Injection Of Glutaraldehyde Cross-linked Collagen Research Articles

Calcification of Glutaraldehyde Cross-Linked Collagen in Bladder Neck Injections in Children With Incontinence: A Long-Term Complication

We report the incidence of calcifications developing at the bladder neck/urethra in pediatric patients treated with glutaraldehyde cross-linked collagen for urinary incontinence. We reviewed charts of patients treated with glutaraldehyde cross-linked collagen injections for urinary incontinence between 1994 and 1999. Etiology of incontinence, pertinent medical history, operative details and postoperative imaging were examined. Of 31 patients 4 (13%) had development of submucosal calcifications in the bladder neck/urethra. All 4 patients had received multiple injections of glutaraldehyde cross-linked collagen for incontinence secondary to neurogenic bladder. The calcifications were confirmed surgically. Pathology reports available for 2 of 4 patients showed chronic inflammation without dysplasia or malignant changes. Mean followup was significantly different between calcified and noncalcified cases (10.3 vs 7.2 years, p = 0.009), as was total volume of collagen injected (21 vs 12 cc, p = 0.012). Mean time to diagnosis of calcifications was 8.8 years (range 7 to 11) after first injection. A total of 24 patients without calcification underwent bladder imaging at a mean of 6.8 years (+/-2.2) after glutaraldehyde cross-linked collagen injection, which was not significantly different than the time to diagnosis (p = 0.089). The number of injections was not significantly different between the 2 groups (p = 0.426). Of our patients 13% had development of calcifications at the site of prior glutaraldehyde cross-linked collagen injections for incontinence. These calcifications were surrounded by chronic inflammation. Patients who have undergone glutaraldehyde cross-linked collagen injections may benefit from long-term followup with bladder imaging to detect and follow calcifications at prior injection sites.

EVALUATION OF ANTIBODY CLASS IN RESPONSE TO ENDOSCOPIC SUBURETERAL COLLAGEN INJECTION IN PATIENTS WITH VESICOURETERAL REFLUX

Clinical problems after glutaraldehyde cross-linked collagen injection for vesicoureteral reflux are the appearance of anticollagen antibodies and a decrease in collagen with time. We evaluated whether antibody production affects reflux recurrence and implanted collagen absorption. We treated 27 patients (39 ureters) who had vesicoureteral reflux with endoscopic subureteral glutaraldehyde cross-linked collagen injection. The maximum diameter of the elevated ureteral orifice was measured 3-dimensionally and the numerical value calculated by multiplying each diameter by approximately pi/6 was used as the ultrasound estimate of injected collagen volume. The 1-to-6-month collagen volume ratio was used as an index of the decrease in implant collagen volume. The antibody class against bovine collagen was characterized by indirect enzyme-linked immunosorbent assay. Seroconversion in 6 patients was noted a mean 6.8 months after the first injection. In these patients the antibody class was IgG dominant and IgA or IgM was not detected. There was no significant difference in the total injected collagen volume, total number of injections or collagen volume ratio in the seropositive and seronegative groups. Reflux recurred in 4 patients and the curve of the reflux-free rate was similar regardless of antibody appearance. The immune response to bovine collagen injection for vesicoureteral reflux does not depend on injected collagen volume or an increased number of treatments. Antibody production had no effects on absorption of the implanted collagen or reflux recurrence.

ENDOSCOPIC SUBURETERAL GLUTARALDEHYDE CROSS-LINKED COLLAGEN INJECTION FOR THE TREATMENT OF SECONDARY VESICOURETERAL REFLUX: COMPARISON WITH PRIMARY VESICOURETERAL REFLUX IN ADULTS

We assessed the effectiveness of endoscopic subureteral glutaraldehyde cross-linked collagen injection for treating vesicoureteral reflux in patients with vesicoureteral disorders. All 51 ureters studied had grade II or greater vesicoureteral reflux. We treated 18 patients (24 refluxing ureters) with secondary and 17 adults (27 refluxing ureters) with primary vesicoureteral reflux. The primary group served as controls to establish normal urination. A total of 14 patients with secondary vesicoureteral reflux had a low compliant autonomous bladder, including 11 with myelodysplasia and 3 after pelvic surgery and radiotherapy. One patient had an unstable bladder due to cerebral palsy and 3 had anatomical abnormalities of the urinary tract. We evaluated the estimated reflux-free rate in the secondary and adult primary vesicoureteral reflux groups. Repeat injection was required in 24 ureters because of recurrent reflux. Average injected volume in the secondary and primary groups was 2.72 and 2.88 ml. per refluxing unit, respectively. The estimated reflux-free rate after the initial injection decreased gradually to about 35% in each group, while 12 and 24 months after the last injection it remained constant at 70% in the secondary group but decreased from 84.7% to 62.1% in the primary group. The percent of late recurrence was higher in the primary group. Long-term efficacy of the endoscopic correction of vesicoureteral reflux in the secondary group was similar to that in the primary group. Thus, endoscopic subureteral glutaraldehyde cross-linked collagen injection is useful for treating complicated secondary vesicoureteral reflux as a minimally invasive procedure. It is considered optional treatment of primary vesicoureteral reflux to avoid long-term prophylactic treatment.

