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Combining Intraoperative Bioprinting and Microsurgery to Promote Scaffold Vascularization
Jessica C. El-Mallah
*1, Miji Yeo
2, Summer N. Horchler
3, Olivia Waldron
3, Mary Landmesser
3, Dishary Banerjee
2, MIngjie Sun
3, Ibrahim Ozbolat
2, Dino Ravnic
11Department of Surgery, Penn State Milton S. Hershey Medical Center, Hershey, PA; 2Department of Biomedical Engineering, Penn State, State College, PA; 3Penn State College of Medicine, Hershey, PA
Background: Intraoperative bioprinting (IOB) of tissue represents the next era of reconstructive surgery. However, success depends on rapid vascularization. Vascularization can be aided with scaffold incorporation of endothelial cells (EC). However, this is still suboptimal and improvement in inosculation to the host are warranted. Recently, we developed a microsurgical approach, termed (MP), that can stimulate capillary outgrowth from the recipient site. We hypothesize that the combination of bioink pre-seeded with ECs and concurrent recipient MP can stimulate scaffold vascularization.
Methods: 60um MPs were introduced into the rat femoral artery and vein at 1mm intervals. Immediately after a bioprinter extruded 4.5mL of a collagen-chitosan (1:2) bioink without or with endothelial cells (5 million/mL) to fabricate a scaffold on top of the vessels. On Day 10 rats either underwent in situ angiography or scaffold explantation for histology. Vascular metrics and EC (CD31) infiltration were quantified with artificial intelligence. Four groups were analyzed: non-MP (nMP)/acellular bioink (nMP/AB), nMP/EC bioink (ECB), MP/AB and MP/ECB. n=6 and a p-value <0.05 indicated significance.
Results: Vascular density (VD) was increased in each group compared to the baseline control (nMP/AB). Bioink addition of ECs led to a 2-fold increase in VD while MP led to a 3.5-fold increase. The combination of MP and ECB resulted in a 4-fold increase. Morphologic analysis showed that microvascular expansion was primarily driven by branch and loop formation with MP/ECB demonstrating the largest rise. EC staining corroborated whole-mount angiogram results (Table 1).
Conclusions: IOB has not yet achieved clinical translation, being mainly limited by the lack of rapid vascularization. Here, we demonstrate that bioink modification via EC and recipient site priming via MP can synergistically augment scaffold vascularization. As the MP approach is highly versatile and customized multicellular bioinks can be fabricated, the next era of tissue reconstruction is being discovered.
Table 1. Microvascular analysis of bioprinted scaffolds.
| | nMP/AB | MP/AB | nMP/ECB | MP/ECB |
| Vascular Density (% vessel area/total image area) | 4.9 | 17.8**** | 10.0** | 20.9**** |
| Vascular Loops (count/image field) | 3.0 | 30.8**** | 10.5* | 38.4**** |
| Average Vessel Length (um) | 2553 | 1038** | 1670 | 1631 |
| Branch Counts (branches/image field) | 14.7 | 103.7**** | 39.1* | 114.3**** |
| CD31 (% staining area) | 1:3 | 3.1**** | 2.3* | 4.0**** |
T-tests were used to compare statistical significance to the baseline nMP/AB group; *p<0.05; **p<0.01; ***p<0.001;****p<0.0001.
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