MMP‐2 Responsive Unidirectional Hydrogel‐Electrospun Patch Loading TGF‐β1 siRNA Polyplexes for Peritendinous Anti‐Adhesion

Abstract

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.

Design of therapeutic biomaterials to control inflammation

“…For example, myeloperoxidase-responsive biomaterials exhibiting luminescent signals can be applied to estimate neutrophil count and allow specific imaging of neutrophils in inflammation-associated diseases 75 , 76 . Similarly, biomaterials with a structure sensitive to proteolytic matrix metalloproteinases, which are abundant in inflammatory sites, can deliver drugs to inflamed tissues 77 , 78 . In addition, low pH is a feature of the inflammatory microenvironment 79 , 80 .…”

Gelatin/Polycaprolactone Electrospun Nanofibrous Membranes: The Effect of Composition and Physicochemical Properties on Postoperative Cardiac Adhesion

“…And pelvic adhesions resulting from gynecologic surgery may also cause chronic pelvic pain, small bowel obstruction, and female infertility ( Al-Jabri and Tulandi, 2011 ; Dawood and Elgergawy, 2018 ). Besides, tendon adhesions not only cause dysfunction and pain, but also usually require surgical intervention to loosen ( Liu et al, 2013 ; Cai et al, 2021 ). In addition, many patients undergoing cardiac surgery require reoperation even multiple operations.…”

Self‐Healing Hydrogel Embodied with Macrophage‐Regulation and Responsive‐Gene‐Silencing Properties for Synergistic Prevention of Peritendinous Adhesion

“…[ 46 ] Our study also suggests that an MMP‐responsive hydrogel with on‐demand siRNA nanoparticle release behaviors could effectively inhibit fibroblast proliferation and precisely prevent tendon adhesion. [ 33 ] To attenuate adhesion more effectively, Smad3‐siRNA nanoparticles were encapsulated into the MMP‐degradable GelMA microspheres, then mixed with the self‐healing HA hydrogel during gel formation. To prepare the Smad3‐siRNA nanoparticles, the effective gene vector of G5‐GBA was synthesized according to previous literature (Figure S9A, Supporting Information).…”

“…We previously demonstrated that the hydrogel–electrospun composite barrier achieved unidirectional siRNA nanoparticle release toward peritendinous tissue. [ 33 ] This unidirectional release of siRNA nanoparticles was only able to transfect the fibroblasts and myofibroblasts outside, and did not interfere with the tenocyte inside. Therefore, tendon healing was not adversely obstructed by the unidirectional release.…”

“…In our previous works, the electrospun nanofibers [ 32 ] and chitosan hydrogel [ 33 ] were fabricated as antiadhesion barriers, in which siRNA nanoparticles were encapsulated into the material carrier for preventing peritendinous adhesion. However, bidirectional drug releasing of siRNA may have side effect on tendon healing.…”