Antiadhesion barriers such as films and hydrogels used to wrap repaired tendons are important for preventing the formation of adhesion tissue after tendon surgery. However, sliding of the tendon can compress the adjacent hydrogel barrier and cause it to rupture, which may then lead to unexpected inflammation. Here, a self‐healing and deformable hyaluronic acid (HA) hydrogel is constructed as a peritendinous antiadhesion barrier. Matrix metalloproteinase‐2 (MMP‐2)‐degradable gelatin‐methacryloyl (GelMA) microspheres (MSs) encapsulated with Smad3‐siRNA nanoparticles are entrapped within the HA hydrogel to inhibit fibroblast proliferation and prevent peritendinous adhesion. GelMA MSs are responsively degraded by upregulation of MMP‐2, achieving on‐demand release of siRNA nanoparticles. Silencing effect of Smad3‐siRNA nanoparticles is around 75% toward targeted gene. Furthermore, the self‐healing hydrogel shows relatively attenuated inflammation compared to non‐healing hydrogel. The mean adhesion scores of composite barrier group are 1.67 ± 0.51 and 2.17 ± 0.75 by macroscopic and histological evaluation, respectively. The proposed self‐healing hydrogel antiadhesion barrier with MMP‐2‐responsive drug release behavior is highly effective for decreasing inflammation and inhibiting tendon adhesion. Therefore, this research provides a new strategy for the development of safe and effective antiadhesion barriers.

Bio‐derived hydrogel patch systems exhibit promising potential in localized drug delivery for the prevention and treatment of various diseases. However, the uncontrolled release from the hydrogel patch both in time and space, is not an optimal strategy for peritendinous anti‐adhesion, leading to transient effect and unnecessary diffusion of therapeutics. Here, an innovative composite anti‐adhesion patch is designed for on‐demand and unidirectional polyplexes delivery to inhibit fibroblasts proliferation and collagen deposition by silencing fibrosis gene transforming growth factor‐β1 (TGF‐β1). Firstly, a metalloproteinase‐2 (MMP‐2) degradable hydrogel is prepared by crosslinking allyl glycidyl ether (AGE) modified carboxymethyl chitosan (CMCS‐AGE) with MMP‐2 substrate peptide CPLGLAGC (MMP‐2 sp). Then, the hydrogel loading TGF‐β1 siRNA polyplexes are attached onto polycaprolactone (PCL) electrospun fibers to form a composite bilayer patch. The hydrogel–electrospun fibers (H–E) patch shows MMP‐2‐responsive and unidirectional release behaviors of encapsulated TGF‐β1 siRNA polyplexes and associated gene silencing effect on TGF‐β1, leading to the inhibition of fibroblasts proliferation. Moreover, after implanting the H–E patch by wrapping the repaired tendon, the formation of adhesion tissue is responsively attenuated in MMP‐2 overexpression microenvironment. This study presents a promising approach employing a composite bilayer patch with on‐demand and unidirectional delivery strategy for peritendinous anti‐adhesion.

and aseptic inflammation are induced, proliferation of fibrosis tissue is promoted, which in turn induces the formation of fibrotic encapsulation and postoperative tissue adhesion. [3][4][5] In response to these phenomena, recent studies have mainly focused on optimizing the properties of the biomaterials. However, the impact on the microenvironment triggered by the implants from an immune biological viewpoint has been neglected. [6][7][8] Currently, the internal mechanism underlying implants in the peripheral immune microenvironment remains unknown, and this has substantially limited the application of biomaterials.As a host immune defense mechanism, FBR to implants occurs in the following steps: after implantation of biomaterials in the body, the first stage of FBR is non-specific protein adsorption on the implant surface which serves as binding sites for inflammatory cells. Thereafter, infiltrating neutrophils and macrophages from peripheral blood recognize the binding sites and integrate with the surface of biomaterials. This induces the formation of the inflammatory microenvironment. [9] Inflammatory factors released by locally enriched macrophages recruit and drive the differentiation of fibroblasts to myofibroblasts. Finally, myofibroblasts secrete large amounts of collagen (Col) and matrix metallopeptidase (MMP), ultimately resulting in Foreign body reactions (FBR) to implants seriously impair tissue-implant integration and postoperative adhesion. The macrophage, owing to its phenotypic plasticity, is a major regulator in the formation of the inflammatory microenvironment; NF-κB signaling also plays a vital role in the process. It is hypothesized that NF-κB phosphorylation exerts a proinflammatory regulator in FBR to polylactide membranes (PLA-M) and adhesion. First, in vitro and in vivo experiments show that PLA-M induces NF-κB phosphorylation in macrophages, leading to M1 polarization and release of inflammatory factors. The inflammatory microenvironment formed due to PLA-M accelerates myofibroblast differentiation and release of collagen III and MMP2, jointly resulting in peritendinous adhesion. Therefore, JSH-23 (a selective NF-κB inhibitor)-loaded PLA membrane (JSH-23/PLA-M) is fabricated by blend electrospinning to regulate the associated M1 polarization for peritendinous anti-adhesion. JSH-23/PLA-M specifically inhibits NF-κB phosphorylation in macrophages and exhibits anti-inflammatory and anti-adhesion properties. The findings demonstrate that NF-κB phosphorylation has a critical role in PLA-induced M1 polarization and aggravating FBR to PLA-M. Additionally, JSH-23/PLA-M precisely targets modulation of NF-κB phosphorylation in FBR to break the vicious cycle in peritendinous adhesion therapy.