Written by Mats Brittberg, Sweden
Category: Sports Surgery

Volume 10 | Targeted Topic - Knee Joint Preservation | 2021
Volume 10 - Targeted Topic - Knee Joint Preservation



– Written by Mats Brittberg, Sweden




Musculoskeletal injuries with traumatized tissues are resulting in a bleeding, blood clot formation and an ingrowth of repair cells into the blood clot scaffold1. Cartilage being devoid of blood vessels and nerves will not have a chance of such repair with just a few cells migrating into the defect and no messenger to instruct a start of a reparative process1. Numerous attempts have been performed to increase the reparative ability of cartilage with most of them involving bone marrow stimulation (BMS) and by that induction of a bleeding with subsequent blood clot scaffolding to attract cells from the bone marrow to repair the defects2,3,4.

Small defects have been treated by BMS alone while larger defects have been augmented by artificial scaffolds to improve the filling2,3,4,5,6. For long, it has been thought that the bone marrow cells are repair cells while recent studies tell us that those cells are more of medicinal signaling cells stimulating the cartilaginous surrounding and synovia7. Recently, Arnold Caplan suggested a change of the name of MSCs from mesenchymal stem cells to Medicinal Signaling Cells to better reflect the fact that these cells home in on sites of injury or disease and secrete bioactive factors7.

The chondrocyte (Figure 1), the one and only cell in cartilage is being responsible for all matrix production and would be the most natural cell to use when to repair cartilage defects8, 9. When chondrocytes are separated from their matrix, the cells could divide, proliferate and become more in numbers10.  Enzymatic digestions of cartilage and in vitro cell expansions are used when to culture chondrocytes to use them as cell source for cartilage repair10,11


The clinical use of chondrocytes

The first clinical use of chondrocytes for clinical cartilage repair was performed in Gothenburg, Sweden in 1987 (Brittberg et al 1994)12.There exist today long-term results up to 20 years with good results based on the 1st generation ACI with chondrocytes in suspension implanted under a periosteal membrane13-16.

Today in 2021 we have now 4 generations of ACI:

·       1st generation ACI: Chondrocytes in suspension injected under a living periosteal membrane12 (Figure 2).

·       2nd generation ACI with cells in suspension injected under a collagen membrane17.

·       3rd generation of ACI with cells either grown on a surface carrier18 or cells grown in a porous matrix/scaffold19. To this generation also scaffold-free ACI is categorized20.

·       4th generation ACI is when chondrocytes are in different ways implanted as one-stage procedures. Examples are when chondrocytes are directly isolated and mixed with directly isolated autologous MSCs21 or allogeneic MSCS seeded in a matrix22. Fourth generation ACI are also variants of particulated or minced autologous or allogeneic cartilage on scaffolds (CAIS23, CAFRIMA24, AutoCart®25, and DeNovo®26).(Figure 3 a and b).

Cell therapies including cultured chondrocytes are examples of cell manipulations and such modulations are requiring special regulatory frameworks developed by FDA27 in USA and EMEA28 in Europe. The way to be approved for cell therapies is long and very expensive and many companies involved in cartilage repair have tried to find cell therapies not involving cell manipulations and by that much easier to use for the surgeons  with less costs. Subsequently, today very few in vitro expanded chondrocytes techniques are available for the patients. Commercially available ACI Gen III techniques today in 2021 are:

·       MACI®29-Vericel USA.

·       Bioseed-C®30 – BioTissue Germany.

·       CaRes- Arthro®31 Kinetics Biotechnology GmbH (Austria).

·       Chondrosphere®32 (spherox)-CoDon Gemany.

·       In clinical trials:

·              Hyalograft-C-HS33.

·       NeoCart®34-Histogenics (USA).

·       NovoCart®35-Aesculap biologics.


Other chondrogeneic cells

Instead of using manipulated cells, the companies have focused on the use of different chondrogeneic cells for repair, cells that can be used as one-stage procedures. Both chondrocytes but also cells not being pure chondrocytes could be used for cartilage repair.

Non chondrocyte Chondrogeneic cells are:

·              Bone Marrow-Derived Stem Cells36,37.

·              Adipose-Derived Stem Cells38.

·              Synovial Membrane-Derived Stem Cells39.

·              Muscle-Derived Stem Cells40.

·              Peripheral Blood Stem Cells41.

·              Menstrual blood progenitor cells42.

Those adult stem cells have limited self-renewal capacities. Furthermore, as a person ages, these cells exhibit decreased proliferation rates and lessened chondrogeneic differentiation potential.

Furthermore, also extra embryonic sources of cells to be used exists such as43:

·       Wharton’s Jelly Stem Cells.

·       Umbilical Cord Blood Stem Cells (BMP-2, BMP-6).

