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Microvascular Integration into Versatile Tissue Engineering Platforms
Eugenia H. Cho, B.S.1, Alina Boico, B.S.1, Natalie A. Wisniewski, Ph.D.2, Kristen L. Helton, Ph.D.2, Janna K. Register, Ph.D.3, Andrew M. Fales, B.S.3, Gregory M. Palmer, Ph.D.1, Tuan Vo-Dinh, Ph.D.3, Thies Schroeder, Ph.D.1, Bruce Klitzman, Ph.D.1.
1Duke University Medical Center, Durham, NC, USA, 2PROFUSA, San Francisco, CA, USA, 3Duke University, Durham, NC, USA.
PURPOSE: To maximize mass transport into biomaterial scaffolds for regenerative medicine, in vivo diagnostics, therapeutics, and cell delivery. We utilized matrix morphology to encourage long-term vascularization.
METHODS: We implanted 1cm-diameter poly-hydroxyethylmethacrylate (polyHEMA) disks with 40 and 80µm nominal interconnected pores into rat subcutis. Solid polyHEMA, silicone, and cotton disks were also implanted. We also investigated a minimally-invasive trocar-assisted delivery of ribbon-shaped porous polyHEMA implants and a suspension of polyHEMA microparticles. Microvessel density was quantified in 50µm-wide zones both into the implants and into the adjacent tissues.
RESULTS: One week after implantation, the microvessel (mv) density closest to the interface was 74±8 mv/mm2 (mean±SEM) for the 80µm polyHEMA and 28±8 mv/mm2 for the 40µm polyHEMA. The rate of vascularization was greater in 80µm polyHEMA, with higher vascular density in the material and adjacent tissues one week and one month post-implantation (p<0.001). After two months, vascular ingrowth was similar for both 40 and 80µm polyHEMA (maximum = 155±32 mv/mm2 and 182±43 mv/mm2, respectively). Solid polyHEMA and silicone exhibited no vascular ingrowth. Notably, despite similar levels of vascularization into both porous materials at two months, the 80µm polyHEMA elicited greater vascularization in the critical 100µm margin of tissue around the implant, compared to other materials. At two months, the microvessel density in the 0-50µm and 50-100µm skin tissue margins was 203±11 mv/mm2 and 317±19 mv/mm2, respectively, compared to 101±15 mv/mm2 and 136±24 mv/mm2 for the 40 µm polyHEMA; 60±16 mv/mm2 and 212±45 mv/mm2 for the solid polyHEMA; and 24±7 mv/mm2 and 116±43 mv/mm2 for silicone. All materials (except 80µm polyHEMA) showed a narrow margin of significantly reduced vascularity at the implant-tissue interface, and convergence to normal microvessel density values at further distances away from the interface (control skin = 242 mv/mm2).
Microvessel diameters (99th percentiles) were 16.3μm in 40μm polyHEMA, 14.5μm in 80μm polyHEMA, and 11.8μm in control tissue. Microvessel diameters were similar for the two pore sizes after two months, but were significantly greater than in the sham wound (p<0.001). Vascularization into ribbons supported our findings in the disks; more microvessels were detected inside and around porous polyHEMA ribbons than for solid materials at all timepoints. Vascularization into porous polyHEMA microparticles was highly variable. Using real-time ultrasonic microscopy, the microshearing that can disrupt microvessel formation was observed to decrease as tissue integrated into the pores.
CONCLUSION: Rigorous evaluation metrics to assess long-term mass transport capabilities are key to successful tissue engineering platforms since poorly vascularized scaffolds have limited utility. Robust vascularization, particularly at the critical implant-tissue interface, makes open interconnected-pore polyHEMA an excellent morphology for scaffolds in regenerative medicine.
Funding: Supported in part by DARPA grant numbers W911NF-11-1-0119 and HR0011-13-2-0003, the Fitzpatrick Institute for Photonics and the Robert Jones Fund, Duke University. The content of the information does not necessarily reflect the position or the policy of the Government, and no official endorsement should be inferred.
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