Autologous matrix-induced chondrogenesis

Autologous Matrix-Induced Chondrogenesis (AMIC) is a biological treatment option which repairs articular cartilage damage. It combines microfracture surgery with the application of a bi-layer collagen I/III membrane. AMIC achieves pain relief and restores functionality in the joint with the goal to regain full mobility, allowing going back to previous lifestyle and activity level. It slows down cartilage degeneration with the intent to avoid or delay partial or total joint replacement (e.g. knee replacement) surgery. The initialism AMIC, often used as a genericized trademark, is a registered trademark of Ed. Geistlich Söhne AG, protected by German Registration No. 30255356 [1] and international Registration No. 840373.[2]

Background

The AMIC procedure was first proposed by Behrens in 2003.[3] It aims to extend the use of microfracture surgery to larger cartilage lesions > 2.5 cm2.

AMIC is based on microfracturing which relies on the body’s own healing potential. Blood and bone marrow which are released through tiny holes in the subchondral bone plate, fill the damaged cartilage area with a so-called super-clot. This blood clot contains all the elements (e.g. progenitor cells, mesenchymal stem cells (MSCs), cytokines and growth factors) necessary to form new cartilage repair tissue as response to the encountered injury.

Adding a collagen membrane to the forming super clot secures it and improves overall clot stability. It also enhances the primary defect fill which is an important parameter for good outcome. Furthermore, the application of a collagen membrane provides an environment where cells can adhere, proliferate and produce repair tissue in a protected setting. The originally proposed collagen membrane for AMIC (Chondro-Gide, Geistlich Pharma AG, Switzerland) consists of two sides, two layers (bi-layer design), one dense, compact side and a loose side.

Its clinical efficiency in autologous chondrocyte implantation (ACI), another cartilage repair technique for larger cartilage lesions, has been studied extensively.[4][5][6]

AMIC surgery is currently performed to treat cartilage damage in the knee and in the ankle (talus).

Procedure

Autologous Matrix Induced Chondrogenesis (AMIC) surgery is a single step procedure. After arthroscopic evaluation of the cartilage damage and decision for an AMIC procedure a mini arthrotomy is performed. An all-arthroscopic AMIC procedure for repair of cartilage defects of the knee is also possible.[7]

First the cartilage defect is exposed and cleaned whereby all unstable degenerated cartilage, including the calcified cartilage layer, are carefully removed. An imprint of the defect is then taken using a sterile moldable material (e.g. aluminium foil) and transferred to the collagen membrane which is cut to shape. The surgeon then creates tiny holes/fractures in the subchondral bone plate (microfracturing) with a special awl. Blood and bone marrow (containing stem cells) are released forming a blood clot which contains cartilage forming elements. The correctly sized collagen membrane is added to the microfractured area either by fibrin glue (autologous or commercially available) or suturing. Through flexion of the joint, the stable positioning of the membrane is verified and the wound is closed.

A critical phase and actually essential requirement for satisfying outcome of the AMIC surgery is the compliance to a strict physical therapy program. Guidelines and recommendations exist, though they have to be adapted to the individual patients needs.

Clinical Results

In general various factors have been identified known to influence the clinical result after cartilage repair regardless of the technique used. Amongst them are the species and age of the individual, the size and localization of the articular cartilage defect, the surgical technique, and the postoperative rehabilitation protocol.[8][9] The latter has been found especially important for microfracture surgery and therefore for AMIC.[10]

Microfracture surgery was developed by Dr. Steadman in the late 80’s and early 90’s. It is a well documented cartilage repair technique and first line treatment option for small cartilage lesions.[11][12][13] AMIC evolved with the aim to improve some of the shortfalls of microfracture surgery as for instance variable repair cartilage volume and functional deterioration over time.[14] Additionally it was intended to provide a simple technique for securely retaining the fragile blood clot in larger defects and to possibly enhance the chondrogenesis of MSCs.

