cartilage regeneration revisited

Review

Page 1 of 6

Com

peti n

g in

tere

sts:

non

e de

clar

ed. C

onfl i

ct o

f Int

eres

ts: d

ecla

red

in th

e arti c

le.

All

auth

ors

cont

ribut

ed to

the

conc

epti o

n, d

esig

n, a

nd p

repa

rati o

n of

the

man

uscr

ipt,

as

wel

l as

read

and

app

rove

d th

e fi n

al m

anus

crip

t. A

ll au

thor

s ab

ide

by th

e A

ssoc

iati o

n fo

r Med

ical

Eth

ics

(AM

E) e

thic

al ru

les

of d

iscl

osur

e.

Licensee OA Publishing London 2013. Creative Commons Attribution Licence (CC-BY)

FOR CITATION PURPOSES: Freymann U, Petersen W, Kaps C. Cartilage regeneration revisited: entering of new one-step procedures for chondral cartilage repair. OA Orthopaedics 2013 Jun 05;1(1):6.

Cartilage regeneration revisited: entering of new one-step procedures for chondral cartilage repair

U Freymann1,2, W Petersen3, C Kaps1,2*

AbstractIntroductionThis article reviews the evolution of cartilage regeneration therapeutic approaches from two-step cell-based autologous chondrocyte implanta-tion procedures to current one-step cell-free scaffold-assisted cartilage repair approaches for chondral carti-lage repair. In particular, our research is focused on clinical data about commercially available cell-free implants used in regenerative medi-cine approaches for the treatment of chondral cartilage defects.DiscussionChondral cartilage lesions do not heal spontaneously and may progress to severe osteoarthritis. For cartilage repair, a variety of surgical techniques have been established over the years. Further research led to the development of current new one-step cell-free scaffold-assisted cartilage repair approaches based on the experience with scaffold mate-rials in previous two-step autolo-gous chondrocyte implantation procedures. Commercially available scaffold-based products for one-step chondral cartilage repair have been recently tested in first case series and showed promising clinical outcome in the short-term follow-up; however, medium- and long-term comparative studies are necessary to evaluate the regenerative potential of this

new one-step cartilage repair proce-dure and to demonstrate its superi-ority over or adequacy to traditional approaches.ConclusionThis critical review summarises the development from two-step cell-based autologous chondrocyte implantation procedures to new one-step cell-free cartilage repair and discusses the first clinical outcome of commercially available cell-free implants. This new approach, based on the principle of cell ingrowths and guidance towards tissue repair, showed promising first clinical results and is considered as an effec-tive and safe treatment option for chondral cartilage repair.

IntroductionDamaged cartilage has a limited self-healing capacity. Focal cartilage lesions of the knee occur frequently, are mostly located on the femoral condyle and display a major health problem because they may progress to severe osteoarthritis, when untreated. Predisposing factors for the development of cartilage defects are traumas, inflammatory condi-tions and biomechanics alterations of the knee1.

In cartilage repair, a variety of surgical techniques have been estab-lished, including bone-marrowstimulation (e.g. abrasion, drilling and microfracturing), osteochondral autograft transfer and autologous chondrocyte implantation (ACI) with or without the use of scaffold mate-rials2,3. Treatment options have to be chosen individually, depending on the defect size, depth and loca-tion of the cartilage lesion. Surgical treatment options for small defects include bone-marrow stimulation techniques as well as osteochondral

autograft transplantation4,5. Espe-cially, for the treatment of large full-thickness chondral articular defects and as second-line carti-lage treatment option, two-step ACI approaches based on the implanta-tion of in vitro cultured autologous chondrocytes have been developed. The implantation of autologous chondrocytes within the prepared defect area improves the formation of hyaline-like, biomechanical resistant and durable repair tissue in contrast to the outcomes after microfracture procedure, leading to a fibrocarti-laginous defect filled with material properties that are inferior to hyaline cartilage6.

