NESPS - Tunable Hydrogel Stiffness Modulates In Situ Microvascular Growth and Long-Term Vascular Maturation

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Tunable Hydrogel Stiffness Modulates In Situ Microvascular Growth and Long-Term Vascular Maturation
MohammadHossein Asgardoon^*2, Saman Zavari¹, Mary Landmesser², Neekita Jikaria², Jenn Park², Amir Sheikhi¹, Dino Ravnic²
¹Chemical Engineering, Penn State University, University Park, PA; ²Surgery, The Pennsylvania State University, Hershey, PA

Background:
In situ scaffold formation is an emerging strategy for intraoperative tissue reconstruction. The easy dispensability of hydrogels allows for precise wound contouring. However, successful integration of these materials depends on durable vascularization to support long-term tissue viability. Previously we showed that hydrogel stiffness regulates early angiogenesis in porous hydrogels, but its influence on long-term microvascular remodeling within these materials remains unknown. We hypothesize that compliant porous hydrogels promote long-term microvascular growth and maturation.
Methods:
Gelatin methacryloyl (GelMA) particles with storage moduli of 1, 5, or 21 kPa were UV-cured in situ to form soft, medium, and hard scaffolds (15×15×3 mm) subcutaneously on the dorsum of rats (n=5/group). On postoperative day 28 (POD28), blood perfusion and surface temperature were assessed using laser Doppler and thermal imaging. Following intravenous FITC-dextran and Evans Blue injection, scaffolds were analyzed by confocal microscopy. Microvascular architecture was quantified using FastTrack AI and a permeability index was calculated from Evans Blue extravasation normalized to FITC-dextran area. Data were analyzed by one-way ANOVA (p<0.05).
Results:
On POD28, Soft scaffolds showed the highest perfusion, surface temperature, and vascular branching, which declined progressively with increasing stiffness. Vascular density, vascular loop, and vessel diameter remained similar across groups. Absolute Evans Blue area did not differ significantly among groups. When normalized to perfused area, permeability index increased with stiffness (Table1).
Conclusion:
GelMA particle stiffness modulates long-term vascular remodeling and maturation. Softer scaffolds promote greater vascularization with progressive maturation at POD28. GelMA particles hold promise as tunable materials for next-generation reconstructive surgery.
Effect of GelMA particle stiffness on vascularization on POD28.

Parameter	Soft	Medium	Hard
Scaffold Doppler intensity (AU)	407.70 ± 119.95*	386.40 ± 114.17	268.90 ± 106.96
Scaffold temperature (°C)	31.32 ± 0.65*	28.66 ± 1.15	27.16 ± 0.54
Vascular density (%)	63.53 ± 13.79	55.66 ± 19.35	44.04 ± 17.48
Number of branches (n)	69.58 ± 24.37*	52.06 ± 18.65	39.93 ± 21.59
Number of loops (n)	48.66 ± 27.98	38.33 ± 19.23	25.46 ± 19.89
Average vessel diameter (µm)	17.22± 2.95	16.69 ± 2.56	18.45 ± 3.73
Evans Blue area (%)	57.32 ± 11.06	69.16 ± 3.85	67.71 ± 23.44
Permeability index (EB/FITC)	0.90 ± 0.12	1.24 ± 0.22	1.42 ± 0.46

Data are presented as mean ± SD. *Indicates p < 0.05 when compared with the hard group.

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