Systematic review on the use of autologous matrix-induced chondrogenesis for the repair of articular cartilage defects in patients

Table 1 Study demographics, lesion location and grade, inclusion and exclusion criteria, and funding sources

Ref.	Treatment period	Patient numbers	Mean age (yr)	Mean follow-up in months (range)	Joint	Defect location and type	Grade of lesion	Lesion dimensions (cm2)	Inclusions	Exclusions	Source of funding
Shetty et al[34]	4 yr	30				MFC, LFC, trochlea, patella	Grade III/IV	2-8		Malalignment of the knee exceeding 5° of valgus or varus. Generalized osteoarthritic changes in the knee
Buda et al[15]	Apr 2006-May 2007	20 (12M, 8F)	15-50	29	Knees		Grade III/IV	Not specified		Diffuse arthritis, general medical conditions (e.g., diabetes, rheumatoid arthritis etc.), haematological disorders and infections	None
Gille et al[26]	2003-2005	27 (16M, 11F)	39	37 (24-62)	Knees	Medial femoral condyle 7, lateral femoral condyle 3, patella 9, trochlea 2, femoral condyle and patella 6	Grade IV	> 1	Clinical symptomatic chondral lesions at femoral condyle, patella or trochlea	Advanced osteoarthritis, rheumatic disease, total menisectomy, BMI > 35, deviation of mechanical axis to the affected compartment	Not specified
Dhollander et al[16]	Jan 2008-Apr 2008	5 (3M, 2F)	18-50	24 (12-24)	Knees	Patella	Grade III/IV	2 (range 1-3)	Symptomatic focal patella cartilage defects	Untreatable tibiofemoral or patellofemoral malalignment, diffuse osteoarthritis, major meniscal deficiency or other general medical conditions	Not specified
Dhollander et al[13]	2008-2009	5 (4M, 1F)	29.8	24	Knees	Right 2 (40%), left 3 (60%) medial femoral condyle (2), lateral femoral condyle (2), trochlea (1)	Grade III/IV	Median 2.3, range 1.5-5	16-40 yr, single symptomatic focal cartilage defect on femoral condyles or patellofemoral joint	Untreated tibiofemoral or patellofemoral malalsignment or instability, diffuse osteoarthritis, bipolar “kissing” lesions, major meniscal deficiency and other general medical conditions	Not specified
Kusano et al[22]	Aug 2003-Jul 2006	40 (23M, 17F)	35.6	28.8 (13-51)	Knees	Full thickness chondral defect in patella (20), femoral condyle (9), osteochondral defect in femoral condyle (11)	Grade III/IV	3.87		Defects in other locations, age > 50 yr, skeletally immature	Not specified
Leunig et al[23]	Mar 2009-Dec 2010	6 (5M, 1F)	22.7	Not specified (12-30)	Hips	Femoral head 5, acetabular 1 chondral 1, osteochondral 5	Grade III/IV	> 2	Full thickness chondral lesions > 2 cm2 or osteochondral lesions > 1 cm2 with defects in weight-bearing areas of acetabulum or femoral head, irreparable by osteotomy in age < 35 yr	Patients unwilling or unable to comply with post-operative rehabilitation protocols. Systematic inflammatory arthritis, advanced arthritis involving both femur and acetabulum, or age > 35 yr	Not specified
Pascarella et al[24]	2006-2008	19 (12M, 7F)		12-36	Knees	Right knee: Femoral condyle (medial 34%, lateral 14%), patella (9%) Left knee: Femoral condyle (medial 29%, lateral 14%)	Grade III/IV	3.6	Age 18-50 yr with single lesion	Osteoarthritis, axial deviations, ligamentous injuries, complete meniscal resection, allergy to collagen membrane components	Not specified
Anders et al[3]	Jan 2004-Mar 2010	38 (Not specified)	37	19 (6-24)	Knees		Grade III/IV	3.4	Age 18-50 yr, 1-2 lesions	> 2 defects, corresponding defects, bilateral defects, signs of osetoarthritis, other general diseases, history of complete menisectomy, mosaicplasty, treatment with cartilage specific medication, chondropathia patallae or patellar dysplasia	None
Gille et al[28]	Not specified	57 (38M, 19F)	37.3	24	Knees	Medial condyle (32), lateral condyle (6), trochlea (4), patella (15) Grouping based on lesion size: Group A 0-3 cm2, Group B 3-6 cm2, Group C 6-9 cm2	Grade III (35), Grade IV (37)	3.4 (1-12)	Age 17-61 yr	Rheumatic disease, total meniscectomy, and revision surgery	Not specified
Valderrabano et al[17]		26 (18M, 8F)	33	31 (25-54)	Ankles	Osteochondral lesions of talus		1.68	First time osteochondral lesion or failure of previous lesion	Age > 55 yr, open ankle physis	Not specified
Wiewiorski et al[25]	2008-2010	23 (16M, 7F)	34	23 (11-49)	Ankles (talus)	Osteochondral lesions of talus	Osteochondral	1.49	Single lesion with history of ankle trauma		Not specified
Dhollander et al[29]	April 2009-May 2011	10 (8M, 2F)	37.2 ± 7.1	24	Knee	Patella (8), trochlea (2)	Grade III/IV	4.2 ± 1.9	Patients aged 18-50 yr with a focal patellofemoral defect and clinical symptoms (pain, swelling, locking, giving way)	Untreatable tibio-femoral or patellofemoral mal - alignment or instability, diffuse osteoarthritis or bipolar “kissing” lesions, major meniscal deficiency and other general medical conditions (diabetes, rheumatoid arthritis)	Not specified
Mancini et al[30]	November 2004-June 2007	31	36.4 ± 10.3	60	Hip	Acetabular chondral defects	Grade III/IV	2-4	Patients 18-50 yr of age with acetabular chondral lesions with radiological Tönnis degree < 2 followed up to 5 yr	Concomitant chondral femoral head kissing lesion, systemic rheumatoid diseases, dysplasia, femoral neck axial deviations, coxa profunda, protrusio acetabuli	Not specified
Fontana et al[31]	November 2004-March 2011	55	39.1 (18 to 55)	36-60	Hip	Acetabular ± femoral head chondral defects	Grade III/IV	2-8	Patients 18-55 years of age with acetabular ± femoral head chondral lesions with radiological Tönnis degree < 2 followed up for 3-5 yr	Rheumatoid arthritis, dysplasia, axial deviation of the femoral neck, coxa profunda, protrusio acetabuli	Not specified but Girolamo is a paid consultant for Geistlich
Kubosch et al[32]	Not specified	17	38.8 ± 15.7	39.5 ± 18.4	Ankle	Osteochondral lesions of talus	Grade III/IV	2.4 ± 1.6	First-time diagnosis or failure of a previous operative treatment	Arthritis of the ankle joint, kissing lesions and rheumatoid arthritis	Not specified