·       Amniotic Fluid Stem Cells.

·       Placenta-Derived Mesenchymal Stem Cells.

A study compared human MSCs derived from bone marrow, Periosteum, Synovium, skeletal muscle and adipose tissue44. The study revealed that synovium-derived MSCs exhibited the highest capacity for chondrogenesis, followed by bone marrow-derived and periosteum-derived MSCs.

Furthermore, it has been shown that culture-expanded chondrocytes have the potential45:

·       to form cartilage in in vitro pellet mass cultures,

·       to form adipose cells in dense monolayer culture,

·       to form a calcium-rich matrix in an osteogenic assay.

Important finding was, however, that in contrast with MSCs, chondrocytes formed cartilage only and not bone with in the study used in vivo osteochondrogenic assay45.

In another study, Karlsson et al46 compared articular chondrocytes and iliac crest derived MSCs and allowed them to differentiate in so called pellet mass cultures. Significantly decreased expression of collagen type I was accompanied by increased expression of collagen types IIA and IIB during differentiation of chondrocytes, indicating differentiation towards a hyaline phenotype46. Chondrogenesis in MSCs on the other hand resulted in up-regulation of collagen types I, IIA, IIB, and X, demonstrating differentiation towards cartilage of a mixed phenotype46. These findings suggest that chondrocytes and MSCs differentiated and formed different subtypes of cartilage, the hyaline and a mixed cartilage phenotype, respectively46and the bone marrow stem cells are prone to produce bone instead of cartilage. Such a finding is important to know about as when surgeons are doing bone marrow stimulation like micro-fracturing (MFX) with a risk of too much bone ingrowth. Some factors that promote chondrogenesis while inhibiting hypertrophic changes from MSCs might be necessary for the cartilage engineering from non-chondrocyte MSCs. 


The future ACI

Combinations of chondrocytes and MSCs

New findings demonstrate that co-culturing human MSCs with human articular chondrocytes in HA-hydrogels enhances the mechanical properties and cartilage specific ECM content of tissue-engineered cartilage47. However, co-culture decrease the expression of collagen type X by MSCs, which is an important marker of MSC.

 Initially, it was thought that when mixing chondrocytes with MSCs, the MSCs were recruited by the chondrocytes to go into a chondrogeneic lineage. Recent studies instead show that MSCs are functioning as medicinal signaling cells to stimulate the chondrocytes for a stronger repair response7

Subsequently when to repair a cartilage defects at least for larger defects, chondrocytes are needed in some form. With the complicated regulations regarding chondrocyte cultures, the possibility of using direct isolation of chondrocytes mixed with MScs as one-stage procedures has open new doors for cartilage repairs21,22.

One-stage ACI techniques are called ACI 4th generation. In the INSTRUCT study, the surgeons harvested bone marrow cells from iliac crest and mixed them with chondrocytes directly isolated in the OR21. The cell mixture was then injected in a scaffold for a direct cartilage lesion implantation. In a 24 months study in 40 patients, good lesion fill and sustained clinically important and statistically significant improvement were found in all patient-reported outcome scores throughout the 24-month study. Hyaline-like cartilage was observed on biopsy specimen in at least 22 of the 40 patients21.

Another such one-stage procedure is the IMPACT study22 where instead of direct isolation of chondrocytes, chondrocytes with surrounding pericellular matrix is isolated as chondrons. The chondrons are then mixed with allogeneic MScs and injected in fibrin glue into the defect. Using allogenic MSCs, no signs of a foreign body response or serious adverse reactions were recorded after 5 years. The majority of patients showed statistically significant and clinically relevant improvement in the KOOS and all its subscales from baseline to 60 months22.


Minced cartilage derived ACI

However, even if those above described techniques are one-stage procedures, they involve cell isolations through minor manipulations and cells with osteogenic potential that may influence the degree of chondrogenesis. A simpler, one-stage procedure is then to use particulated or fragmented cartilage for repair. The initial technique called CAIS was studied in two RCTS23,48 showing in both studies significant improvement of the patients treated by cartilage fragments in resorbable scaffold versus microfracture. Unfortunately, the company developing CAIS decided not to launch the technique for further use commercially. Instead, other companies have used the technology to develop modified versions of CAIS with fragments in different scaffolds. 

Williams and co-workers49 have identified a population of chondroprogenitor cells from the surface zone of bovine articular cartilage using differential adhesion to fibronectin49. This population of cells can form large numbers of colonies from a low seeding density and is capable of extended culture without losing the chondrogenic phenotype and they are subsequently cartilage progenitor cells49.

