Painless oral delivery of biopharmaceuticals using microneedle robots driven by intestinal peristalsis

Compared with injection, oral administration requires less professional skills and is more acceptable to patients, so it has always been the preferred method of administration. However, biological drugs such as peptides, proteins and nucleic acids are easily inactivated in the harsh biochemical environment of the gastrointestinal tract, and it is difficult to pass through the absorption barrier of the gastrointestinal mucosal cells. The direct oral bioavailability is extremely limited (less than 1%), resulting in these biological drugs still being mainly delivered by parenteral injection. Parenteral injection, especially drugs such as insulin that require long-term injection, will inevitably cause pain and skin infections. Therefore, it is urgent to overcome the difficulties of oral delivery of biological drugs and improve the bioavailability of oral drugs.

Although research has developed sustained-release devices such as adhesive patches and hydrogel retention that extend drug release time, they have not truly overcome the physiological barriers of the digestive tract, and the clinical effect still needs to be verified. The gastrointestinal microneedle device directly uses drug-loaded microneedles to penetrate the gastrointestinal wall that lacks pain nerves for drug delivery. It can directly break through the absorption barrier of the gastrointestinal tract and will not cause pain and discomfort to patients. It is an emerging oral drug delivery method. However, the one-time trigger mode driven by springs or balloons proposed in previous studies is difficult to ensure the reliability of microneedle penetration, and external field control methods such as magnetic fields still require additional equipment. At the same time, the use of metal springs, non-degradable plastics or magnetic particles to make oral drugs is bound to cause concerns among patients. Therefore, it is of great significance to develop a new oral drug delivery device to solve the above problems.

Recently, Professor Zhang Mingjun and Associate Professor Xu Jing of the School of Medicine at Tsinghua University were inspired by the swelling of the porpoise and jointly developed a painless and degradable drug delivery robot that uses intestinal peristalsis to drive microneedles to penetrate the intestinal wall. Animal experiments on miniature Bama pigs showed that the bioavailability of insulin delivered by the microneedle robot reached 23.6%, and it was able to pass through the digestive tract of miniature pigs smoothly without causing intestinal obstruction. Intestinal histological analysis showed that the intestinal wall of the microneedle punctured part recovered rapidly and the inflammatory response was limited. The related work was published in the journal Sciencevances under the title "Pain-free al delivery of bio drugs using instinal peristalsis–tuated microneedle robots".

In this study, the researchers designed a three-layer microneedle robot. The innermost layer is super absorbent hydrogel particles synthesized by high-viscosity sodium carboxymethyl cellulose (SCMC), and the middle layer is a stretchable film formed by mixed cross-linking of polyvinyl alcohol (PVA) and acrylamide (AAm). On the one hand, the film wraps the internal hydrogel particles, and on the other hand, it serves as a substrate for the outermost drug-loaded microneedles. The drug-loaded microneedle is a double-layer barb structure made of a cross-linked mixture of polyethylene glycol diacrylate (PEGDA) and polyethylene glycol (PEG), and the upper barbs are loaded with biological drugs. The microneedle robot can be loaded into a No. 00 medical enteric-coated capsule, and can pass smoothly through the highly acidic environment of the stomach after oral administration. After reaching the small intestine, the enteric-coated capsule melts, and the microneedle robot begins to absorb water and swell, while the microneedle is pierced into the intestinal wall under the extrusion of intestinal peristalsis. When the intestine relaxes, the barbs of the drug-loaded microneedle break and remain in the intestinal wall, the drug continues to dissolve and the microneedle gradually degrades, while the main body of the microneedle robot is constantly squeezed and ruptured with intestinal peristalsis, and is gradually excreted from the body (Figure 1).

Figure 1 Intestinal peristalsis-driven porcupine-inspired microneedle robot for oral delivery of biopharmaceuticals

In order to design the size of the robot to ensure that the microneedle can penetrate the intestinal wall when squeezed by the small intestine, the researchers conducted intestinal pressure measurement and microneedle penetration evaluation on Bama mini pigs. The intestinal peristaltic pressure of robots of different sizes was measured by capsule-shaped pressure measurement, and the minimum size of the microneedle robot was determined by comparing it with the force required for the microneedle to penetrate the small intestinal tissue. Then, by mechanical analysis of the expansion process of the microneedle robot, the size of the microneedle robot before expansion, the elastic modulus of the stretchable membrane, and the filling rate of the hydrogel particles were designed. It can be placed in an enteric-coated capsule, and can reach a sufficient size after expansion to generate sufficient peristaltic pressure, while maintaining sufficient hardness to support the drug-loaded microneedle to penetrate the intestinal wall (Figure 2). In addition, the researchers designed the drug-loaded microneedle into a double-layer barbed structure, which can ensure that the drug-loaded layer can break in the intestinal wall when the intestine is dilated, so as to achieve continuous drug delivery (Figure 3).



Figure 2 Intestinal pressure measurement and microneedle puncture experiment



Figure 3 Barbed microneedle design and experiment

Finally, experiments conducted on Bama miniature pigs showed that the use of the barbed microneedle robot proposed in this study to deliver insulin can achieve a bioavailability of 23.6%, which is 37.7 times that of direct oral insulin. At the same time, the comparison with the delivery effect of the barbless microneedle robot also illustrates the contribution of the barb structure. In addition, X-rays taken for a week showed that the five barium sulfate capsules delivered to the esophagus of the miniature pigs all passed through the pig's digestive tract smoothly, and did not cause obvious abnormalities such as intestinal obstruction and changes in eating habits in the pigs. The above experiments verified the effectiveness and safety of the microneedle robot as a platform for oral delivery of biological drugs (Figure 4).



Figure 4 Verification of the effectiveness and safety of the microneedle robot

In summary, the intestinal peristalsis-driven microneedle robot proposed in this study provides a promising platform for the oral delivery of biological drugs, which has the potential to improve the comfort of treatment in multiple areas. However, since the frequency and intensity of intestinal peristalsis vary greatly among different people, future clinical studies may need to consider how to make it work within a larger range of individual differences.

Professor Zhang Mingjun of the School of Medicine and Associate Professor Xu Jing of the Department of Mechanical Engineering of Tsinghua University are the co-corresponding authors of the paper, and doctoral student Gao Xize of the School of Medicine and doctoral student Li Jiacong of the Department of Mechanical Engineering are the co-first authors. This research was funded by the National Natural Science Foundation of China and other projects.

Paper link:

https://www.science.org/doi/10.1126/sciadv.adj7067

Review editor: Liu Qing