Novel applications of biomaterials in the management of parastomal hernia and anal fistula

MD (res)The aim of this thesis was to explore novel applications for both traditional and contemporary biomaterials in the management of parastomal hernia and anal fistula. Parastomal hernias can be prevented or repaired using synthetic mesh; however, reported complications include infection, fibrosis and potential bowel erosion. The prophylactic role of a cross-linked collagen implant was assessed in terms of safety, feasibility and potential efficacy. Additionally, the human host response to this implant was evaluated. There were no complications related to infection or the implant‟s proximity to the bowel. The implant had excellent biocompatibility and resistance to degradation in most patients, and although fibrovascular in-growth and ECM deposition were limited, it seems to have excellent potential for soft tissue reinforcement and, more specifically, prevention of parastomal hernias. Anal fistulas are in the main successfully treated by surgical fistulotomy, however damage to the anal sphincter complex and subsequent incontinence have led to the development of other techniques which aim to either lessen or avoid such disturbance. One strategy involves the traditional cutting seton, and a modification of this technique, the „snug‟ silastic seton was assessed. In the short-medium term, this modification was demonstrated to be an effective addition to the fistula surgeon‟s armamentarium, although minor incontinence remained a concern. Other approaches employing contemporary biomaterials, fibrin glue and porcine intestinal submucosa, are aimed at tissue repair, rather than minimizing destruction. Their success rates however are highly variable. A pilot study aiming to assess the safety and potential efficacy of an 4 alternative biomaterial, cross-linked collagen in two different physical formats, was presented. In the short-medium term, both formats were shown to be safe, and equally effective. The results justify continued research into the use of biologically derived materials to heal anal fistulas. In conclusion, although disparate pathologies were addressed, both they and the thesis are unified by demonstrating that an understanding of the specific disease pathology, wound healing, and the host response to materials (synthetic and biological) are central to their successful management

Mechanisms of Biomaterial-Mediated Cardiac and Esophageal Repair

Biologic scaffolds derived from mammalian extracellular matrix (ECM) have been extensively used in pre-clinical and clinical applications to promote constructive tissue remodeling in a number of anatomic locations. The clinical success of these technologies depends on a number of factors including the species and tissues from which they are derived, the efficacy of the decellularization process, and post-processing modifications such as crosslinking and solubilization, among others. The ECM is produced by the resident cells of every tissue and hence, it is thought to constitute the ideal substrate for each unique cell population. It is therefore logical to assume that a substrate composed of site-specific ECM would be favorable for clinical use in homologous anatomic locations. However, the advantages of using site-specific (homologous) ECM scaffolds in clinical applications is still a matter of debate. Part of the difficulty in addressing this issue arises from the fact that most studies have investigated the application of ECM-derived scaffolds in either homologous or non-homologous locations independently, but they have rarely been directly compared in properly designed studies. The present dissertation shows the development of ECM-based biomaterials derived from cardiac and esophageal tissues. The decellularized scaffolds are compliant with decellularization standards and are then used to evaluate the tissue specific effects of homologous ECM in vitro and in a preclinical models of cardiac and esophageal repair

Strategies and trends in the treatment of (giant) omphalocele

The management of giant omphaloceles remains a challenge for pediatric surgeons. Although the mortality rate is still high (up to 20%) in case of multiple congenital anomalies, surviving patients with omphalocele achieve a state of health and quality of life comparable to that of general population peers. Results from our study confirm the hypothesis that neonates with a congenital abdominal wall defect have a high risk for adhesive small bowel obstruction and could benefit from adhesion prevention. Awaiting complete epithelialisation before operation of giant omphalocele might reduce serosal injury and limit adhesiogenic areas. The liver was partly unprotected in all giant omphaloceles evaluated in this thesis. In case of an incisional hernia, the liver was located underneath the abdominal defect. A pre-operative ultrasound study is recommended, therefore. Furthermore, the parents should receive good documentation and information. The question remains whether contact sports and other risk behaviour should be advised against, as there is no indication of more blunt trauma in these patients in the literature. The results of the questionnaire sent to the authors do not show a consensus for a generally accepted treatment method after more than thirty years of innovations in the management of patients with a giant omphalocele. The newly introduced Component Separation Technique seems to have a good outcome. The herniation rate is low, and prosthetic materials are not needed. However, the question remains if delayed closure with this technique is better than immediate staged closure. There is not yet an evidence base; we shall have to await the long-term results of the published techniques. Based on these outcomes, a randomized multicenter trial comparing the staged and delayed techniques is recommended. Until then, we remain dependent on expert opinion

