Wound healing in endoscopic sinus surgery: Phase 1 clinical trial evaluating the role of Chitogel with adjuvants.

OBJECTIVES: This study aimed to determine the safety and efficacy of Chitogel, with and without Deferiprone (Def) and Gallium Protoporphyrin (GaPP), as a promoter of wound healing to improve surgical outcomes after endoscopic sinus susgery. DESIGN: A double-blinded, randomised control human clinical trial was conducted in patients undergoing ESS as a treatment for chronic rhinosinusitis. Participants underwent functional ESS or FESS with drill out as required and were randomised to receive test product Chitogel, Chitogel in combination with Def or Def-GaPP versus no packing (control). SETTING: Ostial stenosis and persistent inflammation are the main reasons for revision endoscopic sinus surgery (ESS). Post-operative (PO) dressings can improve PO wound healing and patient outcomes after ESS. PARTICIPANTS: Eighty two patients were included in this study with 79 patients completing the study with 40 undergoing full house FESS and 39 FESS plus frontal drillout. MAIN OUTCOME MEASURES: Patients were followed up at 2, 6 and 12 weeks PO, and outcome scores such as SNOT-22, VAS and LKS, pre and post-surgery (12 weeks) were compared. RESULTS: Seventy nine patients completed the study, there was a significant reduction in SNOT-22 score and improvement of VAS at 12 weeks in patients treated with Chitogel compared to control (p < .05). In those patients, the mean ostium area for the Chitogel and the Chitogel + Def + GaPP groups was higher across all three sinuses compared to the no-treatment control group, without statistical significance. Sphenoid sinus ostium was significantly more patent in patients treated with Chitogel compared to the control at the 12-week time point (p < .05). CONCLUSION: Chitogel as a PO dressing after ESS results in the best patient-reported symptom scores and objective measurements. The combination of Def and GaPP to Chitogel though proving safe, had no effect on the ostium patency or mucosal healing.

Efficacy and Safety of Novel Beta-Chitin Patches as Haemostat in Rat Vascular and Neurosurgical Model.

Background: Intraoperative hemorrhage is a major cause of poor post-operative outcome. Beta-chitin patch has previously been found to be an effective haemostat, but whether modifying the patch can improve its efficacy and safety, remains unknown. In this study, beta-chitin patches were modified using polyethylene oxide, Pluronic-F127 (Chi/F127), calcium (Chi/20%Ca), increased thickness (Chi/Thick) or polyphosphate (Chi/PP). Objective: Using rat (Wistar Albino; 8-10 weeks old) vascular and neurosurgical models, this project investigated and compared the efficacy and safety of beta-chitin patches with gauze, Surgicel and FloSeal. Methods: Ninety rats underwent a standardized femoral artery injury and were randomized to receive either beta-chitin patches, gauze, Surgicel or FloSeal. The bleeding time and total blood loss was measured. For the neurosurgical model, forty-four rats underwent a standardized cortical injury and randomization to a treatment group. Following a 48 h recovery period, their brains were collected for histopathological examination. Results: The mean bleeding time with Chitin (120.8 s) and Chi/PP (117.3 s) was ~60 s lower than Chi/F127, Chi/20%Ca and Chi/Thick (p < 0.05). Chitin and Chi/PP had a significantly lower bleeding time than FloSeal (174.2 s) (p < 0.05), but not Surgicel (172.7 s). Gauze (400 s) had a significantly higher bleeding time compared to all other groups (p < 0.05). There were no significant differences in the total blood loss between the groups. Histopathological examination of brains found no adverse inflammatory reaction to any of the haemostatic compounds. Conclusion: Chi/PP had superior haemostatic efficacy compared to Surgicel and FloSeal, but not compared to non-modified beta-chitin patch. All of the haemostats were equally safe.

Pharyngocutaneous Fistula Following Primary and Salvage Laryngectomy: Aetiology and Predictive Factors.

