Skip to main content

Contigen — Glutaraldehyde Cross-Linked Bovine Collagen (GAX-Collagen)

Contigen (C.R. Bard, Covington, GA) was the first FDA-approved injectable urethral bulking agent (October 1993) — glutaraldehyde cross-linked bovine dermal collagen (GAX-collagen) for female SUI. It served as the gold-standard comparator in virtually every subsequent bulking-agent pivotal trial until the manufacturer voluntarily discontinued production in 2011 as non-immunogenic alternatives entered the market.[1][2]

Composition & Material Properties​

  • Active: highly purified bovine dermal collagen cross-linked with glutaraldehyde.[1]
  • Composition: ≥ 95% type I, 1–5% type III collagen.
  • Carrier: phosphate-buffered physiological saline.
  • Biodegradable: implant gradually resorbed and replaced by host tissue.[3][4]
  • Xenogeneic / immunogenic: skin testing mandatory before injection.[1][5]
  • Glutaraldehyde cross-linking improved durability and reduced (but did not eliminate) immune-type reactions.[6]

Mechanism​

Periurethral / transurethral submucosal injection at the bladder neck and proximal urethra creates immediate bulk that improves coaptation — urodynamically increasing opening pressure without changing urethral closure pressure.[6]

Remodeling:[3][4][7]

  • Host fibroblasts invade the bovine collagen implant.
  • New human type I and III collagen is laid down, replacing the implant.
  • Minimal localized inflammatory reaction without granuloma formation (unlike PTFE).
  • Implant does not hinder subsequent reimplantation surgery.

The biodegradation is also the fundamental limitation — as the implant is resorbed, the bulking effect diminishes and incontinence recurs.

Skin-Testing Requirement​

Unique among bulking agents:[1][5][8][9][10][11][12]

  • Positive skin test in ~3–3.8% of candidates → ineligible.[8]
  • ~28% of treated patients developed anti-bovine type I collagen antibodies (predominantly IgG; IgA ~40%; no IgE).[5]
  • Delayed hypersensitivity in up to 2.5% despite negative skin test — could cause prolonged urinary retention.[10]
  • HLA-DR2/DR4 phenotype associated with positive skin-test responses.[11]
  • Dermatomyositis / polymyositis: historical cohort (~345,000 bovine-collagen implant recipients) found statistically increased incidence (SIR 18.8; 95% CI 8.1–37.0).[12]

The 4-week wait between skin test and treatment was a significant logistical disadvantage compared to non-immunogenic alternatives.

Injection Technique​

Transurethral or periurethral under cystoscopic guidance:[13][14][6]

  • Local anesthesia; office / outpatient ~30 minutes.[15]
  • Volume: mean 6.2–6.6 mL per course — the highest of any bulking agent.[16][17]
  • Sessions: typically 2–3 in women, 3–5 in men; cumulative collagen often substantial (mean 11.9 mL in women achieving continence; up to 28.3 mL in men).[14][18][19]

Indications​

FDA-approved: female SUI due to intrinsic sphincter deficiency (ISD).[13][6]

Off-label use: female SUI with urethral hypermobility, male post-prostatectomy SUI, pediatric VUR.[18][20][21][22][23]

Clinical Efficacy​

Female SUI — ISD (Primary Indication)​

StudynFollow-upOutcome
Smith 19979614 mo median67% continence (38.3% dry, 28.7% socially continent); 82.9% maintained at 1 yr; mean 2.1 procedures, 11.9 mL.[14]
Richardson 19954246 mo mean83% cured/improved; median 2 treatments; mean 28.3 cc total.[19]
Cross 199813918 mo median74% substantially improved; 72% continent after ≤ 2 injections.[24]
Gorton 199961> 5 yrOnly 26% subjectively improved; only 1 completely dry; MUCP > 20 cmH₂O predicted success.[25]
Chrouser 20044362 mo medianOnly 5% effective at last follow-up; 9% at 36 mo.[26]

