Basic ScienceMitomycin C-polyethylene glycol controlled-release film inhibits collagen secretion and induces apoptosis of fibroblasts in the early wound of a postlaminectomy rat model
Introduction
Epidural fibrosis is an expected healing consequence after laminectomy. This extradural fibrotic tissue may extend into the vertebral canal and adhere to the dura mater and nerve roots, causing recurrent symptoms including pain [1], [2], [3], [4], possibly leading to the failure of spinal surgery [5]. Furthermore, epidural adhesions make reexposure of the same operative area technically difficult and dangerous because the risk of nerve root injury and dural tears are greatly increased [6], [7].
The control of scar formation has been one of the main concerns in spine surgery and the subject of research for many years. A large number of materials and methods for preventing epidural fibrosis have been studied including free or pedicle fat grafts [8], [9], absorbable gelatin films and sponges, cellulose mesh [9], [10], hyaluronic acid [11], and local or systemic pharmaceuticals such as methylprednisolone and dexamethasone [12], [13], [14], [15], [16] in an attempt to physically or chemically inhibit scar ingrowths.
Polyethylene glycol (PEG) is a water-soluble polymer, has no electric charge and no affinity for any specific organ, and is nonimmunogenic and nontoxic [17], [18], [19]. Although PEG significantly reduced postlaminectomy proliferative scar without affecting the integrity of incisional wound healing, the process of readsorption would result in a fibrotic mass and leave a gap between the sheet and the dura [20]. Meanwhile, PEG could not prevent nerve root adhesion.
Mitomycin C (MMC), a widely used chemotherapeutic drug, has been proposed as a potential adjuvant for the control of scar tissue in surgical wounds [21], [22], [23] because of its capacity to inhibit proliferation and induce the apoptosis of fibroblasts [24], [25]. The toxic characteristics of MMC were most likely responsible for the greater tissue damage that occurred when it was used in the injected form or at high concentration in long-term use, causing increased scar tissue formation and even the failure of the wound healing [26]. The strategy to reduce the dose of MMC in topical application would be encouraging.
In the current study, we used a new controlled-release delivery system in which a small dose of MMC was adsorbed on the PEG film. The purpose of our research was to investigate the efficacy of MMC-PEG film as a biophysical and chemical barrier to suppress postlaminectomy scar invasion. We hypothesize that with the decomposition of PEG film, MMC would be continuously released and induce the apoptosis of fibroblasts. If true, it will offer a novel strategy to apply MMC in the prevention of postlaminectomy adhesions in spine surgery.
Section snippets
Animals
A total of 64 mature male Sprague-Dawley rats, weighing 300±20 g, were used in this study (protocol approved by the Animal Care and Research Committee of the Nanjing Medical University, China).
Preparation of MMC-PEG film
First, three different liquids were prepared. Liquid A: 20 g polyvinyl alcohol-124 was resolved in 85% ethanol, dried at 50°C, and redissolved completely in 200 mL water and was sterilized. Liquid B: the mixture of 2.0 g sorbic acid and 2.0 g glycerin was resolved in 50 mL water and sterilized. Second, 50
Macroscopic evaluation of epidural scar adhesion
The recovery of all rats was uneventful after the operations. There was no case of wound infection or neurological deficit in any rat. In the laminectomy sites of rats treated with PEG, the dura mater was covered by a thin adhesion, which could be easily removed and expose clean dura mater with little bleeding. But in the laminectomy sites of rats treated with saline, severe, thick, and tenacious epidural scar adhesions were found between the dura mater and surrounding tissue. The dissection of
Discussion
Epidural fibrosis remains a great challenge in the recovery after spine surgery. Fibroblasts, originating from the overlying muscles and following extension of postoperative hematoma into the vertebral canal, release excessive extracellular matrix and cause the abundance and strong adhesion of the tissue [27]. Thus, the migration of fibroblasts from the raw surface of the erector spine musculature was stated as the source of postoperative scar tissue [28].
Various reagents and materials have
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FDA device/drug status: not applicable.
Author disclosures: JL (stock ownership, including options, warrants, paper; grants, Key Technique Project, Shanghai; other relationships, paper); BN (stock ownership, including options, warrants, paper; grants, Key Technique Project, Shanghai; other relationships, paper); LZ (other relationships, paper); JY (other relationships, paper); XC (stock ownership, including options, warrants, paper; other relationships, paper); WZ (stock ownership, including options, warrants, paper; other relationships, paper).
This project was funded by the Key Technique Project of Shanghai (08JC1406900), the Key Project of Nanjing Medical University (08NMUZ023), and the Natural Science Foundation of Jiangsu Provincial Education Department (06KJD320075).