Ultrasound-Responsive Core-Shell Microspheres for On-Demand Release of Bioengineered rhBMP-2 Enhances Bone Regeneration

Every year millions of patients worldwide suffer from bone defects caused by trauma or surgery. Recombinant human bone morphogenetic protein-2 (rhBMP-2) is a potent osteoinductive factor, yet its clinical application has been severely constrained by high production costs and adverse effects—such as ectopic bone formation—resulting from uncontrolled burst release from conventional carriers.

To that end, a research team from Southeast University, in a study published in the journal Supramolecular Materials, has developed an innovative strategy that may overcome these long-standing barriers.

The researchers first established a high‑yield Pichia pastoris expression system to produce highly active rhBMP‑2 at substantially reduced cost. They then encapsulated the protein into chitosan–sodium tripolyphosphate core–shell microspheres.

“These microspheres exhibited remarkable stability under physiological conditions, retaining over 80% of their payload for 21 days,” shares Dr. Ting Wang, co‑corresponding author of the study. “Upon exposure to low‑intensity ultrasound, more than 80% of the encapsulated rhBMP‑2 was released within 15 minutes.”

Beyond acting as a trigger, ultrasound was found to reversibly modulate the pore structure of the microspheres via cavitation, enabling an “on–off” release profile while simultaneously activating the YAP/TAZ mechanotransduction pathway to directly promote osteogenic differentiation of stem cells.

“We have demonstrated for the first time that ultrasound serves a dual role—acting as both a switch for drug release and a biological stimulator of bone regeneration,” says Wang. “In a rat calvarial defect model, the treatment group achieved a 50.3% reduction in bone void volume and a 1.9‑fold increase in new bone area at four weeks, significantly outperforming all control groups.”

“Notably, the yeast expression system addresses the cost bottleneck, while the ultrasound‑responsive design enables precise delivery of the growth factor exactly when needed, avoiding the safety risks associated with excessive dosing,” notes co-corresponding author Dr. Yan Cai.

The team is now optimizing microsphere size to accommodate larger segmental bone defects, paving the way for clinical translation of this intelligent, cost‑effective bone repair platform.

Contact author details:

Chenglong Cai (caiclong@163.com), Ting Wang (tingwang@seu.edu.cn), Yan Cai (yancai@seu.edu.cn), State Key Laboratory of Digital Medical Engineering, Jiangsu Key Laboratory for Biomaterials and Devices, School of Biological Science and Medical Engineering, Southeast University, Nanjing, China.

Funder:

This work was supported by the Key Project of the National Natural Science Foundation of China (Grant No.52533005) and National Natural Science Foundation of China (Grant No. 12472307).

Conflict of interest:

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

See the article:

Chenglong C., et al. Ultrasound-responsive core-shell microspheres for on-demand release of bioengineered rhBMP-2 enhances bone regeneration, Supramolecular Materials, Volume 5, 2026, Pages 100138, https://doi.org/10.1016/j.supmat.2026.100138.