Failure of subureteral bovine collagen injection for the endoscopic treatment of primary vesicoureteral reflux in long-term follow-up

Objectives. To evaluate the long-term efficacy of subureteral glutaraldehyde cross-linked collagen injection (GAX 35) for endoscopic treatment of primary vesicoureteral reflux (VUR). Methods. We prospectively studied 36 patients (58 ureteral renal units), 30 girls and 6 boys with a median age of 6 years (range 2 months to 18 years). All patients had primary VUR and were treated with a single subureteral collagen injection (GAX 35). The patients were followed up by voiding cystography. Results. According to the International Reflux Study Classification, we found the following reflux grades preoperatively: grade I, 2 ureteral units; grade II, 21 units; grade III, 28 units; grade IV, 4 units, and grade V, 3 units. All patients were treated with subureteral bovine collagen injection (GAX 35, mean volume 1.7 mL, range 0.7 to 3.5). All but 3 cases of reflux resolved initially. The mean follow-up was 13 months (range 1 to 108). After 37 months of follow-up, only 5 (9%) of 57 treated units remained reflux free. One unit was followed up for 17 months and also remained reflux free. Conclusions. These data suggest that a single endoscopic subureteral collagen injection is not effective in the long-term follow-up of patients with primary VUR. In the future, it will be important to determine whether the new, currently used, and soon be approved bulking agents show better long-term clinical results to prevent VUR recurrence than bovine collagen does.

LONG-TERM EFFICACY OF SUBURETERAL COLLAGEN INJECTION FOR ENDOSCOPIC TREATMENT OF VESICOURETERAL REFLUX IN NEUROGENIC BLADDER CASES

We evaluated the long-term efficacy of subureteral glutaraldehyde cross-linked collagen injection (GAX 35) for endoscopic treatment of vesicoureteral reflux in patients with neurogenic bladder dysfunction due to meningomyelocele. We prospectively studied 12 women and 8 men (26 ureteral renal units) with a median age of 8 years (range 1 to 51) who had neurogenic bladder due to meningomyelocele. Reflux into single collecting systems was treated with subureteral collagen injection (GAX 35). Followup with video urodynamics included voiding cystography. All patients performed intermittent catheterization to control the bladder. During the study all bladders were areflexic with normal compliance. Preoperative reflux according to the International Reflux Study Classification was grade I in 1, II in 9, III in 10, IV in 4 and V in 2 ureteral renal units. All patients were treated with subureteral collagen injection (mean volume 1.9 ml., range 0.7 to 3.5). Reflux resolved initially in all but 2 cases. Mean followup was 16 months (range 1 to 71). Reflux was still absent in only 15% of treated units after 24 months. Our data suggest that endoscopic subureteral collagen injection in neurogenic bladder cases is not effective with long-term followup. New biocompatible and biodegradable materials should be tested to control vesicoureteral reflux.

COMPLICATIONS OF STERILE ABSCESS FORMATION AND PULMONARY EMBOLISM FOLLOWING PERIURETHRAL BULKING AGENTS

Agents currently used in the treatment of urinary incontinence secondary to intrinsic sphincter deficiency are effective and minimally invasive. Ensuring a lack of sensitivity to the product or use of autologous material, such as fat, minimizes significant problems. However, local and systemic complications can occur with any bulking agent. We describe rare complications of periurethral bulk injections. Three cases of sterile abscess formation and 1 of pulmonary embolism after periurethral bulk injections were reviewed. Two patients with intrinsic sphincter deficiency were treated with transurethral injection of glutaraldehyde cross-linked collagen at the Mayo Clinic, 1 also treated with collagen for intrinsic sphincter deficiency was referred from elsewhere and 1 underwent periurethral injection of autologous fat for intrinsic sphincter deficiency elsewhere. Clinical information and patient followup were obtained from medical records and discussion with treating physicians. Three patients treated with collagen presented with sterile abscesses at the injection site after routine transurethral injection. Documentation of the abscesses included cystoscopic findings, magnetic resonance imaging of the pelvis and/or transvaginal ultrasound. Drainage procedures for relief of obstructive and irritative voiding symptoms were required in 2 patients. In 1 of these patients transurethral unroofing failed, and transvaginal incision and drainage were required while the other had slow spontaneous improvement but a mass remained at the injection site 3 months later. Repeat skin testing was negative in 2 of 3 cases. Currently, these 3 patients are asymptomatic except for continued urinary incontinence. Pulmonary embolism was documented in 1 patient who underwent periurethral autologous fat injection. This patient survived without long-term consequences but was maintained on ventilatory support for a short time. In general, periurethral injection of bulk agents is safe and effective. However, injectable bulk agents are not without risk of complications, some of which are life threatening and others of considerable morbidity that may require operative intervention.