Therefore, these populations are expected to be extra interesting potential cell sources for cartilage repair as being cartilage pluripotent “stem cells”. Migratory ability enables cartilage-derived pluripotent cells to migrate to the injured site and repair cartilage damage. Even stem cells from human OA cartilage also have the potential for cartilage repair. Koelling et al50 observed that also cartilage progenitor cells from late stage OA knee joints regained a round chondrocyte-like phenotype and exhibited collagen type II mRNA expression as well as collagen type II protein expression in a 3D-alginate culture without any chondrogenic supplementation50.

Based on such findings, the use of fragmented cartilage is of increasing interest as it has been shown in laboratory experiments that new cartilage tissue is formed in direct connection to the fragments. Endogenous cartilage progenitor cells migrate from the fragments into the surrounding scaffolding material to start new matrix production. With special harvest instruments mini fragments are produced which could be put onto different scaffolds and be implanted fixated with a biological glue25.

Marmotti et al51 have shown that there is an age-dependent and time-dependent chondrocyte migration. A significant difference (P < 0.05) was observed between young and older donors51. Furthermore, it has also been shown that at one month high cellularity and intense extracellular matrix (ECM) production could be seen and that a two months, ECM was positive for collagen type II52. Furthermore, the matrix production is influenced by the degree of fragmentation and Bonasia et al53found that a chondral paste of fragments with size < 0.3 mm performed best in histology comparisons53.

Juvenile chondrocytes have shown in vitro superior capabilities of producing cartilage extracellular matrix 54. With the knowledge of chondral fragments for cartilage repair, now also allogeneic juvenile cartilage fragments have been introduced for chondral repair26,55.


3D-printing of chondrocytes in Bio-ink with Biopens

The concept of 3D-printing involves a construct production having a control over spatial resolution, shape, and mechanical properties56. When to repair a cartilage defect, a gradient repair is important where cells in different layers may be able to via cross-talking develop a good quality repair. Many of the 3D printing concepts involve several cell types and different materials for the bone and cartilage layer. Most often an osteochondral repair approach is best with a 3D printing addressing the bone defect with printing of bone cells into layers of bone substitute materials like hydroxyapatite and followed by different chondrocytes printed layered between a more cartilage specific matrix materials like hyaluronic acid57,58.


The status of the Chondrocyte for cartilage repair in randomized controlled trials

Randomized controlled clinical trials (RCTs) are considered to be the gold standard for evidence-based medicine. Subsequently, RCTs are important in also cartilage repair methods, steering the surgeons to use well-controlled and validated methods. In 2019, Matar and Platt59 published a paper on RCTs in orthopedic reseach59. The authors included 1078 RCTs across seven most commonly performed elective procedures. Unfortunately, cartilage repair procedures were not included in their review. Of the seven procedures studied, only 16% of the RCTs reported significant findings.

However, from 2003 to 2021, 21 RCTs have been performed23,48,60-79. Sixteen of those RCTs involved different generations of ACI versus other cartilage repair techniques23,48,63-78. In 9 of those 16 studies, ACI showed significant superiority in different parameters studied versus the other cartilage repair method23,48,65,70-74,76. Ten of those studies involved different generations of ACI versus bone marrow stimulation without scaffold (MFX (9) and abrasion arthroplasty (1)23,48,68,69,70-74,76. ACI was significantly better in different parameters than BMS without scaffold in 8/10 studies23, 48, 70-74, 76 (Figure 4).


How and when to use chondrocytes for a cartilage repair?

There are numerous algorithms to use for cartilage repair. Most often the surgeons trend to overestimate the size of the lesions to repair.

The mean size width of the both condyles in a man is a little less than 9 cm90. A defect with a size of 1 cm located centrally on a condyle is subsequently quite a large defect to repair.

The authors’ suggestions of methods to use for a cartilage defect are:

·       BMS ( like MFX or drilling) for small defects 0.5 cm²

·       Augmented BMS (with a scaffold) for small-medium sized defect 0.6-2 cm²

·       Alternative also for re-operations in such defects if a simple BMS has been done before

·       ACI-one stage with autologous or allogeneic chondral fragments >1cm²

·       ACI-two stage with cultured chondrocytes > 2 cm²

·       ACI-one stage with mixed chondrocytes and MSCs > 2 cm²

·       Above Cell based treatments for re-operations > 1 cm²

·       Osteochondral Allografts for extra-large defects  like condylar replacements.

It is also important not to forget that unloading osteotomies are useful in combination with local repairs.

Furthermore, as mentioned earlier in the text, the activities of chondrocytes are depending on the patients’ age. A local cartilage repair can be done for local trauma defects, local degenerative lesions but may also be used for a local well-defined lesion in an early OA joint. However, local repairs are not used in a full established osteoarthritic joint. 

