Medical Application of Nonwoven Fabrics - Intra-abdominal Spacers for Particle Therapy

The authors aimed to introduce a medical application for nonwoven fabric as spacers in particle therapy. Particle therapy, exhibiting more focused effects on target tissues, has emerged as a promising treatment modality. However, close proximity of tumor tissue and adjacent organs makes delivery of curative doses to the tumor difficult because severe radiation morbidities might occur. A method using surgically placed GORE-TEX sheets as a spacer has been reported. Although this method provides for separation of adjacent organs, the material is not resorbed. To overcome these anatomical and therapeutic difficulties, and to deliver effective radiation doses to treat upper abdominal tumors, we have developed a nonwoven fabric spacer composed of bioabsorbable suture material. The absorbable polyglycolic acid (PGA) spacer had water-equivalent, biocompatible, and thickness-retaining properties. Although further evaluation is warranted in a clinical setting, the PGA spacer may be effective to block particle beams and to separate normal tissues from the radiation field. These findings suggest that the nonwoven-fabric PGA spacer might become a useful device in particle therapy.


Introduction
Two of the properties of nonwoven fabrics that have justified previous use in medical products are economic viability in single-use scenarios and reliable performance [1]. The design and performance characteristics of these products-which come into close contact with the human body-are driven by their end use, which determines the desired function and barrier, absorption, and strength properties, and the fact that any chemical additives need to be biocompatible. Nonwoven products remain the component of choice for providing appropriate protection because of their ability to create barriers due to either the structure of the nonwoven material itself or an additional active coating for personal protective apparel. Nonwoven materials are also beginning to play a role in extracorporeal devices, such as artificial lungs, hearts, and kidneys, as well as in ligament repairs and other skeletal scaffolds, yet these uses are still rare compared with their other uses [2].
Radiotherapy is one of the strategies used against several cancers, and X-ray or particle beams are mainly used for cancer treatment. Particle therapy, exhibiting more focused effects on target tissues, has emerged as a promising treatment modality. Several systematic reviews associated with proton or carbon-ion beam therapy discuss the extensive use of particle therapy to treat various malignant tumors, including chordoma, ocular melanoma, and prostate cancer [3][4][5]. Several studies have indicated the efficacy of proton therapy for the treatment of hepatocellular carcinoma or pancreatic cancer [6][7][8][9]. However, in certain cases, it is difficult to deliver curative doses of radiation to treat upper abdominal tumors without damaging adjacent radiosensitive organs, such as the duodenum, jejunum, and stomach. To overcome these anatomical difficulties and to deliver effective radiation doses to treat upper abdominal tumors, nonwoven fabric barriers have been applied as spacers to separate tumors and adjacent organs [10,11].

Medical application of nonwoven fabric spacers
Nonwoven fabric is a fabric-like material manufactured from long fibers bonded together by chemical, mechanical, heat, or solvent treatment. The performance characteristics of nonwoven fabrics vary according to the material components and the manufacturing process. A characteristic of nonwoven fabrics is not to have directionality for strength or growth. In addition, specific features of nonwoven fabrics include "water absorbency," "chemical resistance," "breathability," "abrasion resistance," and "flexibility." These characteristics of nonwoven fabrics support their use as surgical gowns and hats, masks, drapes, water-absorbing mats, and machine covers. The GORE-TEX sheet is a waterproof, breathable fabric membrane and has been widely used in permanent implants, including the artificial blood vessel, for many years. The GORE-TEX sheet was the first nonwoven fabric to be applied as a spacer in the field of particle therapy [10][11][12] (Figure 1). The use of this spacer allows the application of particle therapy in cases in which particle therapy may result in severe incurable damage to adjacent organs. However, although the GORE-TEX spacer is useful during the period of particle therapy, it becomes a foreign body after the therapy [12]. Problems related to the ongoing presence of the spacer may be avoided by removal during a second surgery, but repeated operations might be a risk for the patient.

