Controlling Microvascular Development with Surgical Bioengineering
Jessica C. El-Mallah*1, Zaman Ataie2, Summer N. Horchler3, Mary Landmesser3, Arian Jaberi2, Alexander Kedzierski2, Mingjie Sun3, Amir Sheikhi2, Dino J. Ravnic2
1Department of Surgery, Penn State, Hershey, PA; 2Department of Chemical Engineering, Penn State, State College, PA; 3College of Medicine, Penn State, Hershey, PA
Conventional bulk hydrogel scaffolds are a vital platform for tissue vascularization and surgical repair. However, their slow and random vascularization precludes true tissue regeneration. We have developed a microsurgical approach to expedite vascularization. In micropuncture (MP), the recipient macrovasculature is precisely perforated, facilitating cellular extravasation and angiogenesis. Concurrently, we have developed granular hydrogel scaffolds (GHS) with tailored porosity that can guide microvascular development. However, it is unknown how the combination of MP+GHS-induced microvasculature remodeling over time.
Rat femoral vessels underwent MP after which GHS made with 80um diameter spherical gelatin methacryloyl hydrogel microparticles were adjacently placed. Following a 7- or 28-day implantation period, in situ fluorescence angiography was performed. Scaffold explants were prepared as whole mounts for detailed microvascular analysis with artificial intelligence. Controls did not receive MP.
MP was associated with an increase in mean scaffold microvascular density at both 7 and 28 days compared with non-MP controls. This was paralleled by augmented development of vascular loops. Mean loop intercapillary distance was similar between MP and non-MP scaffolds at comparable timepoints, indicating that the neomicrovasculature was encircling GHS-embedded microgels. However, mean intercapillary distance regressed approximately 35% between days 7 and 28, possibly related to microgel degradation kinetics (Table 1; n=4 per group).
Slow and random scaffold vascularization profoundly limits the scale-up of regenerative surgery. Here, we demonstrated that both limitations can be overcome by a combined microsurgical-bioengineering approach. However, further material refinements appear needed to achieve precise control of microvascular remodeling in this novel platform.
Table 1. Comparisons of mean vascular density, vessel loop count, and intercapillary distance.
| Day of Explant | MP | Non-MP | p-value | |
| Vascular Density (% vessel area/total area) | Day 7 | 16.85% | 10.80% | 0.0023* |
| Day 28 | 23.26% | 15.92% | 0.0003* | |
| Loop Count (loops/image field) | Day 7 | 20.45 | 12.42 | 0.0381* |
| Day 28 | 41.00 | 19.50 | 0.0002* | |
| Intercapillary Distance (um) | Day 7 | 72.67 | 75.29 | 0.2136 |
| Day 28 | 45.92 | 47.53 | 0.5475 |
*Indicates significant p-value <0.05.
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