Chang and co-workers81 have detected multipotent mesenchymal progenitor cells in human articular cartilage of all ages. Of interest to know is that chondral progenitor cells accounted for 94.69%±2.31%, 4.85%±2.62%, and 6.33%±3.05% of cells in articular cartilage obtained from fetuses, adults, and elderly patients, respectively (P<.001)81. Furthermore, fetal mesenchymal progenitor cells had the highest rates of proliferation measured by cell doubling times and chondrogenic differentiation as compared to those from adult and elderly patients81. With that in mind, the repair quality is expected to become better, the younger patient that is treated but ACI may be used in elderly patients still having in total a healthy cartilage as there also exist cartilage progenitor cells but with less chondrogeneic differentiation ability.



The chondrocytes are the masters of the cartilaginous tissue and they are subsequently still most valuable to use when to repair a traumatized cartilage. DNA methylation is essential for normal development and is associated with a number of key processes82. Besides what has been mentioned about the strong chondrogeneic ability of primary chondrocytes compared to MSCs of different origins, Bomer et al82 have nicely shown that In vitro engineered neo-cartilage tissue from primary chondrocytes exhibits a DNA methylation landscape that is almost identical (99% similarity) to autologous cartilage, in contrast to neocartilage engineered from bone marrow-derived mesenchymal stem cells (MSCs).

I still believe that we will use chondrocytes for a biological repair in the future but with fewer manipulations of the cells due to the strict regulations world-wide making cell expansion and culture expensive. Different variants of one-stage procedure will appear more and more with both autologous or allogeneic cells and even mixtures. The dream goal is a full cartilage regeneration still not achieved in a clinical setting. However, when to reach as near as possible regeneration, true committed chondrocytes and chondral progenitor cells seem still to be the best choice in 2021.




Mats Brittberg M.D, Ph.D.


