Skip to main content

Autologous Chondrocyte Injection — Historical Bulking Agent

Autologous chondrocytes were a tissue-engineered, autologous biological bulking agent pioneered by Anthony Atala in the early 1990s. The concept: harvest the patient's own auricular cartilage, isolate and expand chondrocytes in monolayer culture, suspend the cells in a calcium alginate gel, and inject endoscopically to create a living, nonantigenic cartilage nidus.[1][2] Studied for VUR in children and female SUI with intrinsic sphincter deficiency, the technology never reached FDA approval and has been abandoned — superseded by simpler off-the-shelf agents (Deflux for VUR; Bulkamid / Macroplastique for SUI).

Historical Timeline​

  • 1993 — Atala (Harvard / Boston Children's): foundational preclinical study; chondrocyte-alginate gels formed cartilage at 34/36 (94%) subcutaneous sites in athymic mice; no migration or granuloma.[1]
  • 1994 — Mini-pig VUR model (n = 4): subureteral chondrocyte-alginate injection produced cystographic reflux resolution on all treated sides; histologically viable cartilage at the injection site.[2]
  • 1999 — Diamond & Caldamone: first clinical VUR trial (29 children / 46 ureters, grade II–IV); 83% overall correction after 1–2 injections.[3]
  • 2001 — Caldamone & Diamond long-term: 1-year maintenance dropped to 70% of ureters / 65% of patients; failures showed mound volume loss and shifting.[4]
  • 2001 — Bent: only clinical SUI study (n = 32 women with ISD, single injection); 50% dry, 81.3% dry or improved at 12 months.[5]
  • 2004 — Paltiel sonographic analysis: 34% mean mound volume loss over 12 months.[6]
  • 2009 — Gargollo: 37% mound calcification at median 9 years.[7]

Composition & Material Properties​

A fundamentally different concept from inert bulking — the goal was living autologous cartilage at the injection site.[1][2][5][8]

  • Cell source: posterior auricular cartilage, harvested via retroauricular incision.[3][5]
  • Cells: chondrocytes isolated by enzymatic digestion and expanded ~6 weeks in monolayer culture.[3][4]
  • Concentration: 40 × 10⁶ cells/cc in preclinical work.[2]
  • Carrier: calcium alginate gel (seaweed-derived, biodegradable) as 3D scaffold.[1][5]
  • Autologous, non-immunogenic, non-migratory (confirmed preclinically).[1]
  • Living tissue — designed to produce a permanent type-II-collagen / proteoglycan matrix that progressively replaces the alginate scaffold.

Mechanism​

Two-phase:[1][2]

  1. Immediate bulking — alginate gel provides volume at the subureteral / periurethral injection site.
  2. Cartilage formation — chondrocytes lay down ECM as the alginate degrades; preclinically the polymer was progressively replaced by cartilage with size proportional to seeded chondrocyte concentration.

The theoretical advantage: a permanent, stable bulking effect, unlike biodegradable collagen / fat or potentially migratory synthetics. In practice, the volume loss data (below) argue the cartilage matrix was incompletely or unstably established.

Procedure — Two Stages​

Stage 1 — Cartilage harvest (with concurrent diagnostic cystoscopy in VUR cases):[3][4]

  • GA in children / local in adults.
  • Small posterior-auricular cartilage piece.
  • Cells isolated, expanded ~6 weeks; excess cryopreserved for retreatment.

Stage 2 — Endoscopic injection (6 weeks later):

  • VUR: transurethral injection of chondrocyte-alginate at the ureterovesical junction (STING-type technique).[3][4]
  • SUI: single periurethral injection just distal to the bladder neck, local + outpatient.[5]

Clinical Efficacy​

Vesicoureteral Reflux​

StudynFollow-upOutcome
Diamond / Caldamone 199929 children / 46 ureters (grade II–IV)3 mo57% after 1 injection, 63% after 2nd; 83% overall.[3]
Caldamone / Diamond 200129 children / 47 ureters> 1 yr86% at 3 mo → 70% ureters / 65% patients at 1 yr; failures showed volume loss and mound shifting on cystoscopy.[4]
Paltiel 2004 (sonographic)32 / 56 ureters12 mo meanAbsent or multilobed mound associated with persistent reflux; mean mound volume 0.56 → 0.37 cm³ (34% decrease, p = 0.004).[6]
Gargollo 200927 patients9 yr median37% developed mound calcification at median 2.1 yr; 7/10 with hematuria ± flank pain; 3 mimicked UVJ stones.[7]