Further research led to the devel-opment of one-step cell-free scaffold-assisted regenerative approaches for in situ cartilage repair. This innova-tive procedure combines the well-known microfracture technique with the benefits and long-term experi-ence of biomaterials used in earlier ACI procedures.

This critical review shows the evolution of different generations for two-step ACI procedures up to the development of the current new one-step scaffold-assisted regen-erative procedures and reports on the clinical applications of scaffold-based products for chondral carti-lage repair. In particular, our research is focused on published clinical data for commercially available cell-free implants used for one-step cell-free scaffold-assisted cartilage repair.

DiscussionThe authors have referenced some of their own studies in this review. These referenced studies have been conducted in accordance with the Declaration of Helsinki (1964) and the protocols of these

Diag

nosi

s &

Trea

tmen

t

* Corresponding authorEmail: [email protected] TransTissue Technologies GmbH, Berlin,

Germany2 Tissue Engineering Laboratory, Department

of Rheumatology and Immunology, Charit Campus Mitte, Charit Universittsmedizin Berlin, Berlin, Germany

3 Department of Orthopaedics and Trauma Surgery, Martin-Luther-Krankenhaus Berlin, Berlin, Germany

Review

Page 2 of 6

Com

peti n

g in

tere

sts:

non

e de

clar

ed. C

onfl i

ct o

f Int

eres

ts: d

ecla

red

in th

e arti c

le.

All

auth

ors

cont

ribut

ed to

the

conc

epti o

n, d

esig

n, a

nd p

repa

rati o

n of

the

man

uscr

ipt,

as

wel

l as

read

and

app

rove

d th

e fi n

al m

anus

crip

t. A

ll au

thor

s ab

ide

by th

e A

ssoc

iati o

n fo

r Med

ical

Eth

ics

(AM

E) e

thic

al ru

les

of d

iscl

osur

e.



studies have been approved by the relevant ethics committees related to the institution in which they were performed. All human subjects, in these referenced studies, gave informed consent to participate in these studies.

Generations of two-step ACI proceduresThe classic first generation ACI is based on the implantation of a suspension of cultured chondro-cytes underneath a sealed periosteal cover in a two-step procedure7. Since Brittberg et al. introduced this tech-nique in 1987, more than 15,000 patients have been treated with ACI worldwide8. The first step includes arthroscopic cartilage biopsy harvest from a minor weight-bearing area of the injured knee followed by in vitro cell expansion under good manu-facturing practice (GMP) conditions to a defined cell number (Figure 1). The second operation includes arthrotomy, preparation of the defect, periosteal harvest, suturing the peri-osteum over the defect, application of fibrin glue sealant and the injec-tion of the cell suspension under-neath the periosteal flap (Figure 2). Autologous chondrocytes in a cell suspension are offered by different manufacturers (Carticel, Genzyme, USA; ChondroCelect, Tigenix, Belgium; Novocart, B. Braun-Tetec, Germany). First-generation ACI has

inherent disadvantages, including periosteal complications such as periost hypertrophy, periosteal graft detachment and delamination as well as loss of cells into the joint cavity911 leading to a revision surgery rate of up to 25% to 40%12,13.

Second-generation ACI uses a collagen membrane rather than a periosteal flap to cover the carti-lage defect before cell injection. The use of a bi-layer type-I/type-III collagen membrane (Chondro-GideTM, Geistlich, Switzerland) reduces the length and number of incisions, surgical morbidity and the risk of hypertrophy compared with periosteal flap suturing12. The use of first and second-generation ACI is limited and may be difficult in knee defect locations lacking a stable and intact cartilage rim as known from post-traumatic and/or focal degen-erative cartilage defects.