Cartilage Research Unit, University of Gothenburg

Region Halland Orthopaedics – RHO, Kungsbacka Hospital

Kungsbacka, Sweden






  1. Buckwalter JA. Articular cartilage: injuries and potential for healing. J Orthop Sports Phys Ther. 1998;28(4):192-202.
  2. Johnson LL. Arthroscopic abrasion arthroplasty. Historical and pathological perspective:present status. Arthroscopy 1986; 2: 54-59
  3. Pridie KH. A method of resurfacing osteoarthritic knee joints. J Bone joint Surg 1959; 41B: 618-619
  4. Steadman JR, Rodkey WG, Rodrigo JJ. Microfracture: surgical technique and rehabilitation to treat chondral defects.Clin Orthop Relat Res. 2001 Oct;(391 Suppl):S362-9. Review.
  5. Brittberg M, Faxén E, Peterson L. Carbon fiber scaffolds in the treatment of early knee osteoarthritis. A prospective 4-year followup of 37 patients.Clin Orthop Relat Res. 1994 Oct;(307):155-64.
  6. D'Ambrosi R, Valli F, De Luca P, Ursino N, Usuelli FG. MaioRegen Osteochondral Substitute for the Treatment of Knee Defects: A Systematic Review of the Literature. J Clin Med. 2019;8(6):783. 
  7. Caplan AI. Mesenchymal Stem Cells: Time to Change the Name!. Stem Cells Transl Med. 2017;6(6):1445-1451. doi:10.1002/sctm.17-0051
  8. Stockwell RA. Chondrocytes. J Clin Pathol Suppl (R Coll Pathol). 1978;12:7-13.
  9. Muir H. Proteoglycans of cartilage. J Clin Pathol Suppl (R Coll Pathol). 1978;12:67-81.
  10. Smith, A. Survival of Frozen Chondrocytes Isolated from Cartilage of Adult Mammals. Nature 1965  205, 782–784 
  11. Green WT Jr: Articular cartilage repair: Behavior of rabbit chondrocytes during tissue culture and subsequent allografting. Clin Orthopaed Relat Res  1977; 124:237
  12. Brittberg M, Lindahl A, Nilsson A, Ohlsson C, Isaksson O, Peterson L. Treatment of deep cartilage defects in the knee with autologous chondrocyte transplantation. N Engl J Med 1994;331:889-95.
  13. Peterson L, Vasiliadis HS, Brittberg M, Lindahl A.Am J Sports Med. 2010 Jun;38(6):1117-24.
  14. Nawaz SZ, Bentley G, Briggs TW, Carrington RW, Skinner JA, Gallagher KR, Dhinsa BS. Autologous chondrocyte implantation in the knee: mid-term to long-term results. J Bone Joint Surg Am. 2014 May 21;96(10):824-30
  15. Rosa D, Balato G, Ciaramella G, Soscia E, Improta G, Triassi M. Long-term clinical results and MRI changes after autologous chondrocyte implantation in the knee of young and active middle aged patients. J Orthop Traumatol. 2016 Mar;17(1):55-62.
  16. Ogura T, Mosier BA, Bryant T, Minas T. A 20-Year Follow-up After First-Generation Autologous Chondrocyte Implantation. Am J Sports Med. 2017 Oct;45(12):2751-2761
  17. Krishnan SP, Skinner JA, Carrington RW, Flanagan AM, Briggs TW, Bentley G. Collagen-covered autologous chondrocyte implantation for osteochondritis dissecans of the knee: two- to seven-year results. J Bone Joint Surg Br. 2006 Feb;88(2):203-5.
  18. Brittberg M. Cell carriers as the next generation of cell therapy for cartilage repair: a review of the matrix-induced autologous chondrocyte implantation procedure. Am J Sports Med. 2010 Jun;38(6):1259-71.
  19. Kon E, Filardo G, Gobbi A, Berruto M, Andriolo L, Ferrua P, Crespiatico I, Marcacci M. Long-term Results After Hyaluronan-based MACT for the Treatment of Cartilage Lesions of the Patellofemoral Joint. Am J Sports Med. 2016 Mar;44(3):602-8
  20. Siebold R, Suezer F, Schmitt B, Trattnig S, Essig M. Good clinical and MRI outcome after arthroscopic autologous chondrocyte implantation for cartilage repair in the knee. Knee Surg Sports Traumatol Arthrosc. 2018 Mar;26(3):831-839.
  21. Słynarski K, de Jong WC, Snow M, Hendriks JAA, Wilson CE, Verdonk P. Single-Stage Autologous Chondrocyte-Based Treatment for the Repair of Knee Cartilage Lesions: Two-Year Follow-up of a Prospective Single-Arm Multicenter Study. The American Journal of Sports Medicine. 2020;48(6):1327-1337
  22. Saris TFF, de Windt TS, Kester EC, Vonk LA, Custers RJH, Saris DBF. Five-Year Outcome of 1-Stage Cell-Based Cartilage Repair Using Recycled Autologous Chondrons and Allogenic Mesenchymal Stromal Cells: A First-in-Human Clinical Trial. Am J Sports Med. 2021 Mar;49(4):941-947
  23. Cole BJ, Farr J, Winalski CS, Hosea T, Richmond J, Mandelbaum B, De Deyne PG. Outcomes after a single-stage procedure for cell-based cartilage repair: a prospective clinical safety trial with 2-year follow-up. Am J Sports Med. 2011 Jun;39(6):1170-9
  24. Brittberg M. Emerging technologies in cartilage repair. In Cartilage restoration:  Clinical application. Farr J, Gomoll A (eds). Springer International publishing group 2018. 389-400.
  25. Salzmann GM, Ossendorff R, Gilat R, Cole BJ. Autologous Minced Cartilage Implantation for Treatment of Chondral and Osteochondral Lesions in the Knee Joint: An Overview. Cartilage. 2020 Jul 25:1947603520942952
  26. Yanke AB, Tilton AK, Wetters NG, Merkow DB, Cole BJ. DeNovo NT Particulated Juvenile Cartilage Implant. Sports Med Arthrosc Rev. 2015 Sep;23(3):125-9
  27. Sridharan B, Sharma B, Detamore MS. A Road Map to Commercialization of Cartilage Therapy in the United States of America. Tissue Eng Part B Rev. 2016;22(1):15-33. doi:10.1089/ten.TEB.2015.0147
  31. Nehrer, Stefan & Halbwirth, Florian & Luksch, Thomas. (2014). CaReS®, Cartilage Regeneration System: Autologous Chondrocyte Transplantation in a Collagen Gel. Techniques in Cartilage Repair Surgery. 245-250. 10.1007/978-3-642-41921-8_21.
  33. de Windt TS, Concaro S, Lindahl A, Saris DB, Brittberg M. Strategies for patient profiling in articular cartilage repair of the knee: a prospective cohort of patients treated by one experienced cartilage surgeon. Knee Surg Sports Traumatol Arthrosc. 2012 Nov;20(11):2225-32.
