Rice University engineers have developed a new strategy for controlling how therapeutic peptides are released from gelatin-based materials, a step that could make the small but powerful molecules more useful in tissue engineering and drug delivery.
Peptides can be designed to encourage biological processes such as bone formation, blood vessel growth and tissue repair. Compared with larger proteins, they are often more stable and easier to manufacture. Their small size, however, creates a major delivery challenge: When placed inside water-rich materials such as hydrogels, peptides can diffuse out rapidly rather than remaining at the treatment site for the days or weeks needed to support healing.
In a new study published in Cell Biomaterials , Rice engineers, led by Antonios Mikos , the Louis Calder Professor of Bioengineering and Chemical and Biomolecular Engineering, in collaboration with researchers at Kyoto University, addressed that problem by adjusting the electrical charge of a model bone-promoting peptide and the gelatin microparticles used to carry it. They found that electrostatic attraction between the peptide and the gelatin — similar to the attraction between opposite poles of magnets — could slow the peptide's release for as long as two to three weeks.
"Therapeutic peptides are promising because they can be designed to perform very specific biological functions, but their small size makes it difficult to keep them in place and release them over time," said Mikos. "By modifying the peptide's charge, we were able to strengthen its interaction with the gelatin carrier and substantially extend its release."
The study focused on osteogenic growth peptide, or OGP, a small molecule associated with bone formation. The researchers added short sequences of charged amino acids to the peptide, creating positively charged, negatively charged and electrically balanced versions. They then loaded the modified peptides into gelatin microparticles. Gelatin was selected because it is biocompatible, commonly used in regenerative medicine and naturally carries an electrical charge that can vary depending on how it is processed; that versatility allowed the team to systematically study how the charge of both the peptide and the carrier affected loading and release.
The researchers also attached charged peptide sequences directly to some of the gelatin particles to determine whether adding more concentrated charge sites to the carrier would provide additional control. They measured how much peptide the particles could hold, how quickly the peptide was released and whether the modifications changed the particles' swelling or degradation.
The results showed that the electrical charge added to the therapeutic peptide itself played the largest role in determining its behavior. Positively charged peptide modifications generally increased retention within the gelatin particles and reduced the initial "burst release" that often occurs when a drug delivery material is first placed in a liquid environment.
The charge of the gelatin carrier also influenced delivery, but adding extra charged sequences directly to the gelatin had a more limited effect and did not significantly change the particles' swelling or overall degradation.
Notably, one positively charged version of the peptide was released gradually for 14 to 21 days under enzyme-containing conditions designed to mimic aspects of a healing tissue environment. Previous hydrogel-based approaches have often struggled to deliver small, soluble peptides for more than several days without chemically binding them to the carrier.
"This study demonstrates that relatively simple charge modifications can provide a powerful way to tune peptide delivery," said Emily Jiang , the study's first author and a doctoral student in Mikos' lab. "Because the peptide is held through noncovalent interactions rather than permanently attached to the carrier, it can still be released in its soluble form and potentially remain available to interact with surrounding cells and tissues."
This approach could help researchers tailor how long a therapeutic peptide remains active in the body, potentially allowing for the design of a delivery system that releases treatments at different rates. Although the team evaluated a peptide linked to bone growth in this study, the same strategy could potentially be adapted for other peptides that support blood vessel formation or tissue regeneration.
"This platform gives us several variables that can be adjusted to create a desired release profile," Mikos said. "The broader goal is to develop adaptable delivery systems that can provide therapeutic peptides at the right location and over the right period of time for a particular regenerative application."
This research was supported by the National Scientific Foundation Graduate Research Fellowship Program as well as the Rice Academy Fellows and the National Institutes of Health Interdisciplinary Translational Postdoctoral Program.
