Biomimetic Designer Scaffolds Made of D,L-Lactide-ɛ-Caprolactone Polymers by 2-Photon Polymerization

Traditionally tissue engineering (TE) strategy relies on three components: cells, signaling systems (e.g., growth factors), and extracellular matrix (ECM). Nowadays the combination of cells, signaling systems, an artificial ECM, and appropriate bioreactor systems has recently been defined as the “Tissue Engineering Quadriad”(1) taking into consideration the fundamental role of the dynamic physiological environment. Not surprisingly, the establishment of an artificial ECM with the necessary flexibility seems to be a mission impossible without advanced materials and fabrication techniques. This claim applies to therapeutic (regeneration) as well as diagnostic (disease-modeling) approaches. To meet the challenge to mimic the hierarchical structured and complex milieu of the natural ECM it was tried in this study to combine a flexible photosensitive polymer platform based on (D,L)-lactide-ɛ-caprolactone methacrylate (LCM) with a nanoscale rapid prototyping technique based on two-photon polymerization (2-PP). Polyesters, such as poly-ɛ-caprolactone or poly-(D, L)-lactide, are very popular candidates for mimicking the ECM, because of their adjustable biophysical and biochemical properties. 2-PP represents a versatile lithographic method for the generation of scaffolds with defined size and shape, due to a spatial resolution <100 nm. This unique performance enables the fabrication of mathematically defined structures (scaffolds) based on triply periodic minimal surfaces with a tailor-made stiffness, permeability, and degradation behavior. Especially the Schwarz P minimal surface, which divides the interior of a scaffold into two intertwining labyrinths, plays an important role in generating custom-made or designer scaffolds. This review gives an overview of materials, techniques, and appropriate geometries to establish a conceptual framework to engineer such scaffolds. Furthermore, selected application scenarios in bone and tumor TE were introduced in the sense of a first proof of principle to show the high potential of this concept in therapeutic (regeneration) and diagnostic (disease-modeling) approaches. IMPACT STATEMENT: In tissue engineering (TE), the establishment of cell targeting materials, which mimic the conditions of the physiological extracellular matrix (ECM), seems to be a mission impossible without advanced materials and fabrication techniques. With this in mind we established a toolbox based on (D,L)-lactide-ɛ-caprolactone methacrylate (LCM) copolymers in combination with a nano–micromaskless lithography technique, the two-photon polymerization (2-PP) to mimic the hierarchical structured and complex milieu of the natural ECM. To demonstrate the versatility of this toolbox, we choose two completely different application scenarios in bone and tumor TE to show the high potential of this concept in therapeutic and diagnostic application.