Fake or adulterated medicines are a major healthcare security problem, but the huge growth in online pharmacies, coupled with supply chain issues, has made it easier for counterfeiters to profit from their activities. As one approach to help identify counterfeit medicines, an international research team has harnessed genetically engineered silk worms to create edible tags based on fluorescent silk proteins, which could be placed directly on pills or in a liquid medicine, and which contain codes that can be read by a smartphone app to verify their source and quality.

Reporting on their method in a paper in ACS Central ScienceEdible Matrix Code with Photogenic Silk Proteins,” Seong-Wan Kim, at the National Institute of Agricultural Sciences, Republic of Korea, and Young L. Kim, at Purdue University, claimed, “Owing to the unique silk protein structures, this all protein-based code is not only tolerated in liquid solutions with a high alcohol content but also exhibits biocompatibility, photostability, and thermal reliability … The edible code affixed to each medicine can serve as serialization, track and trace, and authentication at the dosage level, empowering every patient to play a role in combating illicit pharmaceuticals.”

Online pharmacies have taken off in recent years, delivering many types of medications directly to consumers’ homes. “Thirty-five thousand to 40 000 active online pharmacies worldwide, with 600 added every month, sell medicines to patients,” the authors wrote. Some of these businesses are legitimate, but others operate illegally, supplying counterfeit drugs that are substandard, incorrectly labeled or laced with unwanted components. In addition, global supply chain problems have made it easy for fake medications to infiltrate the market.

“Counterfeited medication not only poses a serious threat to patient safety and public health but also causes heavy economic losses, accounting for 10% of the global pharmaceutical trade and $200 billion annually,” the investigators further noted. In their paper the team cited figures suggesting that counterfeit malaria and pneumonia medicines may be responsible for some 250,000 child deaths every year.

To instill trust in consumers, pharma companies label the outside packaging of their products with barcodes, QR codes, holograms and radio frequency identifiers, allowing distributors and retailers to manage products throughout the supply chain. But there are no equivalent codes for consumers to verify the source of individual pills or liquid doses that are inside a container. Researchers have developed fluorescent synthetic materials, such as microfibers and nanoparticles, as tracking codes, but the substances are potentially unsafe to consume. As a result, the team noted, “Current anticounterfeiting methods are limited due to the toxicity of the constituent materials and the focus of secondary packaging level protections.”

The investigators wanted to see whether silk, which is an edible and “generally recognized as safe” material, could be placed directly onto medications and made to fluoresce, helping consumers make sure their purchases are what they claim to be.

To do this they genetically modified silkworms to produce silk fibroins—these are edible proteins that give silk fibers their strength—with either a cyan, green or red fluorescent protein attached. They dissolved the fluorescent silk cocoons to create fluorescent polymer solutions, which they applied onto a thin, 9-mm-wide film of white silk in a seven-by-seven grid. Shining blue violet, blue, and green light onto the grid revealed the 3D cyan, green and red square patterns, respectively.

Silkworms can produce edible, fluorescent silk cocoons (left side of left image); the proteins from the cocoons can be used in codes (right) to verify the authenticity of medications. [Adapted from ACS Central Science 2022, DOI: 10.1021/acscentsci.1c01233]

Using optical filters over a phone’s camera, an app the team designed can then scan the fluorescent pattern, decoding the digitized key using a deep learning algorithm and opening up a webpage, which might host information about the drug’s source and authenticity. Some liquid medications are alcohol-based, and encouragingly, when the researchers placed a coded silk film in a clear bottle of Scotch whisky, they found that the fluorescent code was still readable with the app. “Owing to the unique silk protein structures, this all protein-based code is not only tolerated in liquid solutions with a high alcohol content but also exhibits biocompatibility, photostability, and thermal reliability,” they stated.

Finally, they showed that the fluorescent silk proteins are broken down by gastrointestinal enzymes, indicating that the silk codes are not only edible, but also can be digested by the body. “While most fluorescent material-based codes primarily rely on synthetic materials and polymers for inedible applications, the constituent materials of the code reported in this study are all proteins (silk fibroin and fluorescent proteins) that can be easily denatured and degraded by gastric proteolytic enzymes in the digestive system,” the authors commented. “Overall, the digestibility, biocompatibility, and physical stability support the idea that all protein-based edible codes can be easily and safely consumable for on-dose or in-dose authentication in a reliable manner.”

They suggested that placing these edible code appliqués onto pills or in liquid doses could empower patients and their care providers to avoid the unintentional consumption of fake treatments. “We also envision that this edible code can potentially be used for other security and cryptographic applications that require obliteration immediately after being scanned,” they further suggested.

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