BMI: Body mass index.

Table 2 Treatment algorithms

Ref.	Drilling technique	Scaffold/fixation	Associated surgery	Joint	Rehab
Buda et al[15]	No drilling	Hyalofast + PRP	3 osteotomy	Knees	NWB 4 wk, run 6 mo, RTS 12 mo
Gille et al[26]	Awl/sharp cannula	ChondroGide Fibrin glue	2 realignments, 1 capsular shift	Knees	Immobilization 1 wk, passive motion 6 wk, NWB 6 wk
Dhollander et al[16]	Microdrill	ChondroGide + PRP Sutures	3 osteotomy + 1 medial patello-femoral ligament reconstruction	Knees	NWB 2 wk, brace 0-90 for 4 wk, full ROM at 8 wk, Low impact sports 12 mo
Dhollander et al[13]	Microdrill	Chondrotissue Pin	1 osteotomy	Knees	NWB 2 wk, 0-90o 4 wk, full range 8 wk, RTS 12 mo
Kusano et al[22]	Awl	ChondroGide Suture/fibrin glue	28 osteotomy	Knees	PWB 6 wk, 0-60 4wk
Leunig et al[23]	Kirchner wire	ChondroGide, fibrin glue	3 osteoplasty, 2 femoral neck lengthening, drilling of acetabular defects	Hips	PWB 6-8 wk, passive motion 6-8 h for 6-8 wk
Pascarella et al[24]	Kirchner wire	ChondroGide Fibrin glue		Knees
Anders et al[3]	Awl	ChondroGide Suture/fibrin glue		Knees	PWB and lymphatic draining massage 3-6 wk, FWB at 4-6 mo, RTS 3-18 mo
Gille et al[28]	Awl	ChondroGide Fibrin glue	2 patella realignments, 3 corrective osteotomies, 6 partial menisectomies, 1 ACL reconstruction	Knees
Valderrabano et al[17]	Microdrill	ChondroGide Fibrin glue	16 osteotomy	Ankles	PWB, ROM of < 200 passive motion machine, lymphatic drainage massage 6wks, FWB 6-12 wk, Light sports 12 wk, RTS 5-6 mo
Wiewiorski et al[25]	Microdrill	ChondroGide Fibrin glue		Ankles (talus)	PWB and lymphatic draining massage 6 wk, FWB 12 wk
Dhollander et al[29]	Slow speed 1.2 mm diameter	ChondroGide Vicryl 6/0	No	Knees (Patellofemoral joint)	NWB for 2 wk, FWB at 10 wk, full range of motion at 8 wk, low impact sports 12 mo
Mancini et al[30]	Awl/sharp cannula	ChondroGide Fibrin glue	All patients had cam-type and/or pincer-type impingement, and underwent arthroscopic femoral head-neck resection arthroplasty and/or arthroscopic acetabular rim trimming and labral reattachment to the acetabular rim with suture anchors	Hips	PWB (30% of body weight) for 4 wk, impact sports 3 mo, complete RTS 6 mo
Fontana et al[31]	Awl/sharp cannula	ChondroGide Fibrin glue	All patients had cam-type and/or pincer-type impingement, and underwent arthroscopic femoral head-neck resection arthroplasty and/or arthroscopic acetabular rim trimming and labral reattachment to the acetabular rim with suture anchors	Hips	PWB for 7 wk, light sporting activities 4 wk, low impact sports 6 mo, complete RTS 12 mo
Kubosch et al[32]	Not specified	ChondroGide Fibrin glue	All patients also underwent autologous cancellous bone grafting to the site	Ankles (talus)	Ankle immobilisation for 2 wk, PWB for 6 wk
Shetty et al[34]	Microdrill	Tiseel Coltrix (atelocollagen)	-	Knees	PWB for 6 wk, gradual increase to FWB by next 6 wk