Urethral prolapse after collagen injection

A woman who was treated for intrinsic urethral sphincteric deficiency with periurethral injection of glutaraldehyde cross-linked collagen had prolapse of the urethral mucosa and recurrence of incontinence. She subsequently required surgical resection and a fascia lata sling. This is the first known occurrence of this postinjection complication. (Am J Obstet Gynecol 1998;178:614-5.)

ILEOCECAL VALVE RESISTANCE AUGMENTATION USING GLUTARALDEHYDE CROSS-LINKED COLLAGEN: A CANINE MODEL FOR ENDOSCOPIC SALVAGE OF THE LEAKING INDIANA RESERVOIR

Periurethral injection of glutaraldehyde cross-linked collagen is a well-established modality for the treatment of patients with incontinence caused by structural defects at the bladder outlet. Little is known about the potential usefulness of this approach to the nonfunctioning continence mechanism of a leaking continent urinary reservoir. An animal model of an incontinent Indiana reservoir was created using the naturally incompetent canine ileocecal valve. The effectiveness and feasibility of endoscopic submucosal injection of glutaraldehyde cross-linked collagen into the ileocecal valve to increase resistance were examined. Seven beagle dogs underwent isolation of the ileocecal segment. The right colon and ileum were brought to the skin as 2 stomas. Baseline leak point pressures of the ileocecal valve were determined while infusing contrast material into the right colon. The leak point was observed fluoroscopically, and the pressure at which contrast material crossed the valve was measured. Glutaraldehyde cross-linked collagen, 4 to 10 ml., was injected endoscopically into the valve in a circumferential pattern. Leak point pressures were measured immediately, 1 month after injection and 3 months after injection. An average of 7.1 gm. (range, 4.1 to 10.1 gm.) was required to create an endoscopically "closed" ileocecal valve. Leak point pressure increased from a mean 3.8 mm. water (range, 2.5 to 6.0 mm. water) at baseline to mean 35.7 mm. water after injection (range, 22.0 to 57.0 mm. water). At 1 month, mean leak point pressure decreased slightly to 26.7 mm. water. This pressure stabilized at 3 months at 29.5 mm. water. Endoscopic delivery of glutaraldehyde cross-linked collagen into the ileocecal valve consistently enhanced resistance as measured by leak point pressure. This effect was durable over a 3-month period of observation. Admittedly, this period of observation is relatively short. Longer followup may have demonstrated significant diminution of collagen migration or resorption. However, this feasibility study demonstrates that collagen injections may provide a minimally invasive means of treating the incontinent continent urinary reservoir.

Endoscopic injection of collagen for the treatment of female urinary stress incontinence.

The objective of our study was to assess the efficacy and safety of glutaraldehyde cross-linked collagen injection in the treatment of female urinary stress incontinence. We conducted a retrospective analysis of the records of 105 women who underwent collagen injection for urinary stress incontinence between March 1991 and April 1995. Preoperative assessment included uroflowmetry, residual urine determination, and urodynamic studies. Of the 105 women in our series, 95 patients (90.5%) had initial successful results at 3 months (61.0% cured, 29.5% significantly improved) while 4 patients (3.8%) had slight improvement and 6 (5.7%) failed surgical correction. One year after the procedure, the success rate dropped to 81.9% (86 patients) with 46.7% cured and 35.2% significantly improved. Nine patients (8.6%) had slight improvement and 10 patients (9.5%) failed surgical correction. Eight patients (7.6%) with initial unsatisfactory results underwent additional sessions of collagen injection and were subsequently either cured or had significant improvement. Twenty-three patients (21.9%) suffered a relapse. The mean time to relapse was 13.3 months, and 6 of those who relapsed underwent repeated injections with favorable results. Complications were minimal; 6 patients had temporary retention of urine, and 2 patients had urinary tract infections. We conclude that glutaraldehyde cross-linked collagen injection is a simple and safe method of treatment for urinary stress incontinence. A longer follow-up period is necessary to assess the long-term efficacy of this treatment.