Further development of tissue engineering/regenerative medicine led to the third-generation of ACI to overcome these limitations. Thereby, three-dimensional scaffolds are seeded with in vitro cultured chon-drocytes and subsequently implanted into the lesion area to generate new functional cartilage repair tissue. After debridement of the defect, the cartilage graft is cut to the defect size and implanted without the use of a periosteal or collagen cover flap (Figure 3). The use of three-dimen-sional scaffolds ensures a homoge-neous cell distribution and avoids

the risk of chondrocyte leakage from the liquid cell suspension. The easy handling of the tissue-engineered graft has surgical advantages and allows for a minimally invasive and faster surgical procedure by avoiding additional periost harvest and defect covering14,15.

Many biomaterials have been tested for scaffold-based chondro-cyte implantation. Therein, various hydrogels were used as three-dimen-sional cell carriers for autologous chondrocytes. Among these gel-type scaffolds, a three-dimensional type-I collagen gel (CaReSTM, Arthro Kinetics, Germany) is clinically used, where isolated chondrocytes are immediately cultivated in the collagen gel without expansion in monolayer culture 16. Other hydrogel-based technologies use either a mixture of autologous chondrocytes with a hydrogel composed of agarose and alginate (Cartipatch; Tissue Bank of France, France), which involves the injection of a cell suspensionfibrin mixture into the cartilage defect (Chondron; Sewon Cellontech Co. Ltd., Korea), or use autologous chon-drocytes cultured on an atelocollagen gel for cartilage repair16.

Other technologies using scaf-folds based on collagen, hyaluronan and resorbable polymers have been shown to be clinically efficient for the repair of cartilage defects16: collagen membranes (ACI-maix/MACI, Matricel, Germany) and hyaluronan-based scaffolds (Hyalograft CTM;

Figure 1: Cartilage biopsy harvest and in vitro cell expansion in mon-olayer cultures.

Figure 2: Principle of autologous chondrocyte implantation (ACI): a harvested periosteum flap (first-generation ACI) or collagen membrane (second-genera-tion ACI) is sutured over the debrided cartilage defect and the cell suspension is injected underneath.

Review

Page 3 of 6

Com

peti n

g in

tere

sts:

non

e de

clar

ed. C

onfl i

ct o

f Int

eres

ts: d

ecla

red

in th

e arti c

le.

All

auth

ors

cont

ribut

ed to

the

conc

epti o

n, d

esig

n, a

nd p

repa

rati o

n of

the

man

uscr

ipt,

as

wel

l as

read

and

app

rove

d th

e fi n

al m

anus

crip

t. A

ll au

thor

s ab

ide

by th

e A

ssoc

iati o

n fo

r Med

ical

Eth

ics

(AM

E) e

thic

al ru

les

of d

iscl

osur

e.



Fidia Advanced Biopolymers, Italy) have been used in combination with autologous chondrocytes in clinical practice since more than a decade16. Other clinically used biomaterials for cartilage repair are, for example, three-dimensional collagen-chon-droitin sulphate scaffolds with embedded autologous chondro-cytes (Novocart 3D, B. Braun-Tetec, Germany) or cell-seeded type I collagen scaffolds produced in a bioreactor (NeoCart, Histogenics Corporation, USA)16. Among resorb-able polymer scaffolds, BioSeed-C (BioTissue Technologies GmbH, Germany), a two-component scaf-fold using a porous gel-like matrix composed of fibrin and a textile poly-glycolic acid-based felt-like scaffold, is one of the most widely used carti-lage grafts, which combines autolo-gous chondrocytes with an initially mechanically stable polymer scaf-fold, allowing stable, subchondral and containment-independent fixa-tion with resorbable nails or anchors for the first time. These character-istics have led to the possibility to treat degenerative defects also for the first time, showing to be clini-cally efficient for cartilage repair of those indications17.

Although the scaffold-based chon-drocyte implantation is already a clinically effective procedure for cartilage repair, there still remain some disadvantages. This method is a two-step operation, which needs the removal of a healthy cartilage biopsy first and second, an implan-tation of the cultivated scaffold or matrix seeded with chondrocytes. The procedure may increase donor-site morbidity, the creation of a new defect at an undamaged cartilage zone has to be accepted and a poten-tially longer rehabilitation time must be tolerated. Furthermore, the time-intensive cultivation period for the autologous chondrocytes under GMP conditions, requiring for example up to 4 weeks, is cost-intensive, may have a potential risk leading to degeneration/de-differentiation of the cells and can resultdepending on the degree of sub-culturing and de-differentiationin an efficiency loss of cartilage regeneration18.

