This article presents methods to fabricate and characterize a conformal, skin-like electronic system and protocols for the use in clinical applications, particularly on cutaneous wound management.
Recent advances in the development of electronic technologies and biomedical devices offer opportunities for non-invasive, quantitative assessment of cutaneous wound healing on the skin. Existing methods, however, still rely on visual inspections through various microscopic tools and devices that normally include high-cost, sophisticated systems and require well trained personnel for operation and data analysis. Here, we describe methods and protocols to fabricate a conformal, skin-like electronics system that enables conformal lamination to the skin surface near the wound tissues, which provides recording of high fidelity electrical signals such as skin temperature and thermal conductivity. The methods of device fabrication provide details of step-by-step preparation of the microelectronic system that is completely enclosed with elastomeric silicone materials to offer electrical isolation. The experimental study presents multifunctional, biocompatible, waterproof, reusable, and flexible/stretchable characteristics of the device for clinical applications. Protocols of clinical testing provide an overview and sequential process of cleaning, testing setup, system operation, and data acquisition with the skin-like electronics, gently mounted on hypersensitive, cutaneous wound and contralateral tissues on patients.
In clinical study and biomedical research, monitoring of wound healing has focused on an invasive method that is based on the histological evaluation of tissue morphologic change in wounds1,2. Recently, rapid advancements in electronic technologies enable the development of high-precision imaging and analysis tools that can visually inspect the wound healing process via digital imaging3,4 or confocal scanning microscopy and spectroscopy4,5. However, those imaging approaches require high cost, complicated optical tools and operations, and more importantly, patients need to be immobilized during testing. Therefore, there exists a need for new devices and systems that are quantitative, non-invasive, easy-to-use, inexpensive, and multifunctional to offer more accurate wound management.
Here, we introduce a skin-like electronic system that provides precise, real-time mapping of temperature and thermal conductivity and delivers a precise level of heating at wound sites via conformal lamination of the device non-invasively. This device presents a class of technology, skin-mounted epidermal electronic systems that are designed to match to mechanical and material properties (total thickness, bending stiffness, effective moduli, and mass density) of the epidermis6-9.
The device is designed in a biocompatible, skin-friendly, water-proof, and reusable form that can be washed and disinfected for clinical applications on patients10. The conformal electronic device mounted near the wound tissues captures the inflammation phase (one of wound healing process), caused by increased blood flow and enzymatic reactions to the wound11,12, through quantitative recording of temperature8 and thermal conductivity13, correlated to hydration. Experimental and computational studies determine an optimal mechanics design to accommodate natural motions and applied strains without mechanical fracture and capture the underlying physics of stretching mechanics of the skin-like electronics that laminates conformally on the skin surface, which offers acquisition of high fidelity signals.
The protocols described in this article present the methods of microfabrication for skin-like electronic systems, testing preparation including device cleaning, equipment setup in a clinical setting, and clinical applications for quantitative monitoring of temperature and thermal conductivity on cutaneous wounds.
The experiments for device fabrication, skin lamination, and characterization shown in Figures 1, 2, and 4 involved two volunteers, all performed in the Bio-interfaced NanoEngineering Laboratory at Virginia Commonwealth University (VCU), Richmond, VA, USA. This study was approved by the VCU Institutional Review Board (protocol number: HM20001454) and followed the research guidelines from the VCU Human Research. The device and clinical data shown in Figures 3 and 5 were acquired from the published article10 where the experiments on patients were conducted under the protocol (number: STU69718) approved by the Institutional Review Board, Northwestern University, Chicago, IL, USA.
1. Device Fabrication
NOTE: Figure 2 presents schematic illustrations for the overall fabrication process.
2. Clinical Testing
Figure 1 presents an overview of the characteristics of the conformal, skin-like electronic system, designed for quantitative, cutaneous wound management on patients. The multifunctional electronic device consists of microscale fractal structures3,14 and filamentary serpentine traces9,17 on a thin elastomeric membrane that offers exceptional mechanical stretchability and bendability. The compliant device that is completely enclosed by silicone layers enables gentle, reversible lamination on the skin through van der Waals interactions alone. The unique characteristics of the device include biocompatibility, waterproofness, ease-of-use, and mechanical flexibility for the use in realistic clinical settings.
The integration of hybrid materials such as polymers and a metal (silicone, polyimide, and copper) yields an electrically safe, waterproof, and biocompatible device (Figure 2A). An array of fractal (copper; Cu) resistors (35 µm in width and 3 µm in thickness) is placed at the neutral mechanical plane, by enclosed polyimide (PI, 1.2 µm in thickness) layers, to minimize applied bending strains on the core material (Cu) in clinical applications.
The total thickness of the device on a silicone membrane is only ~600 µm by offering extreme bendability. The schematic illustrations in Figure 2B describe the microfabrication process of the skin-like electronic system. The fabrication method combines the conventional microfabrication techniques (metallization, photolithography, and etching) with the newly developed transfer-printing techniques (retrieval, transfer, and bonding)9,14,18,19. This type of a device can be scaled up by using large scale transfer printing with an automated printing equipment20,21.