Treatment of urinary incontinence in bitches by endoscopic injection of glutaraldehyde cross-linked collagen.

Thirty-two spayed bitches with urinary incontinence due to urethral sphincter incompetence, non-responsive to phenylpropanolamine administration, were treated by urethral submucosal injection of glutaraldehyde cross-linked collagen. Urinary incontinence resolved after a single injection in 19 of the bitches. Additional medication with phenylpropanolamine was necessary in five of these dogs, however. Of the 13 bitches that remained incontinent, the injections were repeated in nine. This resulted in a return to continence in five dogs, although two of these required additional medication for complete continence. The cure rate due to collagen injections alone is 53 per cent (17 of the 32 cases). A total of 41 injections were performed and no post-operative complications were observed.

Collagen Injections for Treatment of Urinary Incontinence Secondary to Intrinsic Sphincter Deficiency

The injection of glutaraldehyde cross-linked collagen (Contigen) is a recently approved method for treating patients with urinary incontinence secondary to intrinsic sphincter deficiency (ISD). Forty-five patients with ISD, 33 males and 12 females, with a mean age of 60 years (range 5-87 years) have been treated with collagen at our institution since its Food and Drug Administration approval. The etiology of incontinence was radical retropubic prostatectomy (RP) in 22, neurogenic bladder (NB) in 11, and Type III female stress urinary incontinence (FISD) in 12 individuals. The whole group underwent an average of 1.76 treatment sessions (range 1-4), and a mean collagen injection volume of 12.26 cc (range 5-27.5 cc) was delivered per session. There were no postoperative complications. Six patients achieved total continence, 28 were still incontinent but improved, 9 experienced no change, while 2 developed worsening incontinence. Further analysis indicated that male patients with ISD as a result of RP may achieve some degree of improvement, but the chances for eradicating incontinence are minimal, whereas female patients with FISD and individuals with ISD secondary to NB significantly benefit from collagen injection therapy. Longer follow-up is needed to determine the durability of these encouraging results.

Endoscopic injection of glutaraldehyde cross-linked collagen for the treatment of intrinsic sphincter deficiency in women

Objectives To determine the clinical efficacy, safety, and durability of endoscopically injected glutaraldehyde cross-linked (GAX) collagen for the treatment of intrinsic sphincter deficiency (ISD) in women. Methods Forty-two women with a mean age of 64 years (range, 28 to 88) underwent injection of GAX collagen for ISD. Collagen was injected via a transurethral or periurethral approach. Treatment outcome was based on the change in stress leak point pressures (SLPP) and individual incontinence grades before and after collagen injection. Results With a mean follow-up of 46 months (range, 10 to 66), 83% were cured (n = 17), greatly improved (n = 5), or improved (n = 13), and 17% were unchanged (n = 3) or worse (n = 4). The median number of treatments was 2 (range, 1 to 8). The 22 women greatly improved or cured required a mean of 2.4 collagen injection treatments, whereas the 20 women who were improved, unchanged, or worse had a mean of 4.1 treatments ( P = 0.009). The mean amount of collagen injected per patient was 28.3 cc (range, 2.5 to 85). The group of women who were greatly improved or cured had a mean of 17.5 cc of collagen injected, whereas those who were improved, unchanged, or worse had a mean of 39.5 cc injected ( P = 0.002). Mean pretreatment SLPPs of women improved, greatly improved, or cured versus the women unchanged or worse were not significantly different ( P = 0.015). The 35 women who were improved or cured had a significant increase in mean SLPP of 65.4 cm H 2O ( P = 0.001) compared to a mean change in SLPP of 14.7 cm H 2O in those women who were unchanged or worse ( P = 0.038). Conclusions GAX collagen injection for the treatment of stress urinary incontinence secondary to ISD appears to be safe, effective, and durable; hence, it should be considered the treatment of choice in appropriately selected female patients.

Treatment of Vocal Fold Immobility by Glutaraldehyde—Cross-Linked Collagen Injection: Longc-Term Results

