Wnt3a-Modified Nanofiber Scaffolds Facilitate Tendon Healing by Driving Macrophage Polarization during Repair

Abstract

Inflammation is part of the natural healing response, but persistent inflammatory events tend to contribute to pathology changes of tendon or ligament. Phenotypic switching of macrophages within the inflammatory niche is crucial for tendon healing. One viable strategy to improve the functional and biomechanical properties of ruptured tendons is to modulate the transition from inflammatory to regenerative signals during tendon regeneration at the site of injury. Here, we developed a tendon repair scaffold made of biodegradable polycaprolactone by electrospinning, which was modified to deliver Wnt3a protein and served as an implant to improve tendon healing in a rat model of Achilles tendon defect. During the in vitro study, Wnt3a protein promoted the polarization of M2 macrophages. In the in vivo experiment, Wnt3a scaffold promoted the early recruitment and counting curve of macrophages and increased the proportion of M2 macrophages. Achilles function index and mechanical properties showed that the implantation effect of the Wnt3a group was better than that of the control group. We believe that this type of scaffold can be used to repair tendon defects. This work highlights the beneficial role of local delivery of biological factors in directing inflammatory responses toward regenerative strategies in tendon healing.

Advancements in scaffold for treating ligament injuries; in vitro evaluation

“…Increase in cell numbers and biocompatibility [106] PCL/dicalcium phosphate dihydrate (DCPD) mixed scaffolds Increased surface roughness leading to enhanced cell adhesion [108] 2.3 cm long, 2.3 mm diameter PCL scaffold 3-year-long degradation experiment in rats [16] PCL/silk fibers with bFGF Improved cell viability, proliferative capacity, and gene expression [113] PCL/CS with cellulose nanocrystals (CNC) Maximum toughening effect observed with increased tensile strength and elastic modulus [56] Aligned PCL stents of varying thickness Mechanical properties vary with thickness and alignment [116] PLLA vs. PCL scaffolds PCL exhibited superior mechanical properties [117] PLA PLA-based scaffold overview High mechanical strength, biodegradability, biocompatibility [132,133] Derived from fermentation of corn and sugarcane Safe for human use, non-toxic, environmentally beneficial Approved by the FDA for biomedical applications Properties and limitations of PLA Moderate degradation rate, hydrophobicity, low impact toughness [131,132] Can be combined with other polymers for specific target tissues [131] Studies on PLA-based scaffolds Marıt'a C et al: Investigated mechanical properties. Maintained high mechanical properties after 12 months [133] PLA degrades at a 20% weight loss rate in one year [134] Ishii et al: PLA induced lesser inflammatory response and higher volume retention than PLLA [135] Technological advances in PLA scaffolds LTE: Fiber spatial distance increased from 100 to 300 μm, tangential modulus reduction from 6-15 MPa to about 200 kPa [49] Lu et al: Developed capillary channel fiber scaffolds with aligned structures [134] (Continues) Liu et al: Used 3D printing for PLA hydroxyapatite helical scaffolds combined with Pluronic F-127 hydrogel.…”

“…[130] Finally, Wei et al explored the effects of adding Wnt3a protein to PCL that promote the polarization of M2 macrophages, guiding the inflammatory response to heal the injured tissue, a marked improvement compared to pure PCL in the Achilles tendon of rabbits. [131] 3.…”

Tannic Acid-Modified Decellularized Tendon Scaffold with Antioxidant and Anti-Inflammatory Activities for Tendon Regeneration

“…2 Inflammation is an inevitable phase of the healing response, but a long-term inflammatory microenvironment in tendon injury site often leads to aseptic inflammation, resulting in matrix degradation, fibrosis of surrounding tissues, 3 tendon adhesion, 4 and the inhibition of tendon regeneration. 5 Indeed, inflammation also damages the tenogenic capacities of tendon-derived stem cells (TDSCs), such as aberrant differentiation, 6 hindering tendon repair and regeneration. Moreover, inflammation can lead to the production of reactive oxygen species (ROS), including hydrogen peroxide (H 2 O 2 ), hydroxyl radical ( • OH), and superoxide anion radical ( • O 2 − ).…”

Inversely engineered biomimetic flexible network scaffolds for soft tissue regeneration

“…Injuries of soft tissues, such as peripheral nerves, blood vessels, tendons, ligaments, and cartilage, represent a class of major health issues worldwide (1)(2)(3)(4)(5)(6)(7). For instance, in the US, the annual cost of peripheral nerve surgeries before 2010s was more than $150 billion, and more than 200,000 surgeries were performed annually (8,9).…”

“…The flexible network scaffold consists of a tubular network frame with inversely designed curved microstructures to offer desired biomimetic mechanical properties. To provide proper biological activity, an electrospun ultrathin film with a thickness of 0.01 mm was deposited around the scaffold, which allows smoother transportation of nutrition and metabolic waste (7,52,53), as compared to the clinically approved electrospun conduit scaffolds (0.4 mm in thickness). Note that the proposed tubular network designs differ from most of structural designs (54)(55)(56) adopted in flexible electronics in the geometric forms and nonlinear mechanical responses.…”