  36. Caplan AI. Mesenchymal stem cells. J Orthop Res. 1991 Sep;9(5):641-50.
  37. Goldberg A, Mitchell K, Soans J, Kim L, Zaidi R. The use of mesenchymal stem cells for cartilage repair and regeneration: a systematic review. J Orthop Surg Res. 2017 Mar 9;12(1):39.
  38. Rosadi I, Karina K, Rosliana I, Sobariah S, Afini I, Widyastuti T, Barlian A. In vitro study of cartilage tissue engineering using human adipose-derived stem cells induced by platelet-rich plasma and cultured on silk fibroin scaffold. Stem Cell Res Ther. 2019 Dec 4;10(1):369.
  39. Li H, Qian J, Chen J, Zhong K, Chen S. Osteochondral repair with synovial membrane‑derived mesenchymal stem cells. Mol Med Rep. 2016 Mar;13(3):2071-7.
  40. Kuroda R, Usas A, Kubo S, Corsi K, Peng H, Rose T, Cummins J, Fu FH, Huard J. Cartilage repair using bone morphogenetic protein 4 and muscle-derived stem cells. Arthritis Rheum. 2006 Feb;54(2):433-42.
  41. Saw KY, Anz A, Siew-Yoke Jee C, Merican S, Ching-Soong Ng R, Roohi SA, Ragavanaidu K. Articular cartilage regeneration with autologous peripheral blood stem cells versus hyaluronic acid: a randomized controlled trial. Arthroscopy. 2013 Apr;29(4):684-94.
  42. Uzieliene I, Urbonaite G, Tachtamisevaite Z, Mobasheri A, Bernotiene E. The Potential of Menstrual Blood-Derived Mesenchymal Stem Cells for Cartilage Repair and Regeneration: Novel Aspects. Stem Cells Int. 2018 Dec 3;2018:5748126.
  43. Perera, Jonathan & Jaiswal, Parag & Khan, Wasim. (2012). The Potential Therapeutic Use of Stem Cells in Cartilage Repair. Current stem cell research & therapy. 7. 149-56. 10.2174/157488812799219054.
  44. Sakaguchi Y, Sekiya I, Yagishita K, Muneta T. Comparison of human stem cells derived from various mesenchymal tissues: superiority of synovium as a cell source. Arthritis Rheum. 2005;52:2521–2529
  45. Tallheden T, Dennis JE, Lennon DP, Sjögren-Jansson E, Caplan AI, Lindahl A. Phenotypic plasticity of human articular chondrocytes. J Bone Joint Surg Am. 2003;85-A Suppl 2:93-100.
  46. Karlsson C, Brantsing C, Svensson T, Brisby H, Asp J, Tallheden T, Lindahl A. Differentiation of human mesenchymal stem cells and articular chondrocytes: analysis of chondrogenic potential and expression pattern of differentiation-related transcription factors. J Orthop Res. 2007 Feb;25(2):152-63
  47. Bian L, Zhai DY, Mauck RL, Burdick JA. Coculture of human mesenchymal stem cells and articular chondrocytes reduces hypertrophy and enhances functional properties of engineered cartilage. Tissue Eng Part A. 2011 Apr;17(7-8):1137-45. doi: 10.1089/ten.TEA.2010.0531.
  48. T. Spalding, F. Almqvist, M. Brittberg et al. The CAIS project.: European multicenter randomized controlled pilot study of a one stage procedure procedure for cell-based cartilage repair. Bone and joint publishing.  British Orthopaedic association Orthopaedic ProceedingsVolume 2011, 93-B, Issue Suppl  III
  49. Williams R, Khan IM, Richardson K, Nelson L, McCarthy HE, Analbelsi T, Singhrao SK, Dowthwaite GP, Jones RE, Baird DM, Lewis H, Roberts S, Shaw HM, Dudhia J, Fairclough J, Briggs T, Archer CW. Identification and clonal characterisation of a progenitor cell sub-population in normal human articular cartilage. PLoS One. 2010 Oct 14;5(10):e13246.
  50. Koelling S, Kruegel J, Irmer M, Path JR, Sadowski B, Miro X, Miosge N. Migratory chondrogenic progenitor cells from repair tissue during the later stages of human osteoarthritis. Cell Stem Cell. 2009 Apr 3;4(4):324-35.
  51. Marmotti A, Bonasia DE, Bruzzone M, Rossi R, Castoldi F, Collo G, Realmuto C, Tarella C, Peretti GM. Human cartilage fragments in a composite scaffold for single-stage cartilage repair: an in vitro study of the chondrocyte migration and the influence of TGF-β1 and G-CSF. Knee Surg Sports Traumatol Arthrosc. 2013;21:1819–1833
  52. Marmotti A, Bruzzone M, Bonasia DE, Castoldi F, Von Degerfeld MM, Bignardi C, Mattia S, Maiello A, Rossi R, Peretti GM. Autologous cartilage fragments in a composite scaffold for one stage osteochondral repair in a goat model. Eur Cell Mater. 2013;26:15–31; discussion 31-32.
  53. Bonasia DE, Marmotti A, Mattia S, Cosentino A, Spolaore S, Governale G, Castoldi F, Rossi R. The Degree of Chondral Fragmentation Affects Extracellular Matrix Production in Cartilage Autograft Implantation: An In Vitro Study. Arthroscopy. 2015 Dec;31(12):2335-41.
  54. Adkisson HD, Martin JA, Amendola RL, Milliman C, Mauch KA, Katwal AB, Seyedin M, Amendola A, Streeter PR, Buckwalter JA. The potential of human allogeneic juvenile chondrocytes for restoration of articular cartilage. Am J Sports Med. 2010;38:1324–1333
  55. Adkisson HD, Martin JA, Amendola RL, Milliman C, Mauch KA, Katwal AB, Seyedin M, Amendola A, Streeter PR, Buckwalter JA. The potential of human allogeneic juvenile chondrocytes for restoration of articular cartilage. Am J Sports Med. 2010;38:1324–1333
  56. Mouser VHM, Levato R, Bonassar LJ, et al. Three-Dimensional Bioprinting and Its Potential in the Field of Articular Cartilage Regeneration. Cartilage. 2017;8(4):327-340. doi:10.1177/1947603516665445
  57. Nguyen D, Hägg DA, Forsman A, et al. Cartilage Tissue Engineering by the 3D Bioprinting of iPS Cells in a Nanocellulose/Alginate Bioink. Sci Rep. 2017;7(1):658. Published 2017 Apr 6. doi:10.1038/s41598-017-00690-y
  58. Francis SL, Di Bella C, Wallace GG, Choong PFM. Cartilage Tissue Engineering Using Stem Cells and Bioprinting Technology-Barriers to Clinical Translation. Front Surg. 2018;5:70. Published 2018 Nov 27. doi:10.3389/fsurg.2018.00070