The critical signal: initial success was competitive with other VUR agents, but the 1-year maintenance dropped to 65% of patients due to mound volume loss and shifting — not the stable cartilage formation the model predicted.[4]

Female SUI — Bent 2001 (single uncontrolled multicenter study)​

n = 32 women with documented ISD; single periurethral injection just distal to the bladder neck; 12-month follow-up:[5]

  • 50% completely dry.
  • 81.3% dry or improved (16 dry + 10 improved / 32).
  • 26/32 who were dry or improved at 3 mo maintained at 12 mo.
  • Pad weight > 2.2 g at 12 mo in only 4 patients.
  • Significant QoL improvement; UDI and IIQ scores decreased.
  • No significant complications.

This single-injection 50% dry rate compared favorably to Contigen at the time (typically 25–57% cure requiring 2–3 sessions). The absence of a control arm limits interpretation, particularly given the Lee 2001 fat-vs-saline RCT showing equivalent placebo response — see Autologous Fat and the Cochrane review classifying autologous chondrocytes among experimental phase-I/II agents.[9]

Sonographic Mound Features (Paltiel)​

Mound morphology vs reflux outcome:[6]

  • Unilobed → successful correction (28/29 ureters reflux-free had unilobed mounds early).
  • Absent → persistent reflux (6/16 ureters with reflux).
  • Multilobed → persistent reflux (3/16 with reflux vs 1/29 without).

Mean volume 34% decrease at 12 mo (p = 0.004) — the primary mechanism of relapse. Treatment-induced hydronephrosis was uncommon and self-limited.

Long-Term — Mound Calcification (Gargollo)​

The most significant long-term complication:[7]

  • 37% (10/27) calcified at median 9 yr.
  • Median onset 2.1 yr (range 1–5).
  • 7/10 presented with gross or microscopic hematuria ± flank pain; 3 mimicked UVJ stones; 3 incidental on imaging.
  • No obstruction; no hydroureteronephrosis.
  • Univariate / multivariate analysis: no association with gender, initial reflux grade, volume injected, number of injections, or follow-up time.
  • Mechanism: possible endochondral ossification or dystrophic calcification — i.e., cartilage doing what cartilage tends to do.

Analogous calcification has been reported with Deflux (see Deflux page) — likely a general feature of long-standing subureteral implants rather than chondrocyte-specific.

Safety​

Favorable short-term:[3][4][5][7]

  • No significant acute complications in any clinical study.
  • No allergic reactions (autologous).
  • No distant migration (preclinically confirmed).[1]
  • No granuloma.
  • Transient mild hydronephrosis 3/32 children (self-limited).
  • Minimal donor-site morbidity (small retroauricular incision; no cosmetic deformity).

Long-term:

  • Mound calcification 37% at 9 yr.
  • Volume loss 34% over 12 mo.
  • Mound shifting in failures.
  • 3 patients underwent successful open reimplantation after failed chondrocyte injection — prior chondrocyte injection did not hinder subsequent surgery.[4]

Why It Was Abandoned​

[9][10][4][7][11]
  • Logistical complexity — two stages with a 6-week culture interval; requires GMP-compliant cell-culture infrastructure.
  • Volume loss and relapse — 34% mound decrease; 1-yr correction 86% → 65% of patients.
  • Long-term calcification — 37% at 9 yr, mimicking stones, causing hematuria.
  • Simpler alternatives emerged — Deflux (2001) for VUR; Bulkamid (2020) and Macroplastique (2006) for SUI.
  • Regulatory burden — would require a Biologics License Application (Section 351) rather than the device pathway used by synthetic bulking agents.[11]
  • Sparse evidence — one uncontrolled SUI study (n = 32) and one VUR series (n = 29); no RCTs. Cochrane classifies as experimental.[9]
  • Cost — cell culture + two-stage procedure substantially more expensive than off-the-shelf agents.