New one-step scaff old-assisted regenerative procedures To overcome these limitations, a new concept for in situ cartilage repair, based on the use of cell-free scaf-folds for cell ingrowths and guidance towards tissue repair, was devel-

oped. This procedure is an innovative treatment combining the well-known microfracture technique with the benefits and long-term experience of known biomaterials.

Behrens et al. first introduced this new matrix-coupled microfracture with a collagen matrix implant to cover cartilage defects19. Thereby microfracturing of the subchondral bone for the recruitment of human mesenchymal stem cells (MSCs) from the bone marrow blood was combined with a cell-free scaffold, which was fixated with fibrin glue. By covering the defect area, endogenous progen-itor or stem cells that float into the cartilage defect are kept in the scaf-fold/matrix and the resulting blood clot is held in the defect zone. The resorbable scaffold thereby builds up a natural 3D environment, which opti-mises cell migration and ingrowths, leads to a homogeneous cell arrange-ment and supports differentiation into cartilaginous repair tissue (Figure 4).

This new cell-free one-step approach has several advantages as compared with previous cell-based techniques. The scaffolds are off-the-shelf products, which are stor-able and available on demand, allow for a single-stage surgical step with reduced surgery time and avoid donor-site morbidity and costs for cell expansion.

However, at this time there is limited clinical data available on the outcome of the one-step scaffold-assisted regenerative procedures for the repair of chondral knee defects. Different commercially available cell-free medical devices based on collagen (Chondro-GideTM, Geistlich, Switzerland; CaReS-1STM, Arthro Kinetics, Germany; MeRG, Bioteck, Italy), different hydrogels (BST-Cargel, Piramal Healthcare, Canada; GelrinCTM, Regentis Biomaterials, Israel) and resorbable synthetic poly-mers (chondrotissue, BioTissue AG, Switzerland) have been recently tested for one-step chondral carti-lage repair and showed first clinical outcomes.

Figure 3: Surgical steps of third-generation scaffold-based ACI including the transplantation of a chondrocyte-seeded scaffold into the debrided defect.

Figure 4: Principle of one-step scaffold-assisted cartilage repair including bone-marrow stimulation and additional implantation of the cell-free scaffold for a tissue-guided cartilage repair.

Review

Page 4 of 6

Com

peti n

g in

tere

sts:

non

e de

clar

ed. C

onfl i

ct o

f Int

eres

ts: d

ecla

red

in th

e arti c

le.

All

auth

ors

cont

ribut

ed to

the

conc

epti o

n, d

esig

n, a

nd p

repa

rati o

n of

the

man

uscr

ipt,

as

wel

l as

read

and

app

rove

d th

e fi n

al m

anus

crip

t. A

ll au

thor

s ab

ide

by th

e A

ssoc

iati o

n fo

r Med

ical

Eth

ics

(AM

E) e

thic

al ru

les

of d

iscl

osur

e.



One of these products is a bilayer matrix of porcine type I and III collagen with one compact and one porous side (Chondro-GideTM, Geistlich, Switzerland) to cover chon-dral cartilage defects after micro-fracturing. Clinical outcome was recently shown in several case series, including up to 38 patients with a follow-up time of maximum 51 months. Therein, results of patients showed a significant improvement in clinical scores (International Knee Documentation Comitee (IKDC), Lysholm, Tegner, Visual Analog Scale (VAS) pain score) and patient satis-faction with the treatment procedure, whereas magnet resonance imaging showed an incomplete and inhomo-geneous repair tissue formation and defect filling rates between 50% and 58.8%1,20,21. Recently, a controlled, randomised trial was initiated, comparing the use of Chondro-GideTM in second-generation ACI and in a one-step cell-free scaffold-assisted approach for the repair of symptomatic knee cartilage defects. Both techniques use the Chondro-GideTM membrane in an arthrotomic approach to cover the defects of 40 patients each22. So far no preliminary or clinical results are available for this randomised trial.

