Real-time monitoring of chronic or surgical wounds for signs of infection or inflammation can drastically improve the health outcomes from these issues. Such monitoring requires that sensors be embedded deep within the tissue. In addition, the acquired information needs to be communicated to the doctor/caregiver so that patient-specific treatments can be optimized. Although recent miniaturization of sensors, as well as the fabrication of smart materials, has allowed the development of the necessary devices (e.g., electrocardiogram electrodes, temperature sensors, pH sensors, and flexible batteries) to continuously monitor a patient's health status,1–5 there are still several challenges that need to be overcome. Such problems include the mismatch between mechanical and topographical properties of semiconductor-based electronics and biological tissues, as well as flexibility and biocompatibility issues.
To date, materials such as polyimide6 and parylene7 have been used extensively for implantable diagnostic devices and smart wearable systems, but the necessary microfabrication techniques are expensive. Paper has also emerged as a promising substrate for the devices because of its universal availability, environmental friendliness, low cost, and ease of fabrication.8–10 In addition, nanofibrous polymeric substrates have recently been developed to fabricate elastic and flexible electronics that can be sutured.2 These different substrates all hold great promise for the fabrication of wearable and implantable devices. However, the overall structure and form of the substrates is essentially planar (and not necessarily flexible), which means they are limited to interfacing with 2D tissue surfaces (e.g., scalp or skin).1, 2,6
In our recent work,11 we have therefore proposed flexible and biocompatible threads—with embedded sensors, actuators, and electronics—to address the challenges associated with wearable and implantable devices. Our integration of several functional components into the threads means that they can penetrate (as the threads are sutured and woven through) multiple layers of tissue in a 3D topology. In particular, we have fabricated a suite of physical and chemical sensors from nanomaterial-infused conductive threads. These can be integrated with microfluidic networks, i.e., for direct integration with tissues and for monitoring of physiochemical tissue properties. We have also used thread-based flexible interconnects to connect the sensors to electronic circuitry, i.e., for readout, signal conditioning, and wireless transmission (see Figure 1).11
Schematic illustration of the thread-based toolkit of physical and chemical sensors, microfluidic channels, and interconnects.11
We used a low-cost dip-coating approach to fabricate our functional threads. This technique requires no specialized facilities or equipment, making it a cost-effective platform. In our fabrication process, we embroidered hydrophilic threads onto a highly hydrophobic woven fabric to form the microfluidic networks. We also infused the conductive threads with nanomaterials (e.g., carbon nanotubes, carbon nanopowders, and polyaniline) to achieve the thread-based electrodes for in vitro and in vivo measurements of various parameters, such as glucose, pH, temperature, and strain. The outputs from the sensors were connected to the readout electronics in a different layer (see Figure 1) of electronics for signal processing and wireless communication (e.g., to a smartphone or a computer).
In our study, we have demonstrated the effectiveness of our ‘smart’ threads, e.g., as microfluidic channels or flow carriers. The wicking property and flexibility of the threads makes them great candidates for the creation of 3D microfluidic circuits.12 The threads can thus be used to sample interstitial fluids and to transport them, in vivo, through tissues. Indeed, we successfully fabricated a topologically complex 3D microfluidic system for the 3D transportation of liquid. To do this—see Figure 2(a)—we sewed a hydrophilic thread into a polyethylene terephthalate film. This microfluidic system can be used to deliver different samples on a single platform, and we verified—see Figure 2(b)—its ability to deliver samples in biologically relevant substrates (e.g., chicken skin). In this case, the sample (i.e., blue dye) was wicked along the suture without significant leakage (because of the presence of a fat layer in the chicken skin).
(a) 3D microfluidic network pattern created by sewing a thread onto a polyethylene terephthalate film. Three different colored fluids were wicked into the system without them mixing. (b) Illustration of wicking of blue dye into a sutured thread patterned onto chicken skin (images were obtained after 10, 30, and 50 seconds).11
We have also presented a thread-based pH sensor that consists of conductive threads and a microfluidic splitter with three channels for the delivery of a sample to sensing chambers (see Figure 3). We fabricated this microfluidic splitter by patterning hydrophilic threads onto a hydrophobic woven fabric. In addition, we used carbon nanotubes (coated with doped polyaniline) and silver/silver chloride threads as the working and reference electrodes for our pH measurements (following the potentiometric approach). The results of our pH measurements—of various buffer solutions (in a pH range of 3–8), where the threads were passed through chicken skin—demonstrate that the biological fluid analogs are confined to the thread-based microfluidic channel, without significant leakage into the chicken fat.
Optical images of a multiplexed microfluidic pH sensor assay that consists of conductive threads and a three-channel microfluidic splitter.11
PANI: Polyaniline. CNT: Carbon nanotube. Ag: Silver. AgCl: Silver chloride.