Comparison​

ParameterAutologous ChondrocytesContigenDefluxBulkamidAutologous Fat
MaterialAutologous cells + alginateBovine collagenDx/HAPolyacrylamide hydrogelAutologous biologic
ImmunogenicNoYes (skin test)NoNoNo
Two-stage procedureYes (6-wk culture)NoNoNoYes (liposuction)
VUR resolution (1 injection)55–57%63–75%69–87%—5.9%
VUR overall83–86%77–90%85–92%——
SUI cure 12 mo50% (single)25–57% (multi)—47–64%22% (= placebo)
Long-term calcification37% at 9 yrNot reportedReportedNot reportedNot reported
Volume loss34% decreaseComplete resorptionVariableMinimal17–49%
FDA approvedNever1993 (discontinued 2011)20012020Never
Current statusAbandonedDiscontinuedAvailableAvailableAbandoned

Auricular Chondrocytes in Other Applications​

Beyond urologic bulking, auricular chondrocytes have been explored for:[8][12][13]

  • Vocal-fold medialization — Noordzij 2008 feasibility of an injectable cartilage slurry through an 18-G needle.
  • Tissue-engineered urethral stents — Amiel / Atala 2001 chondrocyte-seeded polymer scaffolds.
  • Reconstructive surgery (ear, nasal, tracheal) and cardiovascular prosthesis luminal-surface modification.

Reconstructive-Urology Relevance​

Adult or adolescent patients with prior pediatric autologous chondrocyte VUR injection may present with:

  • Calcified subureteral mounds on imaging, mimicking UVJ stones — important not to mistake for calculi or to over-image.[7]
  • Hematuria of unclear etiology attributable to calcified mound.[7]
  • Recurrent VUR from volume loss / mound shifting — open or robotic reimplantation remains feasible; prior chondrocyte injection has not been shown to hinder subsequent surgery.[4]

See also: Deflux, Contigen, Autologous Fat, Teflon, Historical Bulking Agents.

References​

1. Atala A, Cima LG, Kim W, et al. Injectable Alginate Seeded With Chondrocytes as a Potential Treatment for Vesicoureteral Reflux. The Journal of Urology. 1993;150(2 Pt 2):745-747. doi:10.1016/s0022-5347(17)35603-3

2. Atala A, Kim W, Paige KT, Vacanti CA, Retik AB. Endoscopic Treatment of Vesicoureteral Reflux With a Chondrocyte-Alginate Suspension. The Journal of Urology. 1994;152(2 Pt 2):641-643. doi:10.1016/s0022-5347(17)32671-x

3. Diamond DA, Caldamone AA. Endoscopic Correction of Vesicoureteral Reflux in Children Using Autologous Chondrocytes: Preliminary Results. The Journal of Urology. 1999;162(3 Pt 2):1185-1188. doi:10.1016/S0022-5347(01)68124-2

4. Caldamone AA, Diamond DA. Long-Term Results of the Endoscopic Correction of Vesicoureteral Reflux in Children Using Autologous Chondrocytes. The Journal of Urology. 2001;165(6 Pt 2):2224-2227. doi:10.1016/S0022-5347(05)66170-8

5. Bent AE, Tutrone RT, McLennan MT, et al. Treatment of Intrinsic Sphincter Deficiency Using Autologous Ear Chondrocytes as a Bulking Agent. Neurourology and Urodynamics. 2001;20(2):157-165.

6. Paltiel HJ, Diamond DA, Zurakowski D, Drubach LA, Atala A. Endoscopic Treatment of Vesicoureteral Reflux With Autologous Chondrocytes: Postoperative Sonographic Features. Radiology. 2004;232(2):390-397. doi:10.1148/radiol.2322030551

7. Gargollo PC, Paltiel HJ, Rosoklija I, Diamond DA. Mound Calcification After Endoscopic Treatment of Vesicoureteral Reflux With Autologous Chondrocytes — a Normal Variant of Mound Appearance? The Journal of Urology. 2009;181(6):2702-2707. doi:10.1016/j.juro.2009.02.053

8. Nabzdyk C, Pradhan L, Molina J, et al. Auricular Chondrocytes — From Benchwork to Clinical Applications. In Vivo. 2009;23(3):369-380.

9. 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

10. 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

11. Marks P, Gottlieb S. Balancing Safety and Innovation for Cell-Based Regenerative Medicine. The New England Journal of Medicine. 2018;378(10):954-959. doi:10.1056/NEJMsr1715626

12. Noordzij JP, Cates JM, Cohen SM, et al. Preparation Techniques for the Injection of Human Autologous Cartilage: An Ex Vivo Feasibility Study. The Laryngoscope. 2008;118(1):185-188. doi:10.1097/MLG.0b013e318155a25b

13. Amiel GE, Yoo JJ, Kim BS, Atala A. Tissue Engineered Stents Created From Chondrocytes. The Journal of Urology. 2001;165(6 Pt 1):2091-2095. doi:10.1097/00005392-200106000-00076