PRP: Platelet-rich plasma; ACL: Anterior cruciate ligament; PWB: Partial weight bearing; NWB: Non-weight bearing; FWB: Full weight bearing; ROM: Range of motion; RTS: Return to sport.

Table 3 Summary of patient outcome scores of the 16 reviewed studies

Ref.	Sub-groupings (Where Applicable)	Follow-up (mo)	Outcomes
			KOOS		IKDC		VAS		ICRS		Cincinnati		Lysholm		Other
			Pre-surgery	At follow-up	Pre-surgery	At mean follow-up	Pre-surgery	At mean follow-up	Pre-surgery	At mean follow-up	Pre-surgery	At mean follow-up	Pre-surgery	At mean follow-up	Pre-surgery	At mean follow-up
Buda et al[15]		29 ± 4.1	47.1 ± 14.9	93.3 ± 6.8	32.9 ± 14.2	90.4 ± 9.2
Gille et al[26]		48							31 ± 15	37 ± 4	46 ± 18	37 ± 9	36 ± 21	47 ± 22
Dhollander et al[16]		24	41.6	71.4			5.2	1.4
Dhollander et al[13]		24	37.6 ± 16.7	73.1 ± 25			6.1 ± 2.4	1.9 ± 3.4
Kusano et al[22]	ocF	28.8 ± 1.5			44 ± 25	88 ± 9	6 ± 3	1 ± 1					50 ± 25	94 ± 8
	cP	28.8 ± 1.5			51 ± 25	74 ± 17	6 ± 2	2 ± 2					58 ± 17	85 ± 13
	cF	28.8 ± 1.5			45 ± 26	68 ± 14	6 ± 3	3 ± 3					56 ± 25	76 ± 18
Leunig et al[23]		Not specified
Pascarella et al[24]		24			30	83							54	98
Anders et al[3]	MFx	24							54 ± 21	19 ± 17	40 ± 9	83 ± 8
	Sutured AMIC	24							46 ± 19	14 ± 13	43 ± 16	88 ± 9
	Glued AMIC	24							48 ± 20	16 ± 13	48 ± 15	85 ± 18
Gille et al[28]		24					7 ± 1.8	2 ± 2.1					50.1 ± 19.6	85.2 ± 18.4
Valderrabano et al[17]		31					5 ± 2	2 ± 2							62.2 ± 15.8 (AOFAS)	89.2 ± 12.3 (AOFAS)
Wiewiorski et al[25]		23					4.8 ± 1.6	1.3 ± 2							60.6 ± 15.5 (AOFAS)	90.9 ± 11.4 (AOFAS)
Dhollander et al[29]		24	44.5 ± 17.5	65.0 ± 23.3			73.9 ± 20.8	39.4 ± 28.8							1.5 ± 1.4 (Tegner)	2.5 ± 1.5 (Tegner)
															41.9 ± 15.1 (Kujala)	59.8 ± 21.2 (Kujala)
Mancini et al[30]		60													44.9 ± 5.9 (mHHS)	84 ± 5.9 (mHHS)
Fontana et al[31]	Defect < 4 cm2	60													44.7 (34-60) (mHHS)	Improvements demonstrated on graoh but not quantified
	Defect > 4 cm2	60													44.7 (34-60) (mHHS)
Kubosch et al[32]		39.5 ± 18.4					7.8 ± 2.1	3.2 ± 2.4								82.6 ± 3.4 (AOFAS) 33.7% ± 23.8 (FFI) 52.7 ± 15.9 (MOCART)
Shetty et al[34]		48	64.7	88.2	39	78.6							50.8	80.4

KOOS: Knee injury and Osteoarthritis Outcome Score; IKDC: International Knee Documentation Committee; VAS: Visual Analogue Scale; AOFAS: American Orthopaedic Foot and Ankle Society; ICRS: International Cartilage Repair Society; mHHS: Modified Harris Hip Score; FFI: Foot Function Index; MOCART: Magnetic resonance Observation of Cartilage Repair Tissue.

Table 4 Summary of detailed magnetic resonance imaging evaluation results if provided from studies that reported Magnetic resonance Observation of Cartilage Repair Tissue scores

Number and percentage of patients that achieved a particular result for each category of the MOCART scoring system
Scoring measure	Outcome	Buda et al[15]		Dhollander et al[16]		Dhollander et al[13]		Kusano et al[22]		Leunig et al[23]		Valderrabano et al[17]		Wiewiorski et al[25]		Dhollander et al[29]