Laryngeal cancer treatment is often wrought with challenges, pharyngocutaneous fistula formation (PCF) in patients undergoing either primary or salvage laryngectomy for laryngeal and hypopharyngeal for squamous cell carcinoma is an important one. We aimed to study the factors before and at the surgery that are associated with PCF formation in a South Indian tertiary care hospital. A retrospective chart review of 127 patients who underwent total laryngectomy (TL) between May 2014 and April 2019 at our centre were done. Data was collected, including patient age and gender, comorbidities (Diabetes mellitus, COPD and hypothyroidism), smoking, tumor stage and site, prior tracheostomy, prior radiation, concurrent neck dissection and type of pharyngoplasty, Preoperative hemoglobin and albumin levels, surgical margin status and development of a PCF was also done. Further details specific to the development of a PCF were recorded for that subset of patients including the length of time to fistula, mode of closure, time of closure and modality of management. The overall incidence of PCF was 16.5% (21 of 127 patients), and the median time from TL to the diagnosis of PCF was 6 days (range, 3-20 days). The analysis was done separately for laryngectomies without any pharyngeal reconstruction (112/127 patients). In patients treated with a primary TL, the incidence of PCF was 12.20% (10 of 82) and 26.66% (8 of 30) after salvage TL. Subset analysis for type of pharyngoplasty repair showed 12% (15/127) underwent different types of vascularised/muscular flap for smaller residual pharyngeal mucosa, of which 20% (3/15) developed PCF and one patient developed haematoma needing exploration and re-suturing. The predictive factors for PCF were hypopharynx cancer (P < 0.05), surgical margin positivity (P < 0.0001), female gender (P < 0.05), absence of prior tracheostomy (P < 0.05) and tumor extension into pyriform sinus mucosa (P < 0.05). Preoperative patient factors of gender and site of primary along with histological margin positivity and extension of tumor to the pyriform sinus mucosa were significant risk factors for PCF formation. Pre-Op radiotherapy remains a strong clinical suspicion but not statistically significant.

Prevention of adhesions post-abdominal surgery: Assessing the safety and efficacy of Chitogel with Deferiprone in a rat model.

INTRODUCTION: Adhesions are often considered to be an inevitable consequence of abdominal and pelvic surgery, jeopardizing the medium and long-term success of these procedures. Numerous strategies have been tested to reduce adhesion formation, however, to date, no surgical or medical therapeutic approaches have been successful in its prevention. This study demonstrates the safety and efficacy of Chitogel with Deferiprone and/or antibacterial Gallium Protoporphyrin in different concentrations in preventing adhesion formation after abdominal surgery. MATERIALS AND METHODS: 112 adult (8-10 week old) male Wistar albino rats were subjected to midline laparotomy and caecal abrasion, with 48 rats having an additional enterotomy and suturing. Kaolin (0.005g/ml) was applied to further accelerate adhesion formation. The abrasion model rats were randomized to receive saline, Chitogel, or Chitogel plus Deferiprone (5, 10 or 20 mM), together with Gallium Protoporphyrin (250µg/mL). The abrasion with enterotomy rats were randomised to receive saline, Chitogel or Chitogel with Deferiprone (1 or 5 mM). At day 21, rats were euthanised, and adhesions graded macroscopically and microscopically; the tensile strength of the repaired caecum was determined by an investigator blinded to the treatment groups. RESULTS: Chitogel with Deferiprone 5 mM significantly reduced adhesion formation (p<0.01) when pathologically assessed in a rat abrasion model. Chitogel with Deferiprone 5 mM and 1 mM also significantly reduced adhesions (p<0.05) after abrasion with enterotomy. Def-Chitogel 1mM treatment did not weaken the enterotomy site with treated sites having significantly better tensile strength compared to control saline treated enterotomy rats. CONCLUSIONS: Chitogel with Deferiprone 1 mM constitutes an effective preventative anti-adhesion barrier after abdominal surgery in a rat model. Moreover, this therapeutic combination of agents is safe and does not weaken the healing of the sutured enterotomy site.

A Novel Rat Model to Test Intra-Abdominal Anti-adhesive Therapy.