  59. Matar, H.E., Platt, S.R. Overview of randomised controlled trials in orthopaedic research: search for significant findings. Eur J Orthop Surg Traumatol 2019; 29, 1163–1168 
  60. Bartlett W, Skinner JA, Gooding CR, Carrington RW et al. Autologous chondrocyte implantation versus matrix-induced autologous chondrocyte implantation for osteochondral defects of the knee: a prospective, randomised study J Bone Joint Surg Br. 2005;87(5):640-45.
  61. Schneider U, Andereya S. [First results of a prospective randomized clinical trial on traditional chondrocyte transplantation vs CaReS-Technology]. Z Orthop Ihre Grenzgeb. 2003;141(5):496-97.
  62. Gooding CR, Bartlett W, Bentley G. 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. 2006;13(3):203-10. 
  63. Zeifang F, Oberle D, Nierhoff C  et al.Autologous chondrocyte implantation using the original periosteum-cover technique versus matrix-associated autologous chondrocyte implantation: a randomized clinical trial. Am J Sports Med. 2010;38(5):924-33.
  64. Horas U, Pelinkovic D, Herr G et al. Autologous chondrocyte implantation and osteochondral cylinder transplantation in cartilage repair of the knee joint. A prospective, comparative trial. J Bone Joint Surg Am. 2003;85-A(2):185-92.
  65. Bentley G, Biant LC, Carrington RW et al.A prospective, randomised comparison of autologous chondrocyte implantation versus mosaicplasty for osteochondral defects in the knee. J Bone Joint Surg Br. 2003;85(2):223-30.
  66. Dozin B, Malpeli M, Cancedda R et al. Comparative evaluation of autologous chondrocyte implantation and mosaicplasty: a multicentered randomized clinical trial.Clin J Sport Med. 2005;15(4):220-26.
  67. Clavé A, Potel JF, Servien E et al. Third-generation autologous chondrocyte implantation versus mosaicplasty for knee cartilage injury: 2-year randomized trial. J Orthop Res. 2016;34(4):658-65.
  68. Knutsen G, Engebretsen L, Ludvigsen TC et al. Autologous chondrocyte implantation compared with microfracture in the knee. A randomized trial.J Bone Joint Surg Am. 2004;86-A(3):455-64.
  69. Lim HC, Bae JH, Song SH et al. Current treatments of isolated articular cartilage lesions of the knee achieve similar outcomes. Clin Orthop Relat Res. 2012;470(8):2261-67
  70. Vanlauwe J, Saris DB, Victor J et al. Five-year outcome of characterized chondrocyte implantation versus microfracture for symptomatic cartilage defects of the knee: early treatment matters.Am J Sports Med. 2011;39(12):2566-74
  71. Visna P, Pasa L, Cizmár I  et al. Treatment of deep cartilage defects of the knee using autologous chondrograft transplantation and by abrasive techniques--a randomized controlled study. Acta Chir Belg. 2004;104(6):709-14.
  72. Basad E, Ishaque B, Bachmann G et al.Matrix-induced autologous chondrocyte implantation versus microfracture in the treatment of cartilage defects of the knee: a 2-year randomised study. Knee Surg Sports Traumatol Arthrosc. 2010;18(4):519-27
  73. Crawford DC, DeBerardino TM, Williams RJ 3rd. NeoCart, an autologous cartilage tissue implant, compared with microfracture for treatment of distal femoral cartilage lesions: an FDA phase-II prospective, randomized clinical trial after two years. J Bone Joint Surg Am. 2012 6;94(11):979-89
  74. Saris D, Price A, Widuchowski W et al. Matrix-Applied Characterized Autologous Cultured Chondrocytes Versus Microfracture: Two-Year Follow-up of a Prospective Randomized Trial. Am J Sports Med. 2014;42(6):1384-94
  75. Brittberg M, Recker D, Ilgenfritz J et al. Matrix-Applied Characterized Autologous Cultured Chondrocytes Versus Microfracture: Five-Year Follow-up of a Prospective Randomized Trial.Am J Sports Med. 2018;46(6):1343-51
  76. Niemeyer P, Laute V, Zinser W, et al. A Prospective, Randomized, Open-Label, Multicenter, Phase III Noninferiority Trial to Compare the Clinical Efficacy of Matrix-Associated Autologous Chondrocyte Implantation With Spheroid Technology Versus Arthroscopic Microfracture for Cartilage Defects of the Knee. Orthopaedic Journal of Sports Medicine. July 2019.doi:10.1177/2325967119854442
  77. Fossum V, Hansen AK, Wilsgaard T, Knutsen G. Collagen-Covered Autologous Chondrocyte Implantation Versus Autologous Matrix-Induced Chondrogenesis: A Randomized Trial Comparing 2 Methods for Repair of Cartilage Defects of the Knee. Orthopaedic Journal of Sports Medicine. September 2019. doi:10.1177/2325967119868212
  78. Akgun I, Unlu MC, Erdal OA et al. Matrix-induced autologous mesenchymal stem cell implantation versus matrix-induced autologous chondrocyte implantation in the treatment of chondral defects of the knee: a 2-year randomized study. Arch Orthop Trauma Surg. 2015;135(2):251-263. 
  79. Becher C, Laute V, Fickert S, Zinser W, Niemeyer P, John T, Diehl P, Kolombe T, Siebold R, Fay J. Safety of three different product doses in autologous chondrocyte implantation: results of a prospective, randomised, controlled trial. J Orthop Surg Res. 2017 May 12;12(1):71
  80. Terzidis I, Totlis T, Papathanasiou E, Sideridis A, Vlasis K, Natsis K. Gender and Side-to-Side Differences of Femoral Condyles Morphology: Osteometric Data from 360 Caucasian Dried Femori. Anat Res Int. 2012;2012:679658.
  81. Chang HX, Yang L, Li Z, Chen G, Dai G. Age-related biological characterization of mesenchymal progenitor cells in human articular cartilage. Orthopedics. 2011 Aug 8;34(8):e382-8.
  82. Bomer N, den Hollander W, Suchiman H, Houtman E, Slieker RC, Heijmans BT, Slagboom PE, Nelissen RG, Ramos YF, Meulenbelt I. Neo-cartilage engineered from primary chondrocytes is epigenetically similar to autologous cartilage, in contrast to using mesenchymal stem cells. Osteoarthritis Cartilage. 2016 Aug;24(8):1423-30.



