Biomaterial-associated fibrosis remains a significant challenge in medical implants. To optimize implant design, understanding the interplay between biomaterials and host cells during the foreign body response (FBR) is crucial. Material properties are known to influence cellular behavior and can be used to manipulate cell responses, but predicting the right combination for the desired outcomes is challenging. This study explores how combined physicochemical material properties impact early myofibroblast differentiation using the Biomaterial Advanced Cell Screening (BiomACS) technology, which assesses hundreds of combinations of surface topography, stiffness, and wettability in a single experiment. Normal human dermal fibroblasts (NHDFs) are screened for cell density, area, and myofibroblast markers α-smooth muscle actin (α-SMA) and Collagen type I (COL1) after 24 h and 7 days of culture, with or without transforming growth factor-beta (TGF-β). Results demonstrated that material properties influence fibroblast behavior after 7 days with TGF-β stimulation, with wettability emerging as the predominant factor, followed by stiffness. The study identified regions with increased cell adhesion while minimizing myofibroblast differentiation, offering the potential for implant surface optimization to prevent fibrosis. This research provides a powerful tool for cell-material studies and represents a critical step toward enhancing implant properties and reducing complications, ultimately improving patient outcomes.

Implant‐associated complications arise due to non‐optimized cell–biomaterial interactions. It is well known that cells respond to their physicochemical microenvironment on 2D interfaces and 3D networks. Attempts to manipulate this interaction target surface parameters such as wettability (W), stiffness (S), and topography (T) to influence cell differentiation, adhesion, and morphology, due to induction of gene activation and protein expression. Investigating the combinatorial influence of all three mentioned parameters simultaneously remains challenging, though most realistic, since all three parameters are inherently present on a surface. Herein, a novel high‐throughput screening technology, which allows investigating the cell response of human bone‐marrow‐derived mesenchymal stem cells toward three varying biomaterial surface parameters simultaneously, is presented. The platform provides efficient screening and cell response readout to a vast amount of combined biomaterial surface properties, in a single‐cell experiment. Surface gradients of aligned wrinkle T, S, and W are orthogonally combined giving four combinatorial surfaces. The screening outcome is validated by translating interesting regions to homogeneous surfaces. Cells are found to behave similar to the screening in terms of adhesion, spreading, and vimentin expression. The technology tremendously supports the identification of optimal surface parameter combinations and potentially addressing many of the current implant‐associated complications.

New high‐throughput technologies for cell–material interaction studies provide researchers with powerful tools to speed up research in the field of biomaterial–cell interactions. However, sharing technologies is often difficult due to the necessity of specific knowledge and experiences. Engineered surfaces can elucidate effects of surface topography on cell behavior, which is of critical value for gaining control over cellular processes. Here, the translation of a gradient‐based high‐throughput cell screening approach for aligned nano/micro topographies interacting with cells is presented. An aligned topography 96‐well plate is created by upscaling of highly specific gradient technology. The resulting cell culture dishes are compatible with general laboratory and imaging equipment, and the platform allows for studying cell behavior with regard to adhesion and alignment. The challenge lies in increasing the dimensions of the previous 1 × 1 cm gradient topography substrate, to be able to cover the span of a 96‐well plate and translate it into a standardized cell‐screening tool. Adhesion experiments of human bone marrow derived mesenchymal stem cells confirm the standardization, compatibility, and usability of the technology. In the process of using multi‐system imaging and analysis, it becomes apparent that future challenges need to include universally applied data analysis approaches.

Two-parameter contributions of stiffness and wettability display altered behavior of hBM-MSCs as compared to solely investigating the wettability of the biointerface with a homogenous stiffness. The importance of double parameter influence is identified by using newly developed double linear wettability-stiffness gradients. The interfaces show that substrate stiffness can influence cell adhesion and spreading both positively and negatively in combination with wettability. This effect is validated by decoupling the stiffness gradient using a wettability gradient composed of a monolayer on glass ensuring a homogenous stiffness.