Urethral Hypermobility​

Bent 2001 (n = 90 with hypermobility): 33% dry + 33% improved at 12 mo (ITT 21% + 21%); probability of maintaining initial improvement for 12 mo only 44%.[20]

Head-to-Head RCTs — Contigen as the Gold-Standard Comparator​

ComparatorStudynFollow-upFinding
MacroplastiqueGhoniem 200924712 moMacroplastique superior: dry 36.9% vs 24.8% (p < 0.05); ≥ 1 Stamey 61.5% vs 48%.[27]
DurasphereLightner 200135512 moEquivalent: 80.3% vs 69.1% ≥ 1 Stamey (NS); Durasphere less volume.[28]
BulkamidSokol 201434512 moNon-inferior PAHG: 53.2% vs 55.4% ≥ 50% leak reduction; 47.2% vs 50% zero SUI.[29]
CoaptiteMayer 200729612 moEquivalent: 63.4% vs 57.0% ≥ 1 Stamey (NS); CaHA less volume.[16]

The Ghoniem 2009 Macroplastique RCT was the only trial to demonstrate statistical superiority of a comparator over Contigen.[27]

Male Post-Prostatectomy SUI​

Modest, non-durable:[21][18][30][31]

  • Westney 2005 (n = 322): 17% complete continence; mean duration of response 6.3 months; mean 4.37 injections.
  • Smith 1998 (n = 62): 38.7% social continence, 8.1% dry; median 4 injections.
  • Faerber 1997 (n = 68): 10% cured, 10% greatly improved, 67% minimal/no improvement.
  • Post-TURP responded significantly better than post-RP (62.5% vs 35.2%); bladder neck contracture predicted failure.

Authors' conclusion: collagen is a "good option for short-term therapy" in post-prostatectomy SUI.[18]

Pediatric VUR​

Cure 62.7–75% after single injection; 77–89.7% after 2 injections.[22][7][32] Reunanen 1995: 93.9% at 1 mo declining to 81.8% at 4 yr for simple ureters, only 21.4% at 4 yr for duplex.[23] Superseded by Deflux for this indication.

Safety Profile​

Overall complication rate ~20% (Stothers cohort, n = 337):[33]

  • De novo urgency with incontinence: 12.6% — most frequent and serious; often irreversible.
  • Hematuria ~5% (transient); UTI common in long-term FU; transient retention ~1.9%.
  • Delayed hypersensitivity up to 2.5%; antibody formation 28%.[5][10]
  • Dermatomyositis / polymyositis signal (SIR 18.8).[12]
  • Rare: sterile abscess at the injection site (requiring drainage); pulmonary embolism (described for periurethral autologous fat, listed as a known periurethral-bulking complication); osteitis pubis.[1][34]

Long-Term Durability — The Critical Limitation​

Consistently poor:[25][26][18][35]

  • Gorton 1999: 26% improvement at > 5 yr; 1/53 completely dry.
  • Chrouser 2004: 5% effective at 62 mo.
  • Westney 2005 (men): mean response only 6.3 months.
  • Nature Reviews Urology 2020 conclusion: "positive outcomes are poorly sustained for more than 6 months."

Biodegradability is the cause — as bovine collagen is resorbed and replaced, bulking diminishes, necessitating repeat injections (2–5 sessions, large cumulative volumes).