Header image by James Boyes (Cropped)


Figure 1: A chondrocyte in cell culture. Alcian-Blue.
Figure 2: Chondrocyte implantation under a periosteal flap-1st generation ACI.
Figure 3: (a) Cartilage fragments have been harvested trans-arthroscopic with a shaver and a special cartilage fragment collector (Graftnet collector-Arthrex).The fragments are shown in the collector and will be implanted into the joint. (b) A cartilage defect, first as empty defect and then after filling with cartilage fragments in fibrin glue.
Figure 4: A summary of the RCTs done with ACI versus different other methods from 2003-2021.


Volume 10 | Targeted Topic - Knee Joint Preservation | 2021
Volume 10 - Targeted Topic - Knee Joint Preservation

More from Aspetar Journal

Sports Surgery

Written by – Konrad Słynarski, Poland, Theodorakys Marín Fermín, Venezuela and Emmanouil Papakostas, Qatar


Written by – Khalid Al-Khelaifi MD, FRCSC, Emmanuel Papakostas MD


Written by – Nebojsa Popovic MD PhD

Latest Issue

Download Volume 13 - Targeted Topic - Sports Medicine in Tennis | 2024


From our editor
From our guest editor
Emma Raducanu
Sports Medicine
Sports Medicine
Extensor Carpi Ulnaris injuries in Tennis


Member of
Organization members