Usefulness of nonwoven fabric spacers in the treatment of pancreatic cancer
Despite recent progress in treatment options for pancreatic cancer, survival rates have failed to show any significant improvement [13]. Among these modalities, resection is the only curative treatment for pancreatic cancer, but only 10%-15% of patients have operable tumors [14,15]. The remaining patients cannot undergo resection because of local invasion or distant metastasis at the time of diagnosis [16]. Local invasion is found in approximately 40% of patients with pancreatic cancer at the time of presentation and most commonly includes the superior mesenteric vessels or the celiac trunk [17].
Chemoradiotherapy with concurrent 5-fluorouracil was historically considered the standard therapy for locally advanced pancreatic cancer [18]. Recently, successful results have been reported with the use of a combination of gemcitabine and proton therapy to treat this type of advanced pancreatic cancer. However, reductions of the irradiation doses and target fields were necessary because approximately 10% of the patients subsequently developed Grade 3 or higher gastric ulcers several months after completing the therapy [9]. In such cases, surgical placement of a spacer between the pancreas and the gastrointestinal tract might be an effective option to reduce gastrointestinal toxicity and allow the continued use of high doses of radiation.
Among pancreatic cancers in various regions, good candidates for spacer placement are unresectable pancreatic body and tail cancers. Pancreatic head cancer is not amenable to this treatment strategy because the pancreatic head cannot be separated from the duodenum.
The treatment strategy aims to keep the gastrointestinal tract away from the irradiation field by spacer placement and to allow the application of proton-beam radiotherapy with curative intent. The GORE-TEX sheets and the omentum are superimposed and applied as a spacer to maintain a safety margin of approximately 10 mm from the gastrointestinal tract. The spacer is finely fixed to the retroperitoneum, peritoneum, stomach, and surrounding tissues using 4-0 nylon to avoid hernia formation. The use of absorbable sutures for the fixation must be avoided because it leads to migration of the spacer. In the treatment of pancreatic body and tail cancers, target gastrointestinal tract components to be protected by spacer placement include the stomach, duodenum, small, jejunum, and colon. Of note, the protection of the duodenal bulb and horizontal part of the duodenum in the region of the Treitz ligament is of particular importance. The spacer placement surgery is a first step to allow proton-beam radiotherapy, and no part of the tumor is resected during this procedure.
Until the end of 2013, 8 patients with unresectable pancreatic body and tail cancers were treated by spacer placement and particle therapy as phase I and phase II trials. One-year and 2-year survival rates were 87.5% and 43.8%, respectively. These patients were free from complications associated with the gastrointestinal tract.
We believe that surgical spacer placement can be used to maintain a safety margin around the gastrointestinal tract. In consequence, full-dose particle-beam radiotherapy for pancreatic body and tail cancers can be achieved without serious toxicities.