Contigen vs Other Bulking Agents​

ParameterContigenBulkamidMacroplastiqueCoaptiteDurasphere
CompositionBovine collagenPolyacrylamide hydrogelPDMS macroparticlesCaHA microspheresCarbon-coated ZrO₂
BiodegradableYesNoNoPartiallyNo
Skin test requiredYesNoNoNoNo
FDA approval1993 (discontinued 2011)2020200620051999
Volume / course6.2–6.6 mL (highest)~2–4 mL~5–6.3 mL~4.0 mL~4.8 mL
12-mo cure24.8–57%47–63.7%36.9–75%63.4%66–80%
Long-term efficacy (3+ yr)5–26% (worst)86% at 5 yr49% at ≥ 3 yr60–75%21% at 36 mo
De novo urgency12.6%LowModerate5.7%24.7%

Discontinuation & Legacy​

Voluntarily discontinued by C.R. Bard in 2011 — not a safety recall, but declining commercial viability:[35][13][2][36]

  • Skin-testing burden and 3–4% exclusion rate.
  • Poor long-term durability vs newer agents.
  • Large volumes and multiple sessions required.
  • Non-immunogenic alternatives (Durasphere 1999, Coaptite 2005, Macroplastique 2006, Bulkamid 2020) eliminated the skin-test requirement.
  • BSE-era concerns about bovine-derived products.[37]

Place in history:

  • First FDA-approved urethral bulking agent — established the minimally invasive injection paradigm.
  • Gold-standard comparator in virtually every subsequent pivotal trial.
  • Its limitations — biodegradability, immunogenicity, poor durability — directly informed the design of every successor.

Reconstructive-Urology Relevance​

Contemporary relevance is forensic / clinical:

  • Adult patients with prior Contigen may present years later with recurrent SUI as the implant is resorbed — typically managed today with reinjection (Bulkamid) or progression to midurethral sling.
  • Historical Contigen exposure is not a contraindication to subsequent surgery — the implant does not hinder reimplantation or sling placement.[7]

See also: Bulkamid, Macroplastique, Coaptite, Durasphere, Teflon, Historical Bulking Agents.

References​

1. Kirchin V, Page T, Keegan PE, et al. Urethral Injection Therapy for Urinary Incontinence in Women. Cochrane Database of Systematic Reviews. 2017;7:CD003881. doi:10.1002/14651858.CD003881.pub4

2. Davis NF, Kheradmand F, Creagh T. Injectable Biomaterials for the Treatment of Stress Urinary Incontinence: Their Potential and Pitfalls as Urethral Bulking Agents. International Urogynecology Journal. 2013;24(6):913-919. doi:10.1007/s00192-012-2011-9

3. Frey P, Lutz N, Berger D, Herzog B. Histological Behavior of Glutaraldehyde Cross-Linked Bovine Collagen Injected Into the Human Bladder for the Treatment of Vesicoureteral Reflux. The Journal of Urology. 1994;152(2 Pt 2):632-635. doi:10.1016/s0022-5347(17)32669-1

4. Frey P, Berger D, Jenny P, Herzog B. Subureteral Collagen Injection for the Endoscopic Treatment of Vesicoureteral Reflux in Children. The Journal of Urology. 1992;148(2 Pt 2):718-723. doi:10.1016/s0022-5347(17)36703-4

5. McClelland M, Delustro F. Evaluation of Antibody Class in Response to Bovine Collagen Treatment in Patients With Urinary Incontinence. The Journal of Urology. 1996;155(6):2068-2073.

6. Appell RA. Collagen Injection Therapy for Urinary Incontinence. The Urologic Clinics of North America. 1994;21(1):177-182.

7. Leonard MP, Canning DA, Epstein JI, Gearhart JP, Jeffs RD. Local Tissue Reaction to the Subureteral Injection of Glutaraldehyde Cross-Linked Bovine Collagen in Humans. The Journal of Urology. 1990;143(6):1209-1212. doi:10.1016/s0022-5347(17)40227-8

8. Charriere G, Bejot M, Schnitzler L, Ville G, Hartmann DJ. Reactions to a Bovine Collagen Implant. Clinical and Immunologic Study in 705 Patients. Journal of the American Academy of Dermatology. 1989;21(6):1203-1208. doi:10.1016/s0190-9622(89)70330-3

9. McCoy JP, Schade W, Siegle RJ, et al. Immune Responses to Bovine Collagen Implants. Significance of Pretreatment Serology. Journal of the American Academy of Dermatology. 1987;16(5 Pt 1):955-960. doi:10.1016/s0190-9622(87)70120-0