The first in-vitro work demonstrating that a collagen membrane can retain cartilage building cells (e.g. MSCs) from bone marrow was published in 2006 by Kramer et al.. After perforation of the subchondral bone (microfracturing) the collagen membrane was added to the forming super-clot. Then MSCs were recovered from a tiny surplus of bone marrow soaked membrane. As a proof of their existence, MCSs were successfully differentiated into the adipogenic, osteogenic and most importantly chondrogenic lineage. Chondrification (also known as chondrogenesis) is the underlying process of cartilage formation from condensed mesenchyme tissue, which differentiates into chondrocytes and begins secreting the molecules that form the extracellular matrix, the cartilage repair tissue.[15]

In another in-vitro study Dickhut et al. investigated whether a combination of a collagen membrane (Chondro-Gide) with fibrin glue supports in-vitro chondrogenesis of MSCs and allowed for local release of bioactive transforming growth factor beta-1 (TGF-β1). They could show, that the combination provided high biofunctionality with improved chondrogenesis and long term local supply of TGF-β1. TGF-β1 is a secreted protein that performs many cellular functions, including the control of cell growth, cell proliferation, cell differentiation and apoptosis. Additionally Dickhut et al. could demonstrate that the form stability of the forming repair tissue was enhanced when compared to collagen-membrane-free constructs.[16]

The addition of a collagen membrane to microfractured cartilage lesions has also been tested in a sheep study by Gille et al.. It could be confirmed that the thickness of the repair tissue was greater when a scaffold, especially a collagen I/III membrane, was used as compared to microfracture alone. Hence the authors concluded that repair tissue formation was promoted.[17]

The same author reported first clinical results with the AMIC technique in 2010. A total of 27 patients who underwent AMIC surgery between 2003 and 2005 were included in this prospective investigation. The follow-up period was between 24 and 62 months with a mean of 37 months. The mean age of the patients was 39 years (range 16 – 50 years). The mean defect size was 4.2 cm2 (range 1.3 - 8.8 cm2). Three patients had to be excluded from the study. 20 of the 23 patients questioned answered that they were highly satisfied with the results after surgery and stated overall improvement of knee function. The outcome scores applied (Lysholm, ICRS, Meyer, Tegner, Cincinnati) showed significant increase up to 24 months with a slight decrease from three years post surgery. Patients with lesions larger 8 cm2 had greatly reduced scores. Gille et al. concluded that treatment of chondral knee lesions with the AMIC technique is effective and safe in appropriately selected cases.[18]

Further clinical description of the AMIC technique and its early results can be found in the papers by Benthien, de Girolamo, Wiewiorski and Valderrabano.[19][20][21][22][23]

With one exception, the clinical results are limited to case series and other non-comparative studies. In 2013 Anders et al.[24] published results of a randomized controlled trial (RCT) which was launched in 2004. The aim of the study was to evaluate the efficacy and safety of AMIC over microfracture. The outcome scores applied (modified ICRS, modified Cincinnati, VAS pain) showed no significance between the two treatment methods. Radiologic evaluation showed slightly inferior outcome for AMIC, especially with regard to the surface of the regenerate and degree of integration. The value of the study is limited due to low case numbers, short follow-up periods and weaknesses in the study design and implementation.

As the evidence for AMIC is limited, no final conclusion can be drawn about the value of the procedure. Further clinical trials and health economic data are required to assess the benefit.

Further developments

As further development to use of two-dimensional membranes, a chitosan-based three-dimensional liquid bio-scaffold (BST-CarGel) received the European CE mark approval in April 2012 as EU class III medical device according to the Directive 93/42/EEC.

The bio-scaffold is mixed with autologous whole blood and then applied to the debrided, microfractured cartilage lesion. It stabilizes and protects the blood clot, is biodegradable and enhances the natural wound healing process.

In an international, randomized controlled trial [25] conducted by Stanish et al., the safety and efficacy of the bio-scaffold was compared to microfracturing. Data from the Phase III clinical study were presented at the 10th World Congress of the International Cartilage Repair Society (ICRS), May 2012, in Montreal, Quebec, Canada. The data demonstrated that at a follow-up of 12 months after cartilage repair with the bio-scaffold, both the degree of filling of treated lesions and the quality of the new tissue were statistically significantly superior compared to microfracture alone, with a comparable safety profile.

