3D Bioprinting Method Enhances Bone Repair by Promoting Blood Vessel Growth

Poor vascularization limits nutrient delivery, slows healing, and undermines graft integration. To overcome this limitation, researchers have developed a way to program living, 3D-printed bone-forming cell clusters to promote vessel growth. The approach aims to create vascularized bone tissue that can better survive and integrate after implantation.

An interdisciplinary team at Penn State created bioprinted spheroids—compact clusters of living cells—designed to regenerate bone while supporting new vessel formation. The team introduced specific genetic “switches” into undifferentiated, commercially sourced stem cells before assembling them into spheroids and printing them into a microgel scaffold. The findings, published online in Chemical Engineering Journal, were validated in laboratory experiments and in mouse models.

The technology uses aspiration-assisted bioprinting to pick up individual spheroids and place them with precise spacing inside the scaffold. This control helps organize coordinated cellular networks, which is essential for forming complex tissues. The method aims to overcome a long-standing hurdle in bone tissue engineering, where lack of vascularization has limited the thickness and function of regenerated bone.

Researchers transfected the stem cells with two microRNA (miRNA) strands: miR‑148b to promote bone formation and miR‑210 to enhance vascularization. Spheroids containing one or both miRNA programs were printed into scaffolds, cultured for 28 days, and then evaluated in immunodeficient mice with bone defects over six weeks. Untreated mice regenerated about 35% of the defect area, while mice receiving a control scaffold showed approximately 93% coverage. 

Adding spheroids programmed with both miRNAs yielded greater overall bone coverage and more effective vascularization, with higher CD31 expression than non‑transfected or single‑miRNA groups. The team plans to investigate these co-development effects in larger models and to study how vascularization may influence bone growth in printed tissue.

Co-authors represented Penn State along with collaborators from CHA University, Johns Hopkins University, the University of Wisconsin School of Medicine, and the University of Pennsylvania. The work suggests that carefully patterned, multi-programmed spheroids can help printed bone tissue integrate more effectively with host vasculature.

“There are two pieces to it: We're printing progenitor cells that will eventually help form vascularized bone, and we hope these same cells will also help drive that natural regenerative process. You wouldn't pursue this treatment for a normal bone break. This is for someone who's had substantial trauma or loss of bone due to cancer or an infection,” said Daniel Hayes, head of the Department of Biomedical Engineering at Penn State.

“As these techniques move closer towards clinical application, clinicians will need a great deal of fundamental understanding provided by researchers to best apply these new technologies. There’s a huge opportunity now to establish that knowledge, though, as these materials are commercially available and scalable,” said Ibrahim Ozbolat, professor of engineering science and mechanics and biomedical engineering at Penn State and Huck Institutes of the Life Sciences Chair in 3D Bioprinting and Regenerative Medicine.

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