To help block the flow of counterfeit medications, researchers at Purdue University and the National Institute of Agricultural Sciences in South Korea developed edible fluorescent tags that can be coded and added to pills or liquid medicine. Each tag is made from photoluminescent natural biopolymers and contains an imperceptible matrix code of information about the pharmaceutical. The code can be read with a smartphone app. The timeliness of the development stems from supply chain issues and the rise in the number and popularity of online pharmacies, which have made it easier to introduce counterfeit versions of drugs and medicines to market. Although fluorescent synthetic materials are already available for use as tracking codes, the substances from which they are made are potentially unsafe to consume. In search of an edible, safe, sustainable material that could be placed directly onto medications and made to fluoresce, the researchers turned to silk. They genetically modified silkworms to produce silk fibroins — edible proteins that give silk fibers their strength — with a cyan, green, or red fluorescent protein attached. They then dissolved the fluorescent silk fibroins to create fluorescent polymer solutions, which they applied onto a thin, 9-mm-wide film of white silk placed on a square grid. When the researchers shined blue violet, blue, and green light onto the grid, square 3D patterns in cyan, green, and red appeared, respectively. The researchers then developed a fabrication method for generating imperceptible, multidimensional matrix codes that could be used to encrypt information in a manner similar to conventional barcodes or QR codes. The genetically encoded silk fibroin was used as the material for the matrix codes. Silkworms can produce edible, fluorescent silk cocoons (left side of left image). The proteins from the cocoons can be used in edible codes (right) to verify the authenticity of medications. Courtesy of ACS Central Science, 2022, DOI: 10.1021/acscentsci.1c01233. The edible codes can be read on a smartphone by placing optical filters over the phone’s camera. An app designed by the researchers is used to scan the fluorescent pattern and extract a digitized security key augmented by a deep neural network for overcoming code patterns erroneously formed during fabrication, and a cryptographic hash function for enhanced security. To reliably extract a digitized key from the edible matrix code, the researchers used a 2D convolutional neural network that takes raw fluorescence images of the code as input and returns a binary output key of each fluorescence emission color. After establishing the cryptographic key extraction protocol, the researchers used a smartphone to demonstrate on-dose authentication of an oral-dosage medicine under a simulated setting. To test the ability of the fluorescent code to work with alcohol-based liquid medicines, the researchers placed a coded silk film in a bottle of whisky and found that the fluorescent code was still readable with the app. Investigation of the digestibility of the proposed edible codes showed that the fluorescent silk proteins are broken down by gastrointestinal enzymes. To ensure that the edible code could support dosage-level anticounterfeit measures and authentication features, they characterized the biocompatibility, photostability, thermal stability, and long-term reliability of the code. An edible code affixed to individual doses of medicine could serve as serialization, track and trace, and authentication at the dosage level, enabling each patient to play a role in preventing the disbursement of fake pharmaceuticals. The proposed all-protein-based matrix codes for single-dose medications could also help patients and caregivers prevent the unintentional use of counterfeit medicines. In a hospital pharmacy setting, the edible code could also be used to create single-unit packages and unit-dose packages to lower the risk of dispensing errors. The researchers also believe that the edible code could potentially be used for other security and cryptographic applications that require obliteration immediately after being scanned. The research was published in ACS Central Science (www.doi.org/10.1021/acscentsci.1c01233).