10. Heit M. Prolonged Urinary Retention After Collagen Periurethral Injections: A Sequela of Humoral Immunity. Obstetrics and Gynecology. 1997;90(4 Pt 2):693-695. doi:10.1016/s0029-7844(97)00274-3

11. Cooperman LS, Garovoy MR, Sondel PM. Association of the HLA-DR2/DR4 Phenotype With Skin Test Responses to Bovine Dermal Collagen. Human Immunology. 1986;17(4):471-479. doi:10.1016/0198-8859(86)90305-8

12. Cukier J, Beauchamp RA, Spindler JS, et al. Association Between Bovine Collagen Dermal Implants and a Dermatomyositis or a Polymyositis-Like Syndrome. Annals of Internal Medicine. 1993;118(12):920-928. doi:10.7326/0003-4819-118-12-199306150-00002

13. Committee on Practice Bulletins—Gynecology and the American Urogynecologic Society. ACOG Practice Bulletin No. 155: Urinary Incontinence in Women. Obstetrics and Gynecology. 2015;126(5):e66-e81. doi:10.1097/AOG.0000000000001148

14. Smith DN, Appell RA, Winters JC, Rackley RR. Collagen Injection Therapy for Female Intrinsic Sphincteric Deficiency. The Journal of Urology. 1997;157(4):1275-1278.

15. Silva LA, Andriolo RB, Atallah ÁN, da Silva EM. Surgery for Stress Urinary Incontinence Due to Presumed Sphincter Deficiency After Prostate Surgery. Cochrane Database of Systematic Reviews. 2014;(9):CD008306. doi:10.1002/14651858.CD008306.pub3

16. Mayer RD, Dmochowski RR, Appell RA, et al. Multicenter Prospective Randomized 52-Week Trial of Calcium Hydroxylapatite Versus Bovine Dermal Collagen for Treatment of Stress Urinary Incontinence. Urology. 2007;69(5):876-880. doi:10.1016/j.urology.2007.01.050

17. Ghoniem G, Corcos J, Comiter C, et al. Cross-Linked Polydimethylsiloxane Injection for Female Stress Urinary Incontinence: Results of a Multicenter, Randomized, Controlled, Single-Blind Study. The Journal of Urology. 2009;181(1):204-210. doi:10.1016/j.juro.2008.09.032

18. Westney OL, Bevan-Thomas R, Palmer JL, Cespedes RD, McGuire EJ. Transurethral Collagen Injections for Male Intrinsic Sphincter Deficiency: The University of Texas-Houston Experience. The Journal of Urology. 2005;174(3):994-997. doi:10.1097/01.ju.0000170237.72750.64

19. Richardson TD, Kennelly MJ, Faerber GJ. Endoscopic Injection of Glutaraldehyde Cross-Linked Collagen for the Treatment of Intrinsic Sphincter Deficiency in Women. Urology. 1995;46(3):378-381. doi:10.1016/S0090-4295(99)80223-4

20. Bent AE, Foote J, Siegel S, et al. Collagen Implant for Treating Stress Urinary Incontinence in Women With Urethral Hypermobility. The Journal of Urology. 2001;166(4):1354-1357.

21. Smith DN, Appell RA, Rackley RR, Winters JC. Collagen Injection Therapy for Post-Prostatectomy Incontinence. The Journal of Urology. 1998;160(2):364-367.

22. Leonard MP, Canning DA, Peters CA, Gearhart JP, Jeffs RD. Endoscopic Injection of Glutaraldehyde Cross-Linked Bovine Dermal Collagen for Correction of Vesicoureteral Reflux. The Journal of Urology. 1991;145(1):115-119. doi:10.1016/s0022-5347(17)38264-2

23. Reunanen M. Correction of Vesicoureteral Reflux in Children by Endoscopic Collagen Injection: A Prospective Study. The Journal of Urology. 1995;154(6):2156-2158.