Another collagen-based product for one-step scaffold-assisted carti-lage repair is a round type I collagen gel-matrix derived from rat tails for deep chondral defects (CaReS-1STM, Arthro Kinetics, Germany), which is implanted into the debrided defect in a press-fit manner. Clinical results were shown in first case series for up to 15 patients and with 2436 months follow-up23,24. After 24 months, magnetic resonance imaging showed complete filling with a mainly smooth surface, complete integration, homogenous repair tissue structure and nearly normal signal intensity. Histological exami-nation of one specimen at 42 months after implantation revealed type II collagen positive repair tissue23.

Functional, clinical and subjec-tive assessment sho wed significant improvement when compared with the preoperative values24. First analysis of preliminary results of an ongoing multi-centre study including 37 patients with 324 months follow-up showed identical or better IKDC scores for the one-step cell-free product when compared with those of a multi-centre study with the two-step cell-based product CaReS 2S.

Another collagen product, consisting of a microfibrillar equine type I collagen membrane (MeRG, Bioteck, Italy) was described in a first case presentation. Therein, a 37-year-old man with a 3 cm2 carti-lage lesion of the medial condyle was treated with covered microfracture and bone marrow concentrate for arthroscopic knee cartilage repair25. Magnetic resonance imaging results at 12 months postoperatively showed good defect filling with a tissue signal similar to that of surrounding tissue. In a follow-up of 24 months, the patient remained asymptomatic.

As an alternative to collagen-based matrix, different hydrogels are now being clinically tested for one-step scaffold-assisted cartilage repair. In a mini-arthrotomic approach, these gels are mixed with whole blood or bone marrow released after microf-racturing to fill the chondral cartilage defect. In this group, a chitosan-glyc-erol phosphate/blood implant (BST-Cargel, Piramal Healthcare, Canada) was clinically tested. First clinical results are available for a randomised, comparative multi-centre clinical trial evaluating BST-CarGel and micro-fracture at 12 months for cartilage repair. Therein, BST-CarGel treat-ment achieved significantly better results compared with microfracture in defect filling and in the quality of the repair tissue26.

Other commercially available hydrogels are mixed compositions of polyethylene glycol diacrylate with fibrinogen (GelrinCTM, Regentis Biomaterials, Israel). Thereby, a gel is

inserted as a liquid to fill the cartilage defect and is then converted into a solid through exposure to ultra-violet light. First short-time results of a pilot clinical study including 15 patients with focal cartilage defects showed significantly higher levels of tissue fill and reduced pain levels compared with microfracture controls and an improvement in patients knee func-tion after 6 months27. A multi-centre study is currently recruiting patients to evaluate the safety and effective-ness of the hydrogel in the treatment of articular cartilage lesions28.

Newer one-step scaffold-based cartilage repair approaches favour the use of stable textile polyglycoli-cacidhyaluronan implants (chondro-tissue, BioTissue AG, Switzerland) to cover the defect after microfrac-turing or bone marrow stimulation. This scaffold incorporates biological factors, such as hyaluronic acid, and can be used in combination with for example human serum or platelet rich plasma, to recruit MSCs into the scaf-fold and guide them towards cartilage repair. In contrast to other unstable biomaterials, the textile scaffold provides a mechanically stable formu-lation, which can be stably fixated into the defect by suturing, trans-osseous fixation, pin fixation or fibrin glue and even allows for the implantation into partly un-shouldered degenera-tive defects. First pilot studies have shown that covering of microfrac-tured cartilage defects with the chon-drotissue cartilage implant is safe, improves the patients situation and leads to complete defect filling with histologically confirmed hyaline-like cartilaginous repair tissue forma-tion in a follow-up period of up to 2 years2933. Preliminary clinical results of a randomised, comparative multi-center clinical trial showed that the chondrotissue treatment for carti-lage repair significantly improves the patients situation as assessed by VAS, Knee Injury and Osteoarthritis Outcome Score (KOOS) and IKDC score, while there is no significant

