4D Printing of Multi‐Responsive Membrane for Accelerated In Vivo Bone Healing Via Remote Regulation of Stem Cell Fate

Abstract

Dynamic regulation of substrate micro‐structures is an effective strategy to control stem cell fate in tissue engineering. Translating this into in vivo tissue repair in a clinical setting remains challenging, which requires precise temporal control of multi‐scale structural features. Using 4D printing technique, a multi‐responsive bilayer morphing membrane consisting of a shape memory polymer (SMP) layer and a hydrogel layer, is fabricated. The SMP layer is featured with responsive surface micro‐structures, which can switch the phase between proliferation and differentiation precisely, thus promoting the bone formation. The hydrogel layer endows the membrane with the ability to digitally regulate its 3D geometry, matching the specific macroscopic bone shape in clinical scenario. The authors’ in vivo experiments show that the 4D shape‐shifting membrane exhibits over 30% improvement in new bone formation in comparison to a reference membrane with static micro‐structure. More importantly, the 4D membrane can conformally wrap a bone defect model in a non‐invasive way and this strategy can be extended to repairs involving complex tissue defects.

Emerging 4D Printing Strategies for Next‐Generation Tissue Regeneration and Medical Devices

“…Current studies have demonstrated their ability in shape-morphing with time for dynamic culture, which can encourage more studies of the 4D printed bone tissues and implants. [220,248,249] In addition to the biodegradation and biocompatibility of the 4D bone scaffolds, more deep studies in terms of in vitro differentiation and in vivo implantation should be performed in the future. Considering the in vivo implantation, mechanical properties such as compression strength and fatigue strength are another consideration for the choice of 4D bone materials.…”

“…synthesized a dual stimulus‐responsive SMP that can achieve the swelling‐induced macroscopic morphing and heat‐induced microscopic morphing. [ 248 ] The dynamic cell culturing surface, the static micropillar surface, and the static flat surface were printed using a DLP printer ( Figure A). The study results showed the continuous spreading of the cytoskeleton on the dynamic surface.…”

“…Reproduced with permission. [ 248 ] Copyright 2021, Wiley‐VCH. B) Thermoresponsive shape memory cycle of fabricated 4D scaffolds, changing from the original shape to the deformed shape, and finally recovering to the original shape.…”

“…The macroscopic curvature was programmed by controlling the light exposure.The application examples of 4D printed complex macroscopic geometries and the custom fitting of 4D printed bilayer membranes for bone repair. Reproduced with permission [248]. Copyright 2021, Wiley-VCH.…”

DataSheet1.docx

“…Despite the inherent selfrepair ability of bone, the gold standard for defect treatment is still autologous bone transplantation (Zhang et al, 2017;Annamalai et al, 2019;Li et al, 2020). With the progression of tissue engineering, biomimetic bone scaffolds can guide tissue regeneration with assembled stem cells (Zhao et al, 2019;Swanson et al, 2021;You et al, 2021). Therefore, they have considered a cost-effective and osteoinductive strategy to replace autologous bone grafts (Cui et al, 2019).…”