Tracheal Tissue Engineering

Large airway defects pose a substantial problem to surgeons in both pediatric and adult populations. For example, primary tracheal cancers can result in neoplastic lesions, which are often not diagnosed until the tumor has become inoperable. These patients are palliated, but have a poor prognosis, with only 5% survival after 5 years. Tissue engineered transplants over a life saving new therapeutic option. Recent reports have demonstrated good midterm results with decellularized human homograft tissue. However, these experiments have been limited to compassionate use. To achieve effcacy necessary for more widespread use further study is necessary to investigate alternate approaches and optimize the decellularization technique. Additionally, clinical application of this technology will require translation to a decellularized xenograft to obviate human tissue supply limitations. To this end, we compare the use of 3 alternate detergents (SDS, Triton X-100, and CHAPS) to sodium deoxycholate in the commonly accepted detergent enzymatic method (DEM). Fresh donor rat tracheas were decellularized using a modified 9-day DEM protocol. The pre-implant scaffolds were thoroughly characterized for each experimental group and implanted for 12 weeks using an orthotopic rat tracheal reconstruction model. It was found that detergent choice strongly affects the host remodeling response including host cell infiltration and epithelial differentiation. The clinically relevant sodium deoxycholate and Triton X-100 groups were retested with a final peracetic acid (PAA) rinse. It was determined that the use of PAA greatly improved the in vivo response of the previously poor performing sodium deoxycholate and made little improvement to the Triton X-100 scaffold. The optimum configuration, Triton X-100 with a PAA rinse, was selected for translation to a clinically relevant porcine model. Porcine tracheal decellularization was achieved using a modified 14 day DEM protocol with a novel cyclical pressure approach. The suitability of these porcine tracheas for pre-clinical large animal testing was verified through mechanical analysis (pressure-diameter and suture retention) and in vitro seeding experiments with human bronchial epithelial cells

The Development of a Hybrid Scaffold for Use in Oesophageal Tissue Engineering

The oesophagus as an organ can be affected by a number of medical conditions which may necessitate the need for extensive treatment to correct. One potential approach is to tissue engineer a suitable biomaterial-based replacement for oesophageal tissue. Small intestine submucosa (SIS) is one of a number of naturally-derived extracellular matrix (ECM) biomaterials currently in clinical use; however one of their key limitations is poor mechanical properties. In this work it was found that SIS can be consistently and reliably processed into tubular scaffolds which impart certain potential advantages. The decellularisation of tubular SIS was carried out using four different protocols. One protocol emerged as the most suitable by the criteria mentioned, a perfusion-based method using sodium deoxycholate. Electrospinning was used produce to polymers PLGA nanofibres which mechanically reinforced the tubular SIS. It was hypothesised that this would improve the ECM material’s mechanical properties. Attachment remained an issue between the two layers but this was overcome by altering the shape of the SIS. The SIS-PLGA scaffold was produced with varying fibre alignment, a factor shown to have some influence in vitro and in vivo. The drug delivery potential of the fibres was also considered and the scaffolds had VEGF added to them. Evaluation was by physical testing, in vitro analysis and in vivo implantation. The PLGA scaffold were found to perform well both mechanically and in terms of biocompatibility. They also performed well in vivo with a limited foreign body reaction. The highly aligned fibres (5000 rpm) group was chosen as the best in terms of its all-round properties including good cellular infiltration. The electrospun fibres remained intact at 4 weeks which indicates a potential lasting support role, which was intended. The result of the VEGF incorporation was that there was an increase in the blood vessel density of the tissue surrounding the scaffolds highlighting the benefits of adding growth factors to the scaffold. Overall, it was concluded that the hybrid scaffold have potential for use in oesophageal tissue engineering