Fifty-three cases of unilateral vocal fold immobility treated by glutaraldehyde-cross-linked (GAX) collagen over a 6-year period with a mean follow-up of 4.5 years were reviewed for assessment of the immediate and long-term effects on phonation. The mean amount injected was 1.47 mL. No long-term local or systemic reaction to the collagen was seen. The median preoperative maximum phonation time (MPT) was 7.5 seconds, the median immediate postoperative MPT 12 seconds, and the median long-term postoperative MPT 11 seconds. The median preoperative phonatory quotient (PQ) was 564 mL/s. The median immediate postoperative PQ was 320 mL/s, whereas the median long-term postoperative PQ was 385 mL/s. The quantitative improvement in the voice as measured by the PQ was thus 67% for the short range and 49% for the long range. The decline in the results over time was 20.3%. Vocal frequency analysis showed that the fundamental frequency and harmonics returned and were maintained in the long term for more than 80% of the patients with the help of speech therapy. This relative stability is explained by the findings of previous histological work. The fact that collagen, unlike Teflon, does not cause an inflammatory reaction and the partial maintenance of the improvement achieved, which is to be compared with the instability of the effects produced by resorbable substances, make it the "least objectionable" injectable for the treatment of unilateral glottic fold immobility. One must overcompensate 20% to 30%, given the results of the long-term stability studies.

The Treatment of Urinary Incontinence in Children using Glutaraldehyde Cross-Linked Collagen

Periurethral injection of polytetrafluoroethylene (PolyTef) paste has been used to correct urinary incontinence for 2 decades. The controversy over distant migration of the paste has led to an interest in alternative materials particularly for the pediatric patient. Glutaraldehyde cross-linked collagen, derived from bovine dermal collagen, is effective in treating urinary incontinence in adults. Eight children with structural urinary incontinence underwent glutaraldehyde cross-linked collagen injection. Fluorourodynamic studies preceded and followed the injections. An average of 10.9 cc glutaraldehyde cross-linked collagen was injected per treatment (range 2.5 to 20). The number of injections per child ranged from 1 to 6 (mean 2.1) and followup averaged 13.75 months (range 6 to 33). Overall, 88% of the patients were cured or improved: 5 (63%) became continent, 2 were improved and 1 had no effect.

Para‐urethral Collagen Implantation for Female Stress Incontinence

A series of 25 women with genuine stress incontinence were treated by para-urethral injection of glutaraldehyde cross-linked collagen. The technique was simple and associated with few complications. Follow-up at 3 months revealed 20 patients (80%) to have been symptomatically improved or cured. An increase in urethral closure pressure together with a decrease in urine flow rate and increase in detrusor pressure was found post-operatively. The success rate was significantly higher (90%) in patients who had undergone previous surgery for urinary incontinence when compared with those who had had no previous surgery (73%).

Long-term histological results following glutaraldehyde cross-linked collagen injection into the suburothelial space of the mini-pig bladder

Endoscopic correction of vesicoureteric reflux by subureteric injection has become an accepted method of treatment in selected cases. Its efficacy has been demonstrated in the treatment of well over 1,000 ureters. However, there are doubts as to the long-term safety of the commonly injected substance Teflon. Glutaraldehyde cross-linked bovine collagen, a biodegradable substance, was suggested as an alternative material for injection. The aim of this study was to evaluate the histological long-term behavior of glutaraldehyde cross-linked bovine collagen injected into the mini-pig bladder. One hundred and eight deposits of cross-linked collagen, each containing 0.2 ml (n = 36) or 0.6 ml (n = 72) collagen paste, were injected into the suburothelial space of the bladders of 24 mini-pigs. The histological behavior of the implants was studied at monthly intervals over a period of 12 months. After only 2 months a marked invasion of host fibroblasts and formation of endogenous type I and III collagen could be observed. Over 12 months the invasion of fibroblasts and the formation of new collagen increased dramatically. No migration of collagen particles into the local lymphatic system could be observed. A new staining technique (solophenyl red 3BL) was introduced to selectively demonstrate type I and III collagen fibres. In addition, the efficacy of the subureteric collagen injections could be demonstrated by successfully treating reflux that was iatrogenically induced in the mini-pig bladders.

Treatment of Urinary Incontinence by the Periurethral Implantation of Glutaraldehyde Cross-Linked Collagen

Injectable materials have been used to augment the urethral sphincter and improve urinary continence with some success. However, none of these materials has received widespread use because they are difficult to inject and have been reported to migrate. We investigated the efficacy of transurethral implantation of glutaraldehyde cross-linked collagen, a highly purified bovine collagen. A total of 17 patients (16 men and 1 woman) with urinary incontinence resulting from a previous operation was selected for glutaraldehyde cross-linked collagen injection into the region of the urethral sphincter. Before and after implantation patients underwent urodynamic evaluation. Glutaraldehyde cross-linked collagen was injected into the area of the bladder neck or urinary sphincter under direct endoscopic vision. If no improvement occurred reinjection to increase the implant volume was performed at least 3 months after a previous injection. Of the 17 patients 9 were cured or improved. No complications have been reported. This investigation shows that glutaraldehyde cross-linked collagen can be injected into the urinary tract to correct urinary incontinence without observable or measurable morbidity.