Developing tunable biomaterials that have the capacity to recreate the physical and biochemical characteristics of native extracellular matrices (ECMs) with spatial fidelity is important for a variety of biomedical, biological, and clinical applications. Several factors have made the ECM protein, collagen I, an attractive biomaterial, including its ease of isolation, low antigenicity and toxicity, and biodegradability. However, current collagen gel formulations fail to recapitulate the range of collagen structures observed in native tissues, presenting a significant challenge in achieving the full potential of collagen-based biomaterials. Collagen fiber structure can be manipulated in vitro through mechanical forces, environmental factors, or thermal mechanisms. Here, we describe a new ultrasound-based fabrication technology that exploits the ability of ultrasound to generate localized mechanical forces to control the collagen fiber microstructure non-invasively. The results indicate that exposing soluble collagen to ultrasound (7.8 or 8.8 ​MHz; 3.2–10 ​W/cm²) during hydrogel formation leads to local variations in collagen fiber structure and organization that support increased levels of cell migration. Furthermore, multiphoton imaging revealed increased cell-mediated collagen remodeling of ultrasound-exposed but not sham-exposed hydrogels, including formation of multicellular aggregates, collagen fiber bundle contraction, and increased binding of collagen hybridizing peptides. Skin explant ​cultures obtained from diabetic mice showed similar enhancement of cell-mediated remodeling of ultrasound-exposed but not sham-exposed collagen hydrogels. Using the mechanical forces associated with ultrasound to induce local changes in collagen fibril structure and organization ​to functionalize native biomaterials is a promising non-invasive and non-toxic technology for tissue engineering and regenerative medicine.

开发能够以空间保真度重建天然细胞外基质（ECM）的物理和生化特征的可调谐生物材料对于各种生物医学、生物学和临床应用非常重要。有几个因素使 ECM 蛋白（胶原蛋白 I）成为一种有吸引力的生物材料，包括其易于分离、低抗原性和毒性以及生物可降解性。然而，目前的胶原蛋白凝胶配方无法概括在天然组织中观察到的胶原蛋白结构范围，这对充分发挥胶原蛋白生物材料的潜力提出了重大挑战。胶原纤维结构可以通过机械力、环境因素或热机制在体外进行操纵。在这里，我们描述了一种基于超声波的新型制造技术，该技术利用超声波产生局部机械力的能力来非侵入性地控制胶原纤维微观结构。结果表明，在水凝胶形成过程中将可溶性胶原暴露于超声波（7.8 或 8.8 MHz；3.2–10 W/cm ²）会导致胶原纤维结构和组织的局部变化，从而支持细胞迁移水平的提高。此外，多光子成像显示，超声暴露的水凝胶的细胞介导的胶原重塑增加，但假暴露的水凝胶则没有，包括多细胞聚集体的形成、胶原纤维束收缩以及胶原杂交肽的结合增加。从糖尿病小鼠获得的皮肤外植体培养物显示，超声暴露的胶原水凝胶的细胞介导的重塑有类似的增强，但假暴露的胶原水凝胶则没有。利用与超声波相关的机械力来诱导胶原纤维结构和组织的局部变化，从而使天然生物材料功能化，是组织工程和再生医学中一种有前途的非侵入性和无毒技术。