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Skeletal muscle, peripheral nerve, cartilage and other soft tissues rely on directional organisation of cells and extracellular matrix to execute physiological functions. Recapitulating the native layered anisotropic architecture of myocardium constitutes a core objective for cardiac tissue engineering. Recently, the research team led by Professors Li Dichen and He Jiankang at Xi’an Jiaotong University proposed an innovative fabrication strategy termed gelation-coupled strain locking. This approach enables the construction of large-area layered aligned myocardial tissues. When integrated with piezoelectric scaffolds, the engineered constructs exhibit markedly improved cardiac electrophysiological performance. The technology carries substantial translational potential for in vivo implantation as myocardial infarction repair patches and in vitro cardiac tissue models. Furthermore, the platform can be extended to engineer other anisotropic soft tissues including skeletal muscle and peripheral nerve.

The corresponding work entitled Strain-Driven Topological Reorganization in Soft Fibrin Nanofibrous Networks Enabling Tissue-Like Alignment has been published in Advanced Materials.

Core Innovations & Breakthroughs

Innovative fabrication methodologyFor the first time, uniaxial strain is applied during the dynamic fibrillogenic window of fibrin gel; permanent ordered architectures are locked in place via progressive fibrin crosslinking. The team identified a 90-second pre-gelation optimal processing window and a saturation threshold for fibre alignment at 1.6-fold stretch. This template-free, external-field-free technique permits scalable manufacturing of 3D aligned cell-laden matrices.
Quantitative geometric theory for pore straighteningA geometric model of pore straightening explains the intrinsic mechanism governing alignment saturation at 1.6-fold stretch from a microscale topological perspective. Combined with rheological characterisation and finite element modelling, the study delineates the mechanical mechanisms through which crosslink density regulates fibre mobility and force transmission balance within the network. These findings deliver quantitative design guidelines for controlling alignment in fibrous biological hydrogels.
Integrated structural and functional engineeringOptimisation of scaffold lattice geometries yields biomimetic layered myocardium. Integration with piezoelectric scaffolds enables endogenous electrical stimulation triggered by cellular contraction, establishing an integrated system of “biomimetic layered myocardium + piezoelectric self-stimulation”. The platform concurrently enhances cardiomyocyte structural maturation and electrophysiological function for cardiac repair applications, with broad applicability across multiple soft tissue engineering modalities.

WHAT：Research Scope
Conventional strategies for generating aligned 3D cell-laden fibrous matrices depend on templates or external physical fields, lack quantitative mechanical regulation, and struggle to simultaneously recapitulate layered biomimetic myocardial architecture while tuning electrophysiological function. To address these bottlenecks, the authors present a gelation-coupled strain-induced alignment strategy. By modulating pre-gelation duration, stretch ratio and scaffold geometry, stable ordered fibrin networks are fabricated. A geometric model rationalises the 1.6-fold stretch alignment saturation phenomenon. Optimised lattice designs enable production of centimetre-scale uniaxially aligned and multi-layer biomimetic myocardial constructs, whose translational utility in engineered cardiac tissue and myocardial repair is validated.

Figure 1: Schematic illustration of the overall design

Technical Advantages & Solutions

1. Development of a tunable viscoelastic culture platform
An electrohydrodynamically printed diamond-patterned PCL scaffold serves as the substrate for strain assembly. Fibre organisation and post-unloading recoil behaviour are compared across three pre-gelation timepoints (60 s, 90 s, 10 min). Rheological testing quantifies differences in storage modulus across distinct crosslinking stages, confirming that the intermediate 90 s crosslinking window strikes a favourable balance between fibre slippage and bulk load-bearing capacity. Uniaxial stretch is applied over a gradient of 20%–80% deformation; fibre/cell alignment indices and pore aspect ratios are quantified systematically. A polygon pore straightening geometric model elucidates the microtopological basis for alignment saturation at 1.6-fold stretch. Finite element simulations further reveal disparities in stress propagation and network rearrangement under weak, intermediate and fully crosslinked conditions.

Figure 2: Strain-dependent saturation of fibrin and cellular alignment from unit elements to scaffold arrays

2. Design and fabrication of biomimetic myocardial scaffold geometries

Standard diamond arrays suffer from heterogeneous strain distribution upon stretching. The lattice design is refined with triangular extensions at both termini and optimised distal anchoring to homogenise full-field strain, facilitating centimetre-scale production of gradient-free uniaxially aligned fibrin constructs. A custom multi-axis synchronous stretching apparatus is deployed to stack three optimised lattice layers with 60° angular offset and sequential stretching. This replicates the transmural gradually rotating fibre architecture spanning the endocardium to epicardium in native myocardium, enabling controllable fabrication of multi-scale biomimetic myocardial matrices.

Figure 3: Fabrication of macroscale uniaxially aligned and multi-layer tissue mimicking myocardial fibre architecture via strain-guided scaffold engineering

3. Biological validation of cardiomyocyte structure and contractile function within aligned matrices
Neonatal rat cardiomyocytes are encapsulated within strain-aligned fibrin matrices, with non-aligned disordered hydrogels as controls. Immunofluorescent analysis of sarcomere length and connexin 43 (CX43) gap junction expression verifies that aligned microenvironments promote cardiomyocyte structural maturation. High-speed imaging paired with optical flow tracking algorithms quantifies spontaneous contractile dynamics. Comparisons of peak contraction velocity and directional contractile partitioning along x/y axes confirm that aligned substrates drive rapid, synchronous, anisotropic directional contraction in engineered cardiac tissue.

Figure 4: Uniaxially organised cardiac tissue exhibits improved structural organisation and directional contractility

4. Development and multifunctional validation of piezoelectric composite functional scaffolds
Multi-material electrohydrodynamic co-printing is utilised to manufacture PCL/PVDF piezoelectric composite scaffolds. Mechanical properties, PVDF electroactive phase transformation and electrical signal output are characterised. Results confirm that incorporation of piezoelectric components does not disrupt strain-induced fibre alignment. Electropacing protocols and calcium transient kinetic analysis are performed to compare pacing thresholds, maximum synchronous capture frequency and calcium recovery rates between pure PCL and piezoelectric composite groups. The data verify that spontaneous cardiomyocyte contraction activates endogenous piezoelectric stimulation, comprehensively enhancing cardiac electrophysiological performance. Finally, the full fabrication workflow is validated for building in vitro cardiac models and implantable patches for myocardial infarction repair. The framework is readily adaptable for constructing diverse anisotropic soft tissues including skeletal muscle and peripheral nerve.

Figure 5: Electrohydrodynamically printed piezoelectric diamond scaffolds enhance electrophysiology of aligned cardiac tissue

Conclusions

This study establishes a gelation-coupled strain locking strategy. Uniaxial stretching is applied within the fibrin hydrogel gelation window, and the equilibrium between fibre slippage and network crosslinking generates permanently retained anisotropic architectures. The geometric model clarifies the mechanism of alignment saturation at 1.6-fold stretch. Optimised scaffold lattices enable scalable fabrication of large-area uniaxially aligned and transmural layered biomimetic myocardial matrices. Aligned microenvironments significantly boost cardiomyocyte structural maturation and directional contraction. When combined with PCL/PVDF piezoelectric scaffolds, spontaneous cellular contraction generates intrinsic electrical stimulation to further refine cardiac electrophysiology and calcium handling. The technique features straightforward operation and excellent cytocompatibility, suitable for manufacturing in vitro cardiac models and implantable constructs for myocardial repair. Moreover, this platform can be translated to a broad spectrum of anisotropic soft tissue engineering systems encompassing skeletal muscle and peripheral nerve regeneration.