Review

Page 5 of 6

Com

peti n

g in

tere

sts:

non

e de

clar

ed. C

onfl i

ct o

f Int

eres

ts: d

ecla

red

in th

e arti c

le.

All

auth

ors

cont

ribut

ed to

the

conc

epti o

n, d

esig

n, a

nd p

repa

rati o

n of

the

man

uscr

ipt,

as

wel

l as

read

and

app

rove

d th

e fi n

al m

anus

crip

t. A

ll au

thor

s ab

ide

by th

e A

ssoc

iati o

n fo

r Med

ical

Eth

ics

(AM

E) e

thic

al ru

les

of d

iscl

osur

e.



improvement after microfracture treatment in patients with 1224 months follow-up34.

ConclusionRegenerative medicine led to the development of a variety of cartilage repair treatment options. Cell-based approaches include an initial invasive biopsy harvest to obtain the cells and in vitro proliferation and possibly de-differentiation of the cells before implantation. Newer one-step scaf-fold-based procedures for cartilage repair have been recently developed to simplify and further improve regen-erative techniques. The new one-step treatment option includes the attrac-tion of MSCs to the site of the cartilage defect and thereby overcomes the necessity of in vitro proliferation and differentiation of cells before trans-plantation. This one-step approach also avoids donor-site morbidity, reduces costs, surgical steps and potentially patients rehabilitation time. The use of biomaterials for the treatment of chondral knee cartilage defects is strongly increasing, since the properties of the used polymers are varied, allow for modification and can be adapted to the surgical need.

Clinical applications are described for different types of commercially available cell-free implants, including collagen variations, hydrogels and synthetic textile. For the above-mentioned products, first promising clinical results showed a reduc-tion in pain, a functional improve-ment of the knee and the formation of hyaline-like repair tissue. By the application of cell-free scaffolds for defect covering after bone-marrow stimulation, the newly formed tissue was shown to be structured similar to native cartilage tissue and to be superior to the repair tissue formed after microfracture alone.

Difficulties in comparing various studies arise from the different study populations, follow-up times, evaluation systems, scaffold fixation methods, surgical approaches and

postoperative rehabilitation proce-dures. However, evaluation of current clinical outcome is based on first case series with short- to mid-term follow-up and preliminary results of ongoing controlled, randomised clinical studies. Thus, well-designed mid- to long-term comparative studies are needed to evaluate the potential of these new regenerative one-step cartilage repair approaches and to show its superiority over or adequacy to traditional two-step ACI approaches.

Conflict of Interest C.K. and U.F. are employees of Trans-Tissue Technologies GmbH (TTT), a subsidiary of BioTissue Technologies GmbH. TTT developed the products BioSeed-C and chondrotissue. C.K. is a shareholder of BioTissue AG.

Abbreviations listACI, autologous chondrocyte implan-tation; GMP, good manufacturing practice; MSC, mesenchymal stem cells.

References1. Schiavone Panni A, Cerciello S, Vasso M. The management of knee cartilage defects with modified AMIC technique: preliminary results. Int J Immuno-pathol Pharmacol. 2011 JanMar;24(1 Suppl 2):14952.2. Cole BJ, Pascual-Garrido C, Grumet RC. Surgical management of articular carti-lage defects in the knee. Instr Course Lect. 2010;59:181204.3. Smith GD, Knutsen G, Richardson JB. A clinical review of cartilage repair techniques. J Bone Joint Surg Br. 2005 Apr;87(4):4459.4. Gudas R, Kalesinskas RJ, Kimtys V, Stank-evicius E, Toliusis V, Bernotavicius G, et al. A prospective randomized clinical study of mosaic osteochondral autologous transplantation versus microfracture for the treatment of osteochondral defects in the knee joint in young athletes. Arthros-copy. 2005 Sep;21(9):106675.5. Steadman JR, Briggs KK, Rodrigo JJ, Kocher MS, Gill TJ, Rodkey WG. Outcomes of microfracture for traumatic chondral defects of the knee: average 11-year