See also

References

  1. ↑ "Deutsche Patent- und Markenamt (DPMA), registration # 30255356". 2002-11-11. Retrieved 2013-01-25.
  2. ↑ "World Intellectual Property Organization (WIPO), registration # 840373". 2004-08-18. Retrieved 2013-01-25.
  3. ↑ Behrens P., P. (2005). "Matrixgekoppelte Mikrofrakturierung". Arthroskopie. 18 (3): 193–197. doi:10.1007/s00142-005-0316-0.
  4. ↑ Gomoll AH, Probst C, Farr J, Cole BJ, Minas T (November 2009). "Use of a type I/III bilayer collagen membrane decreases reoperation rates for symptomatic hypertrophy after autologous chondrocyte implantation". Am J Sports Med. 37 Suppl 1: 20S–23S. doi:10.1177/0363546509348477. ISSN 0363-5465. PMID 19841142.
  5. ↑ Steinwachs M, Kreuz PC (April 2007). "Autologous chondrocyte implantation in chondral defects of the knee with a type I/III collagen membrane: A prospective study with a 3-year follow-up". Arthroscopy. 23 (4): 381–387. doi:10.1016/j.arthro.2006.12.003. ISSN 1526-3231. PMID 17418330.
  6. ↑ Gooding CR, Bartlett W, Bentley G, Skinner JA, Carrington R, Flanagan A (Jun 2006). "A prospective, randomised study comparing two techniques of autologous chondrocyte implantation for osteochondral defects in the knee: Periosteum covered versus type I/III collagen covered". Knee. 13 (3): 203–10. doi:10.1016/j.knee.2006.02.011. ISSN 0968-0160. PMID 16644224.
  7. ↑ Piontek, Tomasz; Ciemniewska-Gorzela Kinga; Szulc Andrzej; Naczk Jakub; Słomczykowski Michał (30 August 2011). "All-arthroscopic AMIC procedure for repair of cartilage defects of the knee". Knee Surgery, Sports Traumatology, Arthroscopy: 1–4. doi:10.1007/s00167-011-1657-z. ISSN 0942-2056.
  8. ↑ Alford JW, Cole BJ (Mar 2005). "Cartilage restoration, part 2: techniques, outcomes, and future directions". Am J Sports Med. 33 (3): 443–460. doi:10.1177/0363546505274578. ISSN 0363-5465. PMID 15716263.
  9. ↑ Steinwachs MR, Guggi T, Kreuz PC (Apr 2008). "Marrow stimulation techniques". Injury. 39 Suppl 1: S26–31. doi:10.1016/j.injury.2008.01.042. ISSN 0020-1383. PMID 18313469.
  10. ↑ Hurst JM, Steadman JR, O'Brien L, Rodkey WG, Briggs KK (Apr 2010). "Rehabilitation following microfracture for chondral injury in the knee". Clin Sports Med. 29 (2): 257–65, viii. doi:10.1016/j.csm.2009.12.009. ISSN 1556-228X. PMID 20226318.
  11. ↑ Steadman JR, Rodkey WG, Singleton SB, Briggs KK (October 1997). "Microfracture technique for full-thickness chondral defects: Technique and clinical results". Oper Tech Orthop. 7 (4): 300–304. doi:10.1016/S1048-6666(97)80033-X.
  12. ↑ Steadman JR, Rodkey WG, Rodrigo JJ (Oct 2001). "Microfracture: surgical technique and rehabilitation to treat chondral defects". Clin Orthop Relat Res (391 Suppl): S362–9. ISSN 0009-921X. PMID 11603719.
  13. ↑ Steadman JR, Briggs KK, Rodrigo JJ, Kocher MS, Gill TJ, Rodkey WG (May–Jun 2003). "Outcomes of microfracture for traumatic chondral defects of the knee: average 11-year follow-up". Arthroscopy. 19 (5): 477–84. doi:10.1053/jars.2003.50112. ISSN 1526-3231. PMID 12724676.
  14. ↑ Mithoefer K, McAdams T, Williams RJ, Kreuz PC, Mandelbaum BR (Oct 2009). "Clinical efficacy of the microfracture technique for articular cartilage repair in the knee: an evidence-based systematic analysis". Am J Sports Med. 37 (10): 2053–63. doi:10.1177/0363546508328414. ISSN 1552-3365. PMID 19251676.