24. Cross CA, English SF, Cespedes RD, McGuire EJ. A Followup on Transurethral Collagen Injection Therapy for Urinary Incontinence. The Journal of Urology. 1998;159(1):106-108. doi:10.1016/s0022-5347(01)64027-8

25. Gorton E, Stanton S, Monga A, et al. Periurethral Collagen Injection: A Long-Term Follow-Up Study. BJU International. 1999;84(9):966-971. doi:10.1046/j.1464-410x.1999.00321.x

26. Chrouser KL, Fick F, Goel A, et al. Carbon Coated Zirconium Beads in Beta-Glucan Gel and Bovine Glutaraldehyde Cross-Linked Collagen Injections for Intrinsic Sphincter Deficiency: Continence and Satisfaction After Extended Followup. The Journal of Urology. 2004;171(3):1152-1155. doi:10.1097/01.ju.0000103688.83606.06

27. Ghoniem G, Corcos J, Comiter C, et al. Cross-Linked Polydimethylsiloxane Injection for Female Stress Urinary Incontinence: Results of a Multicenter, Randomized, Controlled, Single-Blind Study. The Journal of Urology. 2009;181(1):204-210. doi:10.1016/j.juro.2008.09.032

28. Lightner D, Calvosa C, Andersen R, et al. A New Injectable Bulking Agent for Treatment of Stress Urinary Incontinence: Results of a Multicenter, Randomized, Controlled, Double-Blind Study of Durasphere. Urology. 2001;58(1):12-15. doi:10.1016/s0090-4295(01)01148-7

29. Sokol ER, Karram MM, Dmochowski R. Efficacy and Safety of Polyacrylamide Hydrogel for the Treatment of Female Stress Incontinence: A Randomized, Prospective, Multicenter North American Study. The Journal of Urology. 2014;192(3):843-849. doi:10.1016/j.juro.2014.03.109

30. Faerber GJ, Richardson TD. Long-Term Results of Transurethral Collagen Injection in Men With Intrinsic Sphincter Deficiency. Journal of Endourology. 1997;11(4):273-277. doi:10.1089/end.1997.11.273

31. Cummings JM, Boullier JA, Parra RO. Transurethral Collagen Injections in the Therapy of Post-Radical Prostatectomy Stress Incontinence. The Journal of Urology. 1996;155(3):1011-1013.

32. Frey P, Lutz N, Jenny P, Herzog B. Endoscopic Subureteral Collagen Injection for the Treatment of Vesicoureteral Reflux in Infants and Children. The Journal of Urology. 1995;154(2 Pt 2):804-807. doi:10.1097/00005392-199508000-00128

33. Stothers L, Goldenberg SL, Leone EF. Complications of Periurethral Collagen Injection for Stress Urinary Incontinence. The Journal of Urology. 1998;159(3):806-807.

34. Sweat SD, Lightner DJ. Complications of Sterile Abscess Formation and Pulmonary Embolism Following Periurethral Bulking Agents. The Journal of Urology. 1999;161(1):93-96.

35. Hillary CJ, Roman S, MacNeil S, et al. Regenerative Medicine and Injection Therapies in Stress Urinary Incontinence. Nature Reviews Urology. 2020;17(3):151-161. doi:10.1038/s41585-019-0273-4

36. Hoe V, Haller B, Yao HH, O'Connell HE. Urethral Bulking Agents for the Treatment of Stress Urinary Incontinence in Women: A Systematic Review. Neurourology and Urodynamics. 2021;40(6):1349-1388. doi:10.1002/nau.24696

37. Tan L, Williams MA, Khan MK, Champion HC, Nielsen NH. Risk of Transmission of Bovine Spongiform Encephalopathy to Humans in the United States. JAMA. 1999;281(24):2330-2339. doi:10.1001/jama.281.24.2330