In summary, we have developed flexible and biocompatible threads that can be embedded with a variety of sensors, actuators, and electronics. These threads can be sutured/woven through multiple layers of tissue to provide unique in situ measurements that are not possible with other flexible diagnostic platforms. Our threads could thus have a wide range of applications, e.g., as smart sutures for surgical implants or smart bandages for monitoring of wound healing. They could also be integrated with textiles or fabrics to realize personalized health monitors, or even be embedded into tissue-engineered constructs for organ-on-chip platforms. In particular, wound fractures and orthopedic implants (which have complex 3D structures) would greatly benefit from the implantation of physical (e.g., strain) and chemical (e.g., pH or inflammation) sensors that can monitor the local tissue environment during healing and provide valuable information for the optimization of patient-specific treatments. In our work so far, we have demonstrated the promise of our thread-based diagnostic platforms for both in vitro and in vivo studies (e.g., to measure strain, as well as gastric and subcutaneous pH). We now need to conduct further work to explore the long-term biocompatibility of different composite threads for diverse applications. In addition, we envision extending our approach by functionalizing the threads with sensing chemistries so that proteins, DNA, and other biomarkers can be measured directly within tissue.
Harvard-Massachusetts Institute of Technology (MIT)
Division of Health Sciences and Technology (HST)
Brigham and Women's Hospital
Pooria Mostafalu is currently a postdoctoral fellow at Harvard-MIT HST, Brigham and Women's Hospital, and the Wyss Institute for Biologically Inspired Engineering. His research interests are flexible electronics, and microelectromechanical systems devices for biomedical applications.
Sameer R. Sonkusale
Sameer Sonkusale is a professor of electrical and computer engineering. His research interests are in the general area of nanoscale sensors, biomedical circuits, flexible electronics, as well as lab-on-chip and biomedical microdevices.
1. D.-H. Kim, N. Lu, R. Ma, Y.-S. Kim, R.-H. Kim, S. Wang, J. Wu, et al., Epidermal electronics, Science 333, p. 838-843, 2011.
2. A. H. Najafabadi, A. Tamayol, N. Annabi, M. Ochoa, P. Mostafalu, M. Akbari, M. Nikkhah, et al., Biodegradable nanofibrous polymeric substrates for generating elastic and flexible electronics, Adv. Mater. 26, p. 5823-5830, 2014.
3. M. L. Hammock, A. Chortos, B. C.-K. Tee, J. B.-H. Tok, Z. Bao, 25th anniversary article: the evolution of electronic skin (e-skin): a brief history, design considerations, and recent progress, Adv. Mater. 25, p. 5997-6038, 2013.
4. J.-Y. Sun, C. Keplinger, G. M. Whitesides, Z. Suo, Ionic skin, Adv. Mater. 26, p. 7608-7614, 2014.
5. J. R. Windmiller, J. Wang, Wearable electrochemical sensors and biosensors: a review, Electronanalysis 25, p. 29-46, 2013.
6. J. Viventi, D.-H. Kim, L. Vigeland, E. S. Frechette, J. A. Blanco, Y.-S. Kim, A. E. Arvin, et al., Flexible, foldable, actively multiplexed, high-density electrode array for mapping brain activity in vivo, Nat. Neurosci. 14, p. 1599-1605, 2011.
7. P. Mostafalu, S. Sonkusale, Flexible and transparent gastric battery: energy harvesting from gastric acid for endoscopy application, Biosens. Bioelectron. 54, p. 292-296, 2014.
8. E. Carrilho, A. W. Martinez, G. M. Whitesides, Understanding wax printing: a simple micropatterning process for paper-based microfluidics, Anal. Chem. 81, p. 7091-7095, 2009.
9. X. Li, J. Tian, T. Nguyen, W. Shen, Paper-based microfluidic devices by plasma treatment, Anal. Chem. 80, p. 9131-9134, 2008.
10. A. W. Martinez, S. T. Phillips, B. J. Wiley, M. Gupta, G. M. Whitesides, FLASH: a rapid method for prototyping paper-based microfluidic devices, Lab Chip 8, p. 2146-2150, 2008.
11. P. Mostafalu, M. Akbari, K. A. Alberti, Q. Xu, A. Khademhosseini, S. R. Sonkusale, A toolkit of thread-based microfluidics, sensors, and electronics for 3D tissue embedding for medical diagnostics, Microsyst. Nanoeng.
2, p. 16039, 2016. doi:10.1038/micronano.2016.39
12. X. Li, J. Tian, W. Shen, Thread as a versatile material for low-cost microfluidic diagnostics, ACS Appl. Mater. Interfaces 2, p. 1-6, 2010.