Varieties of macromolecular biomaterials have been widely applied in the medical field such as wound dressing, tissue engineering scaffolds, artificial organs, electronic skin, and so on. Many biomaterials maintain prolonged contact with human tissues, and in some cases, certain materials may even be permanently implanted. However, implantation of foreign materials often accompanies foreign body reactions, a complex response containing protein adsorption, inflammatory cell recruitment and activation, fibroblast activation, and fibrous capsule formation [1]. Fibroblasts activate and differentiate into myofibroblasts in response to specific mechanical or chemical signals, and further possess enhanced proliferation, migration, and collagen secretion capabilities. Fibroblast to myofibroblast transition (FMT) is always considered to be a key factor in organ fibrosis and abnormal tissue healing outcomes, such as skin pathological scar, nerve scar, corneal scar, postoperative adhesion, fibrous capsule formation, and so on [2]. Excessive FMT and collagen deposition induced by biomaterials can result in the formation of pathological scars or fibrous capsules.

Host-biomaterial interactions are mainly controlled by the surface properties of biomaterials, including stiffness, wettability, roughness, and topography. Materials with aligned structures offer topographical cues, facilitating cell alignment and enabling cell adhesion and elongation along the topographical direction [3].Hypothesis-driven design of the biomaterials interface helps to adapt to the local body environment and optimize treatment outcomes. Aligned structure materials can mimic biological tissues that exhibit similarly aligned topography and show significant potential in tissue engineering. Recently, biomaterials featuring aligned topographical guidance cues have been reported to promote the differentiation of stem cells into osteoblasts, neurons, myoblasts, tendon and ligament fibroblasts. Furthermore, aligned topography has been shown to enhance bone, spinal cord, and tendon regeneration in vivo [4].

Although aligned structure materials have been extensively studied in tissue engineering, the relationship between aligned topography and FMT remains controversial. It has been clearly demonstrated that high-stiffness substrates, mechanical stretch and can promote FMT [5,6]. Mechanical signals play critical roles in FMT via regulating actin cytoskeleton polymerization or depolymerization, and the activation of RhoA and yes-associated protein (YAP). In essence, cell alignment induced by aligned topography is a direct result of cells adapting to their external mechanical environment [7,8,9]. Thrivikraman G. et al. demonstrated that cells could perceive aligned fibrils through the mechanical resistance anisotropy of the fibril network, subsequently adjusting their pseudopod protrusion or retraction [7]. Cells displayed more robust contact guidance in the aligned hydrogels possessing greater mechanical resistance anisotropy, while the addition of function-blocking integrin antibodies reduces this guidance effect. Bersie-Larson LM et al. established a microstructural-mechanical model of aligned fibril networks, and further proved that mechanical anisotropy signals are significantly higher than adhesion and porosity anisotropy signals [10]. Therefore, can fibroblasts on aligned structures differentiate into myofibroblasts when subjected to corresponding mechanical forces or other signal stimulation? Table 1 lists the studies focusing on biomaterials' topographical cues and FMT.

In the above studies, researchers investigated the relationship between biomaterials' aligned topography and FMT in vivo or in vitro. They employed fibroblasts and animal models associated with various tissues, including skin, cornea, heart, dura mater, and vocal fold. The findings provided clear evidence proved aligned topography induced cells' decreased spread area and high migration speed along the topography direction. However, some studies found biomaterials' aligned topography promoted FMT while others found it inhibited or had no effect, and these contradictory conclusions did not appear to be linked to the specific material type used. Moreover, the expression patterns of molecules involved in mechanotransduction, such as YAP, rho-associated kinase, transforming growth factor β, focal adhesion kinase, and integrin, also exhibited similar contradictory trends. This perplexing phenomenon cannot be solely attributed to fibroblast heterogeneity, as some studies arrived at opposing conclusions despite utilizing the same human dermal fibroblast.

Herein, we suggest that the relationship between the topographical cues of materials and fibroblast activation could be hidden or exaggerated by other characterizations of materials. Firstly, there exists an inherent challenge in selectively modifying a single type of anisotropy within biomaterials, whether it is mechanical anisotropy, chemical anisotropy, or steric anisotropy, without simultaneously impacting the others [22]. Electrospun fiber is the most commonly employed material in the study of topography-cell interactions. However, aligned electrospun fibers tend to spontaneously curl along a direction perpendicular to their fiber orientation, indicating the presence of significant mechanical anisotropy within these aligned electrospun fibers. Secondly, other material characteristics also play pivotal roles in FMT. Li Y et al. prepared PCL-based microfiber scaffolds (with a diameter of 1.7 ​μm) and nanofiber scaffolds (with a diameter of 300 ​nm) to investigate their impact on FMT [15]. Their findings revealed that the nanofiber matrix induced a higher proportion of fibroblasts to transition into α-SMA-positive myofibroblasts and activate FAK through the integrin β1 pathway. Jiao Y et al. constructed nanoscale topology on the surface of electrospun microfibers and subsequently observed that the rough surfaces on microfibers inhibited FMT [13]. It remains unclear whether previous researchers strictly controlled other material characteristics when manipulating the topographical cues of materials. Besides, the studies listed in Table 1 utilized a variety of manufacturing methods, and some of them did not furnish parameters for other surface properties. As a result, we were unable to compile a comprehensive summary of the combined impact of other material properties along with topographical cues on FMT, which represents a limitation of this study.

We are of the opinion that, based on the previously mentioned research, topographical cues of biomaterials do not play a central role on FMT. In contrast, other surface properties of biomaterials, such as stiffness, wettability, roughness, appear to have a more pronounced impact on FMT [23]. When it comes to designing novel biomaterials, researchers may not need to prioritize material topographical cues as the primary consideration in preventing scar or fibrous capsule formation. Future studies should isolate steric anisotropy as a singular variable to meticulously elucidate the interaction between topographical cues and FMT. Furthermore, it would be advantageous for future research exploring the relationship between biomaterials and FMT to employ a 3D matrix instead of a 2D membrane, considering that fibroblasts undergo differentiation within the 3D matrix under both physical and pathological conditions. Finally, studies concentrating on biomaterials and FMT will benefit from animal experiments, as the FMT process may be indirectly regulated by factors such as macrophage polarization in vivo.