Bioinspired flexible network scaffolds for soft tissue regeneration
During synthetic scaffold implantation in a clinical setting, graft-host mechanical mismatch is a long-standing issue for soft tissue regeneration. While bioengineers have denoted numerous efforts to resolve this challenge, the regenerative performance of the synthetic scaffolds can be limited by slow tissue growth conditions when compared to autografts, alongside mechanical defects.
In a new report in Science Advances, Shunze Cao and a team of scientists in Engineering, Mechanics, and Orthopedics surgery at the Tsinghua University in China, developed a class of flexible network scaffolds to precisely engineer non-linear mechanical responses. The resulting tissue scaffolds increased tissue regeneration through reduced graft-host mechanical mismatch.
They included a tubular network frame with a flexible network scaffold, with curved microstructures to build the desired mechanical properties and offer a suitable microenvironment for cell growth. The scientists used rat models with sciatic nerve defects or Achilles tendon injuries to show the superior regenerative performance that exceeded the clinically approved electrospun conduit scaffolds.
Bioengineering tissue scaffolds suited for pre-clinical translation
Soft tissue injuries of nerve and blood vessels, tendons, ligaments, and cartilage represent a significant health issue worldwide. Clinically, autografts and allografts are commonly-adopted clinical surgical plans that are in clinical use to treat peripheral nerve defects while facing notable limitations such as limited sources and ethical issues.
Artificial scaffolds for soft tissue regeneration can readily bypass these limits to obtain promising outcomes of regeneration. However, the translational potential of biocompatible scaffolds remain challenging for tissue regeneration due to the mechanical mismatch between the high stiffness of artificial scaffolds and the recipient tissues.
Biologist Lecuit stated that "where shape is at play, forces will function in every single instance." In this work, Cao and colleagues introduced a rational design method for a class of biomimetic, and flexible network scaffolds to replicate nonlinear mechanical responses of tissues, and guide tissue regeneration through greater biocompatibility of the graft and host.
The researchers developed a flexible network and implanted the scaffold in animal experiments with rat sciatic nerve and Achilles tendon defect models to obtain promising results for soft tissue repair in the clinic.
Rational engineering designs to create flexible network scaffolds
The flexible network scaffold contained a tubular soft network structure and an ultrathin nanofibrous film developed at the outer surface of the tubular network. They introduced an inverse-engineering design developed on a model of soft network materials with curvy microstructures.
They then engineered the flexible network scaffolds by combining lithography, chemical vapor deposition and electrospinning to complete the development of a bilayer network scaffold. Using the constructs, they studied the development of curved microstructures for soft tissue regeneration. Then by using finite elemental analysis and in-lab experiments the team tested the mechanical responses of the flexible network scaffolds.
Mechanical behavior of the flexible network scaffolds
The mechanical mismatch between recipient tissue and electrospun conduit scaffolds can result in ineffective regeneration, due to tensile stress on the suture. To assess this effect, they conducted uniaxial tensile responses of flexible network scaffolds in comparison to electrospun conduit scaffolds.
The flexible network scaffold showed much lower risk of suture pull-out than the electrospun conduit scaffold due to much smaller tensile stress. The network scaffolds showed excellent flexibility and a capacity to retain the patency of the luminal conduit, without mechanical failure during the regeneration experiments.
Validating the regenerative performance of the tissue scaffolds
The study team validated the regenerative performance of the flexible scaffold by conducting experiments using rat models with long defects in sciatic nerves.
Aside from the flexible network scaffolds, the team tested electrospun conduit scaffolds and lattice scaffolds with straight microstructures and autologous nerve grafts. The experiments included histological, biomechanical, or functional analyses. Nerve regeneration also accompanied blood vessel regeneration for enhanced regenerative performance of the flexible network scaffolds compared to the electrospun conduit scaffolds.
The flexible network scaffolds showed extensive applications during soft tissue regeneration in a rat Achilles tendon defect model with flexible network and electrospun conduit scaffolds. While the regenerated fibers underwent a remodeling process with the flexible network scaffold, most of the collagen converted from types III to type I. The scientists studied the function of regenerated tendons by conducting quantitative analysis with CatWalk to represent walking videos of rats with Achilles tendon defects repaired post-operatively by two-weeks.
In this way, Shunze Cao and colleagues implemented rational reverse-engineering design and biomimetic flexible network scaffolds to enhance the efficiency of soft tissue regeneration. The lightweight, highly flexible, and mechanically biomimetic features of the network scaffolding are appealing for clinical treatment of soft tissue injuries.
The design platform provided a fundamental tool to study and understand the relationship between mechanical microenvironments and biological responses, alongside biological responses of cells and tissues. The team was able to combine experimental investigations with bioinformatics analyses to reveal molecular mechanisms underlying the pro-regeneration effects of biomimetic flexible network scaffolds.
More information: Shunze Cao et al, Inversely engineered biomimetic flexible network scaffolds for soft tissue regeneration, Science Advances (2023). DOI: 10.1126/sciadv.adi8606
Sean V. Murphy et al, Opportunities and challenges of translational 3D bioprinting, Nature Biomedical Engineering (2019). DOI: 10.1038/s41551-019-0471-7
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