Figure 3 summarizes the mechanical stretchability and electrical functionality of the skin-like electronics, reported in the prior work10. Mechanics and materials study by the finite element method (FEM) offers the optimal system design to accommodate natural motions and applied strains, involved in the clinical use, without mechanical fracture (Figure 3A, top). The experimental study that presents mechanical behavior of the fractal structure with tensile strains up to 30% (Figure 3Aa, bottom) shows a good agreement with the FEM results. The device with microscale resistors is used for quantitative measurement of temperature and thermal conductivity and delivering precise, localized heating (Figures 3B – 3D). The calibration curve of electrical resistance according to temperature change was obtained by using an infrared camera and a high-sensitivity hot plate (Figure 3B). The evaluation method of the measured thermal conductivity was adapted from the 3 omega technique13 that uses 3 omega voltage signals at two different alternating current frequencies (Figure 3c). Applied electrical current (35 mA with 10 mW) to the fractal resistors occurs Joule heating, which offers controllable temperature actuation in a therapeutic mode (Figure 3D).
For practical, clinical applications, the suggested cleaning process of the hand-held device involves disinfection prior to use on patients. Spraying of a disinfectant solution on the waterproof device and following rinsing in water three times prepares the device for clinical testing (Figures 4A and 4B). The assessment of qualitative biocompatibility of the device utilizes a digital contact microscope to visually inspect the skin surface (Figure 4C), which investigates the change of the skin color and texture over multiple cycles of use on patients. An infrared (IR) thermography can make a quantitative assessment of the skin conditions for about two weeks (Figure 4D) since the side effects such as erythema causes temperature elevation22. The examined devices are laminated near the wound tissues and the contralateral location (as a reference). Recording of relevant parameters of temperature and thermal conductivity is conducted using a data acquisition system and IR imaging in an exam room (Figures 4E and 4F).
Figure 5 presents representative data of quantitative measurement of cutaneous wound healing on a patient from a prior study10. A series of photos in Figure 5A shows the monitoring process of wound healing with the skin-mounted device over the course of one month. The wound device dyed with a black ink was laminated near the surgical wound. Pen marks on the skin guided the mounting of the device on the same location for quantitative data comparison from day 1 to day 30. Measurement of temperature and thermal conductivity variation using an array of sensors in the device and comparison between the wound and reference sites captures the wound healing phase, inflammation (Figures 5B – 5E). The highly sensitive, six sensors in the wound device were able to capture minimal change of the body temperature and point intense inflammation on Day 3 (Figures 5B – 5C) and record variation of thermal conductivity (Figures 5D – 5E). A set of reference data was measured from the contralateral side as a control.
Figure 1. Overview of characteristics of the skin-like, wound monitoring device on a patient. Please click here to view a larger version of this figure.
Figure 2. Device fabrication. (A) Schematic illustration of the device layouts (left; layer 1: transparent silicone at the top, layer 2: PI, layer 3: Cu, layer 4: PI, and layer 5: black silicone at the bottom) and the completed, flexible/stretchable electronics (right). (B) Illustration of the step-by-step fabrication process (cross-sectional view). Please click here to view a larger version of this figure.
Figure 3. Device characteristics (reproduced with permission from Advanced Healthcare Materials, 3 (10), 1597-1607, 2014)10. (A) Finite element method (FEM) results (top) and the corresponding experimental results (bottom) of a fractal structure under uniaxial tensile strains up to 30 %. (B) Measurement of temperature using six sensors for device calibration. (C) Measurement of thermal conductivity using three sensors for device calibration. (D) Infrared thermography of the device that was used as a micro-heater with localized Joule heating. Please click here to view a larger version of this figure.
Figure 4. Clinical testing process. (A) Disinfection of the device using a cleaning solution. (B) Rinsing with water to clean the surface for clinical testing. (C) Skin assessment using a digital contact microscope (left) and magnified view of the skin (right). (D) Infrared thermography of the skin for quantitative assessment of temperature variation. (E) Clinical setting for wound management in an exam room. (F) Magnified photo of the laminated devices near the wound (right leg) and contralateral site (left leg) tissues. Please click here to view a larger version of this figure.
Figure 5. Representative data of quantitative management of wound healing with the device (reproduced with permission from Advanced Healthcare Materials, 3 (10), 1597-1607, 2014)10. (A) Photos of the wound with the device over the course of a month. (B) Recording of temperature distribution near the wound for one month with six sensors in the device (inset). (C) Recording of temperature distribution on a contralateral location as a reference. (D) Recording of thermal conductivity near the wound for one month with three sensors in the device (inset). (E) Recording of thermal conductivity on a contralateral location as a reference. Please click here to view a larger version of this figure.
This article highlights the methods and protocols to fabricate a conformal, skin-like electronics system that enables conformal lamination near the wound tissues, which offers quantitative measurement of skin temperature and thermal conductivity mapping on the skin.