follow-up. Arthroscopy. 2003 MayJun;19(5):47784.6. Knutsen G, Drogset JO, Engebretsen L, Grontvedt T, Isaksen V, Ludvigsen TC, et al. A randomized trial comparing autologous chondrocyte implantation with micro-fracture. Findings at five years. J Bone Joint Surg Am. 2007 Oct;89(10):210512.7. 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 Oct;331(14):88995.8. Minas T. Autologous chondrocyte implantation in the arthritic knee. Ortho-pedics. 2003 Sep;26(9):9457.9. Brittberg M. Autologous chondrocyte transplantation. Clin Orthop Relat Res. 1999 Oct;(367 Suppl):S14755.10. Driesang IM, Hunziker EB. Delami-nation rates of tissue flaps used in artic-ular cartilage repair. J Orthop Res. 2000 Nov;18(6):90911.11. Niemeyer P, Pestka JM, Kreuz PC, Erggelet C, Schmal H, Suedkamp NP, et al. Characteristic complications after autolo-gous chondrocyte implantation for carti-lage defects of the knee joint. Am J Sports Med. 2008 Nov;36(11):20919.12. Gooding CR, Bartlett W, Bentley G, Skinner JA, Carrington R, Flanagan A. 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 Jun;13(3):20310.13. Zaslav K, Cole B, Brewster R, De Berardino T, Farr J, Fowler P, et al. A prospective study of autologous chondro-cyte implantation in patients with failed prior treatment for articular cartilage defect of the knee: results of the Study of the Treatment of Articular Repair (STAR) clinical trial. Am J Sports Med. 2009 Jan;37(1):4255.14. Erggelet C, Sittinger M, Lahm A. The arthroscopic implantation of autologous chondrocytes for the treatment of full-thickness cartilage defects of the knee joint. Arthroscopy. 2003 Jan;19(1):10810.15. Sittinger M, Hutmacher DW, Risbud MV. Current strategies for cell delivery in carti-lage and bone regeneration. Curr Opin Biotechnol. 2004 Oct;15(5):4118.16. Filardo G, Kon E, Roffi A, Di Martino A, Marcacci M. Scaffold-based repair for cartilage healing: a systematic review

Review

Page 6 of 6

Com

peti n

g in

tere

sts:

non

e de

clar

ed. C

onfl i

ct o

f Int

eres

ts: d

ecla

red

in th

e arti c

le.

All

auth

ors

cont

ribut

ed to

the

conc

epti o

n, d

esig

n, a

nd p

repa

rati o

n of

the

man

uscr

ipt,

as

wel

l as

read

and

app

rove

d th

e fi n

al m

anus

crip

t. A

ll au

thor

s ab

ide

by th

e A

ssoc

iati o

n fo

r Med

ical

Eth

ics

(AM

E) e

thic

al ru

les

of d

iscl

osur

e.