  15. ↑ Kramer J, Böhrnsen F, Lindner U, Behrens P, Schlenke P, Rohwedel J (Mar 2006). "In vivo matrix-guided human mesenchymal stem cells". Cell Mol Life Sci. 63 (5): 616–26. doi:10.1007/s00018-005-5527-z. ISSN 1420-682X. PMID 16482398.
  16. ↑ Dickhut A, Dexheimer V, Martin K, Lauinger R, Heisel C, Richter W (Feb 2010). "Chondrogenesis of human mesenchymal stem cells by local TGF-beta delivery in a biphasic resorbable carrier". Tissue Eng Part A. 16 (2): 453–64. doi:10.1089/ten.TEA.2009.0168. ISSN 1937-335X. PMID 19705961.
  17. ↑ Gille J, Kunow J, Boisch L, Behrens P, Bos I, Hoffmann C, Köller W, Russlies M, Kurz B (Jan 2010). "Cell-Laden and Cell-Free Matrix-Induced Chondrogenesis versus Microfracture for the Treatment of Articular Cartilage Defects: A Histological and Biomechanical Study in Sheep". Cartilage. 1 (1): 29–42. doi:10.1177/1947603509358721.
  18. ↑ Gille J, Schuseil E, Wimmer J, Gellissen J, Schulz AP, Behrens P (Nov 2010). "Mid-term results of Autologous Matrix-Induced Chondrogenesis for treatment of focal cartilage defects in the knee". Knee Surg Sports Traumatol Arthrosc. 18 (11): 1456–64. doi:10.1007/s00167-010-1042-3. ISSN 1433-7347. PMID 20127072.
  19. ↑ de Girolamo L, Bertolini G, Cervellin M, Sozzi G, Volpi P (Oct 2010). "Treatment of chondral defects of the knee with one step matrix-assisted technique enhanced by autologous concentrated bone marrow: in vitro characterisation of mesenchymal stem cells from iliac crest and subchondral bone". Injury. 41 (11): 1172–7. doi:10.1016/j.injury.2010.09.027. ISSN 1879-0267. PMID 20934693.
  20. ↑ Benthien JP, Behrens P (Apr 2010). "Autologous matrix-induced chondrogenesis (AMIC). A one-step procedure for retropatellar articular resurfacing". Acta Orthop Belg. 76 (1): 260–263. ISSN 0001-6462. PMID 20503954.
  21. ↑ Benthien JP, Behrens P (Jan 2010). "Autologous Matrix-Induced Chondrogenesis (AMIC): Combining Microfracturing and a Collagen I/III Matrix for Articular Cartilage Resurfacing". Cartilage. 1 (1): 65–68. doi:10.1177/1947603509360044.
  22. ↑ Wiewiorski M, Leumann A, Buettner O, Pagenstert G, Horisberger M, Valderrabano V (Jan 2010). "Autologous matrix-induced chondrogenesis aided reconstruction of a large focal osteochondral lesion of the talus". Arch Orthop Trauma Surg. 131 (3): 293–296. doi:10.1007/s00402-010-1048-9. ISSN 1434-3916. PMID 20091174.
  23. ↑ Valderrabano V, Miska M, Leumann A, Wiewiorski M (Mar 2013). "Reconstruction of osteochondral lesions of the talus with autologous spongiosa grafts and autologous matrix-induced chondrogenesis". Am J Sports Med. 41 (3): 519–27. doi:10.1177/0363546513476671. PMID 23393079.
  24. ↑ Anders S, Volz M, Frick H, Gellissen J (May 2013). "A Randomized, Controlled Trial Comparing Autologous Matrix-Induced Chondrogenesis (AMIC®) to Microfracture: Analysis of 1- and 2-Year Follow-Up Data of 2 Centers". Open Orthop J. 7: 133–43. doi:10.2174/1874325001307010133. ISSN 1874-3250. PMID 23730377.
  25. ↑ Follow-Up Study Comparing BST-CarGel and Microfracture in Repair of Articular Cartilage Lesions in the Knee: ClinicalTrials.gov Identifier: NCT01246895

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