Background: Adhesion formation after abdominal surgery is considered almost inevitable and a major cause of morbidity. Novel treatments have been proposed, however there is a lack of suitable small animal models for pre-clinical evaluation, mainly due to inconsistency in adhesion formation in positive control animals. Here, we propose a new rat model of abdominal adhesions using Kaolin as the adhesion-inducing agent at an optimized dosage for testing newer agents in respect to their anti-adhesive property. Materials and Methods: Twenty-five adult (8-10 week old) male Wistar albino rats underwent midline laparotomy and caecal abrasion and were randomized to receive topical applications of normal saline or different concentrations and volumes of a Kaolin-based formulation. At day 14 rats were humanely killed, and adhesions graded macroscopically by an investigator blinded to the treatment groups, using pre-determined adhesion scores and microscopically using histopathology. Results: Kaolin at 0.005 g/mL caused consistent adhesions without compromising rat viability. At higher doses significant morbidity and mortality was observed in the animals treated. Conclusions: Kaolin induced adhesion in a rat abdominal surgery model is reliable and can be safely used to test the efficacy of novel anti-adhesive formulations to prevent intra-abdominal adhesions.

Staphylococcus aureus biofilm exoproteins are cytotoxic to human nasal epithelial barrier in chronic rhinosinusitis.

BACKGROUND: Chronic rhinosinusitis patients (CRS) suffer from chronic inflammation of the sinus mucosa associated with chronic relapsing infections. Mucosal biofilms, associated with Staphylococcus aureus, have been implicated as a cause. We compared the effect of exoproteins secreted from clinical isolates of S aureus from CRS patients in planktonic and biofilm form on the nasal epithelial barrier. METHODS: Clinical S aureus isolates from 39 CRS patients were grown in planktonic and biofilm forms and their exoproteins concentrated. These were applied to primary human nasal epithelial cells grown at the air-liquid interface. Transepithelial electrical resistance, permeability of flourescein isothiocyanate-dextrans, and cytotoxicity were measured. Structure and expression of tight junctions zona occludens-1, and claudin-1 proteins were assessed by electron microscopy and immunofluorescence. The Wilcoxon signed rank test was used for statistical analyses. RESULTS: S aureus biofilm exoproteins showed dose- and time-dependent reduction of transepithelial electrical resistance, increased cell toxicity, and increased permeability (p < 0.001) compared with equal concentrations of planktonic cultures. Discontinuity in zona occludens-1 and claudin-1 immunofluorescence was confirmed as disrupted tight junctions on electron microscopy. CONCLUSION: S aureus biofilm exoproteins disrupt the mucosal barrier structure in a time- and dose-dependent manner and are toxic. Damage to the mucosal barrier by S aureus biofilm exoproteins may play a major role in CRS etiopathogenesis.

Prevention of peridural adhesions in spinal surgery: Assessing safety and efficacy of Chitogel with Deferiprone in a sheep model.

INTRODUCTION: Spinal laminectomy is a common procedure performed to relieve neural compression in patients suffering from myelopathy or radiculopathy. However, up to 40% of patients suffer from persistent post-operative pain and disability, a condition known as Failed Back Surgery Syndrome (FBSS). Excessive scarring in the surgical bed is implicated as a cause. Hydrogels have been proposed to prevent adhesion formation post-laminectomy; however, their efficacy has not been proven. This study uses Chitogel complexed with the iron chelator Deferiprone (Def) to prevent adhesion formation in a sheep laminectomy model. MATERIAL & METHODS: Fifteen Adult Merino sheep (Ovis Aries, 1-5 yrs old) underwent laminectomy at lumbar levels 1-5 and had hydrated aluminum silicate (kaolin) applied to promote adhesion formation. Subjects were randomised to receive at each laminectomy level no-treatment control, Chitogel, Chitogel with Def at 20 mM or 40 mM or Carboxy-methyl-cellulose and Polyethylene oxide (CMC/PEO) gel. The animals were recovered for 3 months post-surgery, followed by assessment with Magnetic Resonance Imaging (MRI) and histopathology of the spinal tissues for evaluating the presence and extent of adhesions. RESULTS: MRI and Histology assessment indicated that Kaolin induced severe inflammation with adhesion formation. Chitogel with and without 20 mM Def decreased inflammation (p < 0.01) and trended to reduce adhesions (p < 0.1). Chitogel with Def 40 mM was not significantly dis-similar to CMC/PEO and did not reduce inflammation or adhesions compared to no-treatment control. CONCLUSION: Chitogel in combination with Def 20 mM is safe and effective in decreasing the inflammatory process and may possibly reduce post-operative adhesions following laminectomy.