Plastic Surgery Research Council
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PSRC 60th Annual Meeting
Program and Abstracts

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A Multifactorial Histologic Analysis of the Foreign Body Response to Intradermal and Subcutaneous Implants
Eugenia H. Cho, BS1, Alina Boico, BS1, Lin Liao, .1, Janna K. Register, PhD1, Natalie A. Wisniewski, PhD2, Kristen Helton, PhD2, Tuan Vo-Dinh, PhD1, Gregory Palmer, PhD1, Bruce Klitzman, PhD1.
1Duke University, Durham, NC, USA, 2PROFUSA Corp, San Francisco, CA, USA.

PURPOSE: Implanted platforms for in vivo diagnostics, therapeutics, and cell therapies depend on the mass transport of target analytes from the blood to the platform. In this study, we examined the development of factors that physiologically influence transport, including the microvasculature and chronic inflammation, at the implant-tissue interface region of intradermal and subcutaneous porous hydrogel scaffold implants.
METHODS: Ribbon-shaped porous poly-2-hydroxyethylmethacrylate (pHEMA) hydrogel scaffolds with 80µm interconnected pores were fabricated using previously reported microsphere templating. Ribbons approximately 0.7mm wide, 0.5mm thick, and 5mm long were injected via 18G needles into pig dermis and subcutaneous (mostly adipose) tissue. Immunohistochemical analyses were performed at 1 week and 1 month post-implantation to quantify the presence of microvessels (CD31), nuclei (Hoechst), and macrophages (CD68) expressing pro-inflammatory M1 (CD80) and pro-healing M2 (CD163) phenotypes at the implant-tissue interface.
RESULTS: After 1 week, histomorphometric analysis of hydrogel scaffolds implanted subcutaneously where adipose tissue predominates, demonstrated faster tissue vascularization within 50µm of the implant-tissue interface compared to intradermal scaffolds (mean±SEM = 418±36 vs. 211±48 microvessels/mm2; p=0.03). After 1 month, intradermal and subcutaneous implants demonstrated similar levels of tissue and pHEMA scaffold vascularization within 50µm of the interface (218±55 vs. 218±30 mv/mm2 in tissue; p=1.00; and 286±37 vs. 290±37 mv/mm2 in pHEMA; p=0.95). From 1 week to 1 month post-implantation, the average diffusion distance from any point in the interior of the scaffold matrix to the nearest microvessel decreased in both the dermis (42±27 to 31±19 µm) and subcutis (36±21 to 28±17 µm). Overall tissue cellularity within 50µm of the implant interface was similar for both intradermal and subcutaneous scaffolds at 1 week (4027±658 vs. 3924±124 cells/mm2; p=0.88), but decreased significantly in the subcutis after 1 month (p=0.01). No change in total cellularity was observed over time in the intradermal implant and adjacent tissues. Immuno-histomorphometric analysis of CD68, CD80, and CD163 cell surface markers at 1 week demonstrated a greater presence of M2 macrophages relative to M1 macrophages in the subcutaneous adipose tissue nearest the implant-tissue interface (743±111 M2 vs. 354±89 M1 cells/ mm2; p=0.05), compared to the tissue adjacent to the intradermal scaffold (441±70 M2 vs.399±55 M1 cells/mm2; p=0.65) (see Figure 1). Over time, subcutaneous scaffolds demonstrated a significant shift in macrophage phenotype from the M1 to M2 state in both the tissue (M2 vs. M1; p=0.01) and implant (M2 vs. M1; p<0.01). Statistical comparison of macrophage surface markers for M2 and M1 phenotype associated with intradermal scaffold implants was borderline (M2 vs. M1; p=0.052).
CONCLUSION: The degree of the foreign body response to tissue-engineered scaffolds may be influenced by the type of tissue into which the scaffold is implanted. In this study, porous pHEMA implanted into pig subcutaneous adipose tissue showed faster neovascularization and reduced cellular infiltration at the implant-tissue interface, coinciding with a shift in macrophage polarization toward the pro-healing M2 phenotype.








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