Porcine small intestine submucosa (SIS) is not an acellular collagenous matrix and contains porcine DNA: Possible implications in human implantation

Abstract

Porcine small intestinal submucosa (SIS) has been recommended as a cell-free, biocompatible biomaterial for the repair of rotator cuff tendon tear. However, we have observed noninfectious edema and severe pain in patients who have undergone SIS implantation for tendon repair. The aim of this study was to conduct an independent assessment of the safety and efficacy of Restore SIS membrane. The Restore orthobiologic implant was examined by histology and the nested PCR technique using porcine immunoreceptor DAP12 gene to examine if SIS membrane contained porcine cells or DNA, respectively. The material was also implanted into mice and rabbits for the evaluation of biological reaction and inflammatory response. Restore SIS was found to contain multiple layers of porcine cells. Chloroacetate esterase staining showed that some of these cells were mast cells. Nested PCR of the DAP12 gene demonstrated that Restore SIS contained porcine DNA material. Subcutaneous implantation of Restore SIS membrane in mice, and in rabbits for rotator cuff tendon repair, showed that the membrane caused an inflammatory reaction characterized by massive lymphocyte infiltration. In conclusion, Restore SIS is not an acellular collagenous matrix, and contains porcine DNA. Our results contradict the current view that Restore SIS is a cell-free biomaterial, and that no inflammatory response is elicited by its implantation. We suggest that further studies should be conducted to evaluate the clinical safety and efficacy of SIS implant biomaterials.

In vitro study comparing two collageneous membranes in view of their clinical application for rotator cuff tendon regeneration

“…21 Because of this, both SIS and GJ are suitable candidates as scaffolds for tendontissue-engineered therapies, because they may provide a natural three-dimensional scaffold for cell and tissue growth, and the presence of growth factors, such as bFGF or TGF-b1, have mitogenic effects on cells and stimulate ECM synthesis. 10 In summary, results of the present study together with the recent concerns on the clinical use of SIS, because of side effects observed in patients, 14,38 support the conclusion that GJ represents more appropriate characteristics than SIS to be used for rotator cuff tendon healing and as a scaffold for in situ tissue engineering and for the in vitro bioengineering of tendons for the regeneration of massive rotator cuff tears. Tenocytes isolated from tendons of animals submitted to GC systemic administration showed a lower proliferation rate and metabolic activity compared with tenocytes from healthy tendons.…”

“…21 However, so far, few studies have been done on rotator cuff tendon regeneration by means of in situ tissue engineering and in vitro bioengineering of tendons as compared to the extensive work on bone and cartilage. 6,14,[22][23][24][25] This previous literature review, showed the necessity for future studies in this area, and, therefore, an in vitro study was performed by isolating tenocytes from the rotator cuff of normal and GC-treated rats. The tenocytes were cultured on two collagenous membranes and cell proliferation and function were recorded.…”

“…SIS has been reported to be an acellular collagen-based matrix primarily composed of more than 90% fibrillar collagen (type I, II, and V) and containing transforming growth factor b 1 (TGF-b1). 14 Many experimental studies support the use of SIS in musculoskeletal soft tissue healing such as meniscus, Achilles tendon, and rotator cuff tears. [15][16][17][18] GJ is reported to retain the major biological component of dermis including collagen types I, III, IV, VII, elastin, proteoglycans (chondroytin sulphate and hyaluronic acid), laminin, tenacin, fibroblast growth factor (bFGF), and blood vessel channels.…”

Scaffolding in tissue engineering: general approaches and tissue-specific considerations

“…Moreover, apart from the excellent biocompatibility of the natural ECM, growth factors preserved in the decellularized matrix may further facilitate cell growth and remodeling [9]. Nevertheless, cell seeding in decellularized ECM may also lead to inhomogeneous distribution while incomplete removal of cellular components may elicit immune reactions upon implantation [129].…”

Strategies in Biologic Augmentation of Rotator Cuff Repair: A Review

“…Allogenic ECMs can still contain some DNA from their allogenic source and may induce inflammatory responses in the host [22]. These inflammatory responses can cause pain and edema at the site of repair and may increase the degeneration of the rotator cuff repair that has been documented in the initial degenerative process of the rotator cuff [59]. They are also less elastic than autogenic tendon, which may result in comparably increased retear rates due to decreased load-carrying abilities [14].…”