and technical note. Arthroscopy. 2013 Jan;29(1):17486.17. Kreuz PC, Muller S, Freymann U, Erggelet C, Niemeyer P, Kaps C, et al. Repair of focal cartilage defects with scaffold-assisted autologous chondrocyte grafts: clinical and biomechanical results 48 months after transplantation. Am J Sports Med. 2011 Aug;39(8):1697705.18. Steinert AF, Ghivizzani SC, Reth-wilm A, Tuan RS, Evans CH, Noth U. Major biological obstacles for persistent cell-based regeneration of articular cartilage. Arthritis Res Ther. 2007;9(3):213.19. Behrens P. Matrixgekoppelte Mikro-frakturierung. Arthroskopie. 2005;18:19397 [German].20. Gille J, Schuseil E, Wimmer J, Gellissen J, Schulz AP, Behrens P. Mid-term results of autologous matrix-induced chondrogen-esis for treatment of focal cartilage defects in the knee. Knee Surg Sports Traumatol Arthrosc. 2010 Nov;18(11):145664.21. Kusano T, Jakob RP, Gautier E, Magnussen RA, Hoogewoud H, Jacobi M. Treatment of isolated chondral and osteochondral defects in the knee by autologous matrix-induced chondrogen-esis (AMIC). Knee Surg Sports Traumatol Arthrosc. 2012 Oct;20(10):210915.22. ClinicalTrials.gov [http://www.clini-caltrials.gov/ct2/results?term=ChondroGide&Search=Search]. ACI-C Versus AMIC. A randomized trial comparing two methods for repair of cartilage defects in the knee; 2012 [updated November 2012].

23. Schuettler KF, Struewer J, Rominger MB, Rexin P, Efe T. Repair of a chondral defect using a cell free scaffold in a young patient a case report of successful scaffold trans-formation and colonisation. BMC Surg. 2013 Apr;13:11.24. Efe T, Theisen C, Fuchs-Winkelmann S, Stein T, Getgood A, Rominger MB, et al. Cell-free collagen type I matrix for repair of cartilage defects-clinical and magnetic resonance imaging results. Knee Surg Sports Traumatol Arthrosc. 2012 Oct;20(10):191522.25. Gigante A, Cecconi S, Calcagno S, Busilacchi A, Enea D. Arthroscopic knee cartilage repair with covered microf-racture and bone marrow concentrate. Arthrosc Tech. 2012 Sep;1(2):17580.26. Podium presentations at the 10th World Congress of the International Cartilage Repair Society (ICRS), Montreal, Quebec, Canada.27. Sharma B, Fermanian S, Gibson M, Unterman S, Herzka DA, Cascio B, et al. Human cartilage repair with a photore-active adhesive-hydrogel composite. Sci Transl Med. 2013 Jan;5(167):167ra6.28. ClinicalTrials.gov [http://www.clini-caltrials.gov/ct2/results?term=GelrinC&Search=Search]. Study to evaluate the safety and performance of treatment of articular cartilage lesions located on the femoral condyle with gelrinC; 2011 [updated November 2011].29. Dhollander AA, Verdonk PC, Lambrecht S, Almqvist KF, Elewaut D,

Verbruggen G, et al. The combination of microfracture and a cell-free polymer-based implant immersed with autologous serum for cartilage defect coverage. Knee Surg Sports Traumatol Arthrosc. 2012 Sep;20(9):177380.30. Patrascu JM, Freymann U, Kaps C, Poenaru DV. Repair of a post-trau-matic cartilage defect with a cell-free polymer-based cartilage implant: a follow-up at two years by MRI and histo-logical review. J Bone Joint Surg Br. 2010 Aug;92(8):11603.31. Zantop T, Petersen W. Arthroscopic implantation of a matrix to cover large chondral defect during microfracture. Arthroscopy. 2009 Nov;25(11):135460.32. Siclari A, Mascaro G, Gentili C, Cancedda R, Boux E. A cell-free scaf-fold-based cartilage repair provides improved function hyaline-like repair at one year. Clin Orthop Relat Res. 2012 Mar;470(3):9109.33. Siclari A, Mascaro G, Gentili C, Kaps C, Cancedda R, Boux E. Cartilage repair in the knee with subchondral drilling augmented with a platelet-rich plasma-immersed polymer-based implant. Knee Surg Sports Traumatol Arthrosc. 2013.34. Personal communication BioTissue AG. Interim evaluation at 2 years of the controlled randomized study comparing chondrotissue treatment with microfrac-turing alone. March 2013.

cartilage regeneration revisited

Documents