An immunologically active, adipose-derived extracellular matrix biomaterial for soft tissue reconstruction: concept to clinical trial.
An immunologically active, adipose-derived extracellular matrix biomaterial for soft tissue reconstruction: concept to clinical trial.
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DOI：
10.1038/s41536-021-00197-1
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发表时间：
2022-01-14
影响因子：
7.2
通讯作者：
Elisseeff JH
中科院分区：
文献类型：
--
作者：
Anderson AE;Wu I;Parrillo AJ;Wolf MT;Maestas DR Jr;Graham I;Tam AJ;Payne RM;Aston J;Cooney CM;Byrne P;Cooney DS;Elisseeff JH
软组织重建仍然是一个棘手的临床挑战，因为目前的手术选择和合成植入物可能会产生不充分的结果。软组织缺损可以使用自体脂肪组织进行手术重建，但这些手术可能导致供体部位发病，需要多次手术，并且结局差异很大。为了满足这种临床需求，我们开发了一种来自同种异体移植人体组织的“现成”脂肪细胞外基质（ECM）生物材料（脱细胞脂肪组织，AAT）。我们应用物理和化学处理方法去除脂质，并创建模拟脂肪抽吸物性质的可注射基质。使用细胞迁移和脂肪生成测定评估生物活性。在鼠肌肉损伤模型中再生免疫特性的表征揭示了同种异体移植物和异种移植物AAT诱导促再生CD 4 + T细胞和巨噬细胞，其中异种移植物AAT另外吸引分泌白细胞介素4（IL 4）的嗜酸性粒细胞。在免疫功能低下的小鼠中，AAT注射液保留了与人类脂肪移植物相似的体积，但缺乏脂肪移植物中观察到的囊肿和钙化。AAT与人脂肪源性干细胞（ASC）的组合导致植入物体积较低。然而，组织重塑和脂肪生成在与ASCs组合时显著增加。当在约克郡杂交猪中同种异体应用时，较大注射体积的猪源性AAT表现出生物相容性和更大的保留。AAT被植入健康志愿者的腹部组织中，随后通过择期手术取出。AAT植入物在所有人类受试者中耐受良好。在1 - 18周之间取出的植入物表现出增加的细胞浸润和免疫群体，表明持续的组织重塑和长期组织替代的潜力。
Soft tissue reconstruction remains an intractable clinical challenge as current surgical options and synthetic implants may produce inadequate outcomes. Soft tissue deficits may be surgically reconstructed using autologous adipose tissue, but these procedures can lead to donor site morbidity, require multiple procedures, and have highly variable outcomes. To address this clinical need, we developed an “off-the-shelf” adipose extracellular matrix (ECM) biomaterial from allograft human tissue (Acellular Adipose Tissue, AAT). We applied physical and chemical processing methods to remove lipids and create an injectable matrix that mimicked the properties of lipoaspirate. Biological activity was assessed using cell migration and adipogenesis assays. Characterization of regenerative immune properties in a murine muscle injury model revealed that allograft and xenograft AAT induced pro-regenerative CD4+ T cells and macrophages with xenograft AAT additionally attracting eosinophils secreting interleukin 4 (Il4). In immunocompromised mice, AAT injections retained similar volumes as human fat grafts but lacked cysts and calcifications seen in the fat grafts. The combination of AAT with human adipose-derived stem cells (ASCs) resulted in lower implant volumes. However, tissue remodeling and adipogenesis increased significantly in combination with ASCs. Larger injected volumes of porcine-derived AAT demonstrated biocompatibility and greater retention when applied allogeneicly in Yorkshire cross pigs. AAT was implanted in healthy volunteers in abdominal tissue that was later removed by elective procedures. AAT implants were well tolerated in all human subjects. Implants removed between 1 and 18 weeks demonstrated increasing cellular infiltration and immune populations, suggesting continued tissue remodeling and the potential for long-term tissue replacement.
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