Squid-inspired technology could replace needles for medications and vaccines

Using jet propulsion inspired by squid, researchers demonstrate a microjet system that delivers medications directly into tissues, matching the effectiveness of traditional needles.

In a recent study published in Nature, a research team led by scientists from Massachusetts Institute of Technology and Novo Nordisk explored a novel, needle-free microjet system to deliver drugs directly into the gastrointestinal tract.

Inspired by the jet propulsion system in cephalopods, these devices were designed to efficiently administer macromolecules such as insulin and ribonucleic acid (RNA) via precise, high-pressure jets into the gastrointestinal tract, potentially improving drug absorption and addressing the challenges associated with traditional injection-based delivery methods.

Background

Drug delivery for macromolecules has depended on needle-based injections, which raises issues such as the need for medical training, the risk of needle-related injuries, and the challenge of disposing of sharps. In recent times, the development of ingestible devices has offered a convenient alternative, potentially enhancing patient compliance.

However, current oral delivery devices struggle to effectively deliver large molecules, such as proteins, due to their vulnerability to digestive breakdown. Many oral systems also fail to achieve bioavailability levels comparable to those of subcutaneous injections. Furthermore, although robotic and autonomous devices have shown some success with self-directing and needle-free drug delivery, these methods have remained largely underexplored for gastrointestinal applications.

About the study

In this study, inspired by the natural propulsion mechanisms observed in cephalopods, the researchers aimed to develop a jet-based drug delivery approach to enhance the safe and effective delivery of large molecules in gastrointestinal tissues. They developed and tested a series of microjet devices (MiDe systems) designed to deliver drugs directly into the gastrointestinal tract.

Four device configurations were created: two autonomous, self-activating versions (MiDeRadAuto and MiDeAxAuto) and two versions compatible with endoscopic guidance (MiDeRadEndo and MiDeAxEndo). Furthermore, the orientation of each device was optimized for specific gastrointestinal tract sections. The radial models were designed to target tubular structures such as the small intestine, while the axial models were suited for wider areas in the stomach.

The devices were first calibrated in laboratory settings through in vitro and ex vivo studies. During these tests, the researchers varied nozzle diameter, input pressure, and jet angle to determine optimal conditions for effective tissue penetration.

Ex vivo trials on porcine gastrointestinal tissue measured the fluid delivery depth and distribution in the tissue layers using computed tomography (CT) to visualize the fluid spread. Following these tests, the researchers fine-tuned the device pressure and nozzle dimensions to produce high-pressure jets suitable for different gastrointestinal regions.

Additionally, in the in vivo trials, the MiDe devices delivered therapeutic agents such as insulin, glucagon-like peptide 1 (GLP-1) analogs, and small interfering RNA (siRNA) into specific gastrointestinal sites in pigs and dogs. Subsequently, the researchers collected blood samples at regular intervals to measure systemic bioavailability.

Moreover, high-speed imaging was used to capture the jetting dynamics, enabling the researchers to assess the stability and recoil of the device. Safety and precision tests were also conducted to confirm the suitability of the device for use in the gastrointestinal tract without causing adverse effects or damage to surrounding tissues.

Results

The researchers demonstrated that MiDe devices significantly improved the delivery and bioavailability of macromolecules within the gastrointestinal tract. The devices achieved high systemic absorption for insulin, GLP-1 analogs, and siRNA, with performance comparable to subcutaneous injections.

Specifically, the radial endoscopic device (MiDeRadEndo) delivered GLP-1 with a 67% bioavailability in pig intestines, while the axial endoscopic device (MiDeAxEndo) achieved an 82% bioavailability for siRNA in the stomach. Autonomous devices, MiDeRadAuto and MiDeAxAuto, demonstrated 31% and 23% bioavailability, respectively, for insulin in pigs.

The results showed that bioavailability was influenced by factors such as jet angle, distance from tissue, and pressure level. A 40% decrease in volumetric delivery efficiency (VDE) was observed when the jet angle reached 45° relative to the tissue.

Furthermore, while the self-orienting design of MiDeAxAuto enabled stable positioning in the stomach, MiDeRadAuto was seen to maintain a co-axial orientation in the intestine despite some variability due to animal movement. Histological analysis also confirmed that the jets delivered therapeutic agents deep within the target tissue layers without causing damage.

The radial devices minimized recoil with a dual-nozzle design, which also enhanced stability. Moreover, the devices demonstrated reliable safety and stability across in vivo and ex vivo tests, suggesting that MiDe systems can safely and effectively deliver large molecules within the gastrointestinal tract.

Conclusions

Overall, the findings demonstrated that the needle-free, microjet-based MiDe systems for drug delivery into the gastrointestinal tract achieved bioavailability levels similar to subcutaneous injections while safely and effectively targeting specific gastrointestinal regions. These findings indicated that the MiDe platform could be used to advance oral drug delivery technology, making it feasible to deliver macromolecule therapies directly into the gastrointestinal tract.