Novel nonwoven fabric bioabsorbable spacer for particle radiotherapy
The purpose to produce a bioabsorbable nonwoven fabric spacer is to overcome problems associated with nonabsorbable GORE-TEX spacer [19]. The nonabsorbable GORE-TEX spacer might cause serious complications after the completion of particle therapy. On the other hand, although previous investigators have reported usefulness of gel spacers for separation of prostate and rectum [20,21], those spacers are inappropriate for the upper abdomen, which contains lots of free space. Therefore, at present, a nonwoven fabric bioabsorbable spacer is necessary and appropriate for the separation of tumor and adjacent organs of upper abdomen malignancies.
The process for producing the nonwoven fabric involves entangling threads in 3 dimensions with a needle-punching process and other methods [22,23]. Spacer placement during radiotherapy is a promising method designed to allow increased tumor dose while limiting radiation exposure to adjacent organs. The spacer exhibits excellent properties related to bioabsorbability, biocompatibility, thickness retention, and water equivalency according to physical and animal experiments (Figure 2). The reason and the advantage for the use of PGA to construct this nonwoven fabric spacer are that PGA is one of the most widely studied polymers and has excellent mechanical properties and biological affinity [24,25]. Historically, PGA has played a central role in surgery since its development as the first synthetic absorbable suture material in 1962 [26]. The PGA is absorbed in 60-90 days after insertion in the body. It is hydrolyzed without any phagocytosis, which results in a weaker immune response than that of absorbable organic sutures [27]. The degradation of PGA generally involves random hydrolysis of their ester bonds. Under physiologic conditions, PGA is also degraded by certain enzymes, especially those with esterase activity [28,29]. The attractiveness of PGA as a biodegradable polymer in medical application is that its degradation product glycolic acid is a natural metabolite [29]. The glycolic acid is nontoxic and can enter the tricarboxylic acid cycle, after which it is excreted as water and carbon dioxide. Part of the glycolic acid is also excreted in urine [26,28].
As for PGA sutures, Chu et al. have reported a simple degradation mechanism via homogeneous erosion [30][31][32]. The degradation process occurs in two stages, the first involves the diffusion of water into the amorphous regions of the matrix and simple hydrolytic chain scission of the ester groups. The second stage of degradation involves largely the crystalline areas of the polymer, which becomes predominant when the majority of the amorphous regions have been eroded. It is important to note that PGA nonwoven fabric spacer is comprised of the PGA suture mainly with a 3-dimensional needle-punching process. Therefore, the degradation mechanism of the content of the PGA spacer could be same as PGA sutures. However, it is possible that because the volume of PGA polymers in the PGA spacer is quite large, inflammatory biological responses might be different from that of relatively small volume of PGA suture (Figure 3).  Although there is no clear definition of a bioabsorbable nonwoven fabric spacer reported, an optimal bioabsorbable spacer must have thickness-retaining and water-equivalency properties according to treatment duration [19]. In particle therapies, because treatment protocols take 2-7 weeks [5,33], a spacer that maintains its thickness for the duration of or slightly longer than the treatment period seems to be ideal. From our investigation, the percentage of thickness retention of the PGA spacer varies according to the concentration of the PGA sutures. The PGA spacer product with 0.2 g/cm 3 of PGA sutures retains more than 90% thickness for 8 weeks. Therefore, this PGA spacer could be applied in various protocols in particle therapy. The bioabsorbable PGA spacer might become a useful device and expand indications for particle therapy.

Future direction of medical application of bioabsorbable nonwoven fabric spacers
Adhesions after surgery might lead to serious complications [34,35]. In the pelvic and abdominal sites, these complications might lead to small-bowel obstruction, infertility, chronic pelvic pain, and difficulty with further surgical access. Therefore, regarding spacer placement, it is necessary to minimize adhesions between the spacer and surrounding organs. In our preclinical study, the efficacy and the safety of a bioabsorbable spacer composed of PGA sutures were investigated in several animal models [19]. The PGA nonwoven fabric spacer exhibited excellent properties, no toxic effects in the animals, and negligible adhesion formation. However, different conditions between experimental animals and clinical settings might affect outcomes, and adhesion formation may be different in the presence of malignant tumors. Therefore, if it is necessary to improve properties of the nonwoven fabric PGA spacer, nextgeneration spacers are expected to avoid adhesion as far as possible. A promising method might be to combine an anti-adhesion material with the PGA spacer. In our recent observation using a healthy rat model, adhesion was significantly decreased, and no exceptional toxicity risk was observed compared with the control group. In the future, less-invasive methods, including endoscopic surgery, might be applied for implantation of the spacer.

Conclusion
The absorbable PGA spacer had water-equivalent, biocompatible, and thickness-retaining properties. Although further evaluation is warranted in a clinical setting, the PGA spacer may be effective to block particle beams and to separate normal tissues from the radiation field. These findings suggest that the nonwoven fabric PGA spacer might become a useful device in particle therapy.