|Engineering tissue microenvironment-inspired electrospun fibrous scaffolds for intervention of disease progression
|Zhao, Xin (BME)
Hong Kong Polytechnic University -- Dissertations
|Department of Biomedical Engineering
|xiii, 183 pages : color illustrations
|Increasing studies have demonstrated the complex and dynamic tissue microenvironment (TME) may not only significantly alter the disease progression, but also affect the implanted scaffolds' properties and their in vivo treatment response. Electrospinning, as a versatile scaffold preparation technique, has many advantages like simple and feasible process, and ability to produce an ultrafine and continuous fibrous membrane with large surface areas and controllable diameters from nano- to micro-scale range, as well as the ease of functionalization for various purposes. Currently, by loading drugs or combining with other techniques or strategies, electrospinning-derived scaffolds have been widely used to modulate TME to intervene in disease progression. In the proposed three projects of this dissertation, we exploited electrospinning as the main fabrication approach and developed a series of intelligent scaffolds according to the implantation microenvironment of tendon and pancreatic cancer (PC) tissues to suppress tendon adhesion formation, promote tendon healing, and prevent PC recurrence, respectively.
Specifically, for the first project, inspired by the increased expression of matrix metalloproteinase-2 (MMP-2) in the exterior area of the injured tendon site, we designed and prepared a MMP-2 triggered stimuli-responsive drug delivery system. To regulate cell behaviors on a long-term basis, the gene was used as the cargo to intervene in disease progress. Here, extracellular signal-regulated kinase-2 (ERK-2)-siRNA was adopted as the therapeutical agent and incorporated into the gelatin methacryloyl (GelMA) nanogels by water-in-oil (W/O) nano-emulsification technique. Then, the siRNA-loaded GelMA nanogels were encapsulated into poly-L-lactic acid (PLLA) fibers by simple blending electrospinning. The resultant siRNA-laden electrospun membrane showed controllable morphology/architecture, superior swelling, degradation, and mechanical properties. Most importantly, the loaded siRNA could be released on-demand from the membrane in response to the MMP-2 and maintain its biofunction to transfect into cells and block the targeted ERK2 expression, thus suppressing fibroblast adhesion, growth, and proliferation in vitro, while attenuating peritendinous adhesion formation in vivo. This project presents a promising approach exploiting a composite nanogel-incorporated membrane scaffold as both a physical barrier to prevent extrinsic cells invasion and a smart drug delivery vehicle to realize on-demand siRNA release, cooperatively suppressing the adhesion formation during tendon healing.
For the second project, inspired by the accumulated reactive oxygen species (ROS) and aggravated inflammation reaction during the early tendon healing stage that may affect the tendon repair outcomes and later adhesion formation, a Janus dual-layer membrane patch was developed, in which the inner layer was the multi-functional electrospun hydrogel patch (MEHP), while the outer layer was the PLLA fibrous membrane. The MEHP was prepared by blending electrospinning of zinc oxide (ZnO) and GelMA, followed by reinforcement with tannic acid (TA) solution treatment to form a secondary hydrogen-bond-mediated network in the polymer matrix. Such simple but delicate material combination rendered the MEHP with outstanding mechanical and adhesive properties, good biocompatibility, superior anti-oxidative, anti-inflammatory, and antibacterial properties as well as pro-healing effects, which showed huge potential as a novel and efficient therapeutical platform for tendon healing. Taking advantage of the good adhesive properties, Janus patch could be easily fabricated by directly attaching MEHP to PLLA physical barrier membrane. The resultant Janus patch exhibited hierarchical structure and integrated biofunctions, which could prevent adhesion formation while creating a favorable microenvironment for tendon repair. This project provides a proof-of-concept demonstration of regulating tendon healing phases: that is, mitigating oxidative stress and inflammatory reaction during the early inflammatory phase, while directing tendon regeneration and preventing adhesion at the later repair and remodeling phases. We envision that our Janus membrane patch will have great clinical potential as a novel bio-scaffold to improve tendon healing.
For the third project, inspired by the presence of bacteria, e.g., Gammaproteobacteria, in the PC microenvironment that may reduce the chemotherapeutic efficacy of gemcitabine (GEM) by converting GEM into the inactive form (20,20difluorodeoxyuridine), an anti-bacterial and anti-cancer system was proposed. Such system was prepared by first blending electrospinning of GEM and PLLA to obtain GEM-loaded PLLA nanofibrous membranes. Subsequently, a two-step TA-mediated silver (Ag) NP reduction strategy was exploited to in-situ form Ag NPs onto the GEM-loaded PLLA fiber surface. Such scaffold exhibited excellent mechanical performances and appropriate GEM release profile, suggesting the feasibility as a local drug delivery system to be implanted at the tumor resection site during the surgical operation for PC treatment. Moreover, such electrospun membrane could avoid the adverse reactions of intravenously administered GEM and display a combination of short- and long-term anti-tumor performance. Combined with synergistic anti-tumor and anti-bacterial effects of Ag NPs anchored onto the fiber surface, we envision that such composite membrane holds great promise as a therapeutical platform to address the issue of chemotherapy drug resistance caused by bacteria in the pancreatic microenvironment and synergistically improve the therapeutical efficacy of cancer recurrence after surgery.
In conclusion, pursuant to the microenvironmental characteristics of corresponding tissues, we developed a series of intelligent electrospun fibrous scaffolds with different biofunctions, aiming to reverse the adverse microenvironmental factors to ultimately intervene in the disease process and improve treatment outcomes.
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