculation and blood vessels. Compared with systemic drug delivery, topical methods and TMD methods have some advantages. A more uniform and smoother drug delivery curve can be achieved, avoiding drug concentration peaks, thereby reducing the risk of toxic side effects. Finally, the technology greatly reduces systemic absorption, allowing the drug effect to be mainly concentrated at the delivery site.

In TMD, many different physical principles can be applied to achieve skin penetration and promote the transport of drug compounds across the skin: chemical enhancers, diffusion, absorption, thermal energy, vibration energy (ultrasound), electrostatic forces (electrophoresis) or electric fields (iontophoresis), and even radiofrequency energy. Phonophoresis uses ultrasound to deliver topical therapeutic drugs from the stratum corneum to the epidermis and dermis. Iontophoresis and electroporation create pulsed electric fields that open pores in cell membranes using low and high voltages, respectively, to allow drugs to penetrate the skin.

All of these technologies are capable of delivering a wide range of drugs without damaging biological tissue. Some of these methods have become standardized in everyday clinical use, including treatments such as patches and ultrasound delivery systems for hormone therapy, contraception or opioid analgesia, while others have only proven their effectiveness in laboratory test studies. Today, medical research is increasingly focusing on the development of simple, needle-free systems for vaccinations.

Impedance measurement is a minimally invasive method for detecting drug delivery, which is highly compatible with non-invasive TMD techniques, as opposed to traditional methods that require needles or other more invasive analytical techniques.

Bioimpedance analysis applied to TMD has opened the door for medical researchers to explore many features, including monitoring insulin delivery in diabetic patients.

Impedances involved in EIS measurements

In order to correctly interpret the electrical measurements applied to the human body, we need to first establish an electrical model of each part of the human body. We must go down to the most basic elements of each model and define the resistance of biological tissue. First, biological tissue can be considered as a layered electrolyte composed of many cells tightly arranged. The characteristics of the cells can be described by ionic conductivity and dielectric relaxation phenomena. This is because the electrical conduction mechanism in the body involves ions as charge carriers. There are several studies that show that when direct current is applied to the human body, the current will flow through the extracellular fluid (ECF). If the spectral components of the current are rich in high-frequency components, the current will flow through both the extracellular fluid (ECF) and the intracellular fluid (ICF).

Figure 1. Electrical conductivity of human tissue

Therefore, according to the above preliminary approximation, the electronic circuit simulating human behavior can be modeled as follows: the resistor Ri (intracellular resistance) is connected in series with the capacitor (cell membrane capacitance), and the two are connected in parallel with another resistor Re (extracellular resistance), as shown in Figure 2. The impedance range of the human body is 10 kΩ to 1 MΩ at low frequencies around 1 kHz, and 1 kΩ to 100 Ω at high frequencies around 1 MHz.

Figure 2. Equivalent model of biological tissue at the cellular level

From basic biological tissue to macroscopic structures of the human body, the part of the impedance spectrum we are interested in may change. Therefore, the excitation frequency of the EIS measurement will change accordingly depending on the medical application and the part of the body to be studied.

Human skin is mainly composed of three layers: epidermis, dermis and subcutaneous tissue. The epidermis is the outer layer exposed to the external environment, and its outermost layer is the stratum corneum. We have established an equivalent electrical model for each layer of skin, and its impedance corresponds to the specific changes from one layer to another. Modeling human skin is indeed a very difficult and complex task, because the characteristics of the skin not only vary from person to person, but also the skin characteristics of the same person will change with factors such as age, moisture, season, etc. Therefore, many different skin impedance models have been proposed by different researchers. Montague, Tregear3 and Lykken models are three of the more popular models, which take into account the layered structure of the skin and are classified as RC layered models (see Figure 3). Among them, the ternary model proposed by Montague has been widely used because it is simple, intuitive and easy to simulate. The reason why this model is popular is mainly because it is easy to simulate, intuitive and easy to understand, and supports lumped parameter analysis.

Figure 3. Three main RC layering models of human skin: (a) Tregear, (b) Lykken, and (c) Montague

Figure 4. Impedance of the simplified Montague model and its dependence on the variance of electrical parameters

Typical ranges are: RSC = 104 ÷ 106 Ω cm2; RS = 100 ÷ 200 Ω cm2; CSC = 1 ÷ 50 nF/cm2.

The key to applying impedance analysis to TMDs is that injecting a conductive substance into a living material changes the impedance of the tissue itself, and this change is related to the amount of conductive substance delivered. Impedance - or more precisely, the change in impedance over time and space - is a key parameter that must be measured and then correlated with the amount of drug delivered to assess whether water has properly penetrated the tissue after transdermal injection in medical applications.

Figure 5. Cross-section of human skin layers and TMD and bioimpedance measurements

Given the noninvasive nature of bioimpedance analysis, two metal electrodes are used to represent the electrical sensor, connecting the analog front end (AFE) circuitry to the patient’s skin. This metal-to-nonmetal contact is another critical part of the overall circuitry, connecting the AFE to the electrical model of the human body. The interaction between charge carriers (electrons in the electrodes and ions in the human body) can have a significant impact on the performance of these sensors and needs to be considered specifically for each application. First, the interaction of the metal in contact with the ionic solution causes a localized change in the ion concentration in the solution near the metal surface. This phenomenon changes the charge neutrality of the region beneath the electrode, causing the electrolyte potential around the metal to be different from the rest of the solution, creating a potential difference between the metal and the bulk of the electrolyte, often referred to as the “half-cell potential.” Second, the DC component of the injected current causes electrode polarization.