The key features include the utilization of novel techniques of materials transfer printing and hard-soft materials integration to design and develop the flexible/stretchable, soft electronic device. The use of biocompatible, electrically safe, silicone layers that completely enclose the device allows the electronics to be used for the first time in a realistic clinical setting, cutaneous wound management on patients.
In the protocol of device preparation, the following steps are critical to enhance the fabrication yield. Wet chemical etching of the metal layer (Cu) in the device should involve extreme time control since the etching rate is faster than other metals. The major drawback of Cu over-etching is the change of the combined electrical resistance of the device, which requires additional optimization and adjustment of equipment parameters in the data acquisition system. It should be noted that multiple layers of a water soluble tape needs to be used to avoid fracture during retrieval process of the electronics dissociated from a carrying PDMS. After the transfer printing of electronics with a water soluble tape, it is very important to completely remove any residue from the dissolvable material (polyvinyl alcohol) using multiple rinsing with DI water. In the process of cable bonding to the device, extra caution is required since the device is on a highly compliant and bendable material (low-modulus silicone), while the cable is thin plastic. Thus, careless handling of the device may lead to cause fracture or plastic deformation of metal resistors.
The device characterization and evaluation reveals some limitations in the clinical use. The data acquisition process using a thin cable still requires the connection with a series of equipment, which hinders continuous, long-term recording of skin parameters, relevant to wound management. The measured electrical signals accompany the downstream analysis for diagnosis, which limits on-site/point-of-care use of the device and system.
Further improvements of the electronic system include the development of the integration of a wireless power supply and telecommunication system with the device and smart-app interface that monitors the skin parameters, collects the data, and diagnoses automatically for alerting to medical personnel.
In conclusion, new strategies and methods of mechanical analysis and materials processing present a class of technology to develop a conformal, skin-like electronic system for quantitative, cutaneous wound management on patients. The biocompatible, waterproof, easy-to-use, mechanically compliant device provides the functions and characteristics for the use in the clinical settings. This type of electronic system has a potential to address important issues in chronic wound management.
The authors have nothing to disclose.
This work was supported by the startup funding from the School of Engineering, Virginia Commonwealth University and some of electronic devices were prepared at the microfabrication facilities in the Wright Virginia Microelectronics Center. We acknowledge researchers who made contributions for the device and clinical data (Figures 3 and 5 in this paper), acquired from the published article10. W.-H.Y thanks Yoshiaki Hattori for the custom-made, data recording software.
3" Silicon wafer | University Wafer, USA | N/A | Use as carrier to fabricate the device |
Acetone | Fisher Scientific, USA | A18-1 | Use to clean a wafer and to remove photoresist |
Isopropanol (IPA) | Fisher Scientific, USA | A459-1 | Use to clean a wafer |
AZ4620 photoresist | AZ Electrionic Materials, USA | N/A | Use to make patterns on metals and polymers |
AZ400K developer | AZ Electrionic Materials, USA | N/A | Use to develop AZ4620 photoresist |
Chromium etchant | Transene, USA | 1020AC | Use to etch Cr layer of device |
Copper etchant | Transene, USA | ASP-100 | Use to etch Cu layer of device |
Sylgard 184 Silicone Elastomer Kit (PDMS) | Dow Corning, USA | 39100000 | Use as a substrate for 'dry' retrieval |
PI2545 polyimide | HD MicroSystem, USA | N/A | Use to encapsulate metal layer |
Solaris | Smooth-On, USA | N/A | Use as substrate and to encapsulate device |
Petridish | Carolina, USA | 741255 | Use as mold to make substrate |
Water-Soluble Wave Solder Tape 5414 | 3M, USA | AM000000217 | Use to retrive device from PDMS layer |
High Activity Liquid Stainless Steel Flux | Worthington, USA | 331929 | Use to remove oxidation layer on Cu |
Flexible, micro-film cable | Elform, USA | N/A (customized) | Use to make the electrical connection between the electronic device and the data acquisition system |
pH Neutral Cleaner | Australian Gold, USA | N/A | Use as disinfectant solution to clean device in clinical testing |
Solder | Kester, USA | 24-6337-9703 | Use as material to solder hard wires |
Ultraviolet lamp | Cole-Parmer, USA | 97600-00 | Use to activate PDMS layer as hydrophilic surface |
Multiplexer | FixYourBoard, USA | U802 | Use to acquire measurements from six sensing components |
DC/AC current source | Keithley, USA | 6221 | Use to supply current |
SMD Digital Hot Air Rework Station | Aoyue, China | 968A+ | Use to solder hard wires, to electrically connect between the device and external instruments |
Infrared camera | FLIR, USA | 435-0001-01-00 | Use to take infrared images in experiment |
Digital multimeter | Fluke, USA | 117 | Use to check electrical connection |
Lock-in amplifier | Stanford Research System, USA | SR830 | Use to perform four-point-probe-measurement |
Electron beam evaporator | 9 scale Vacuum Products, USA | N/A (customized) | Use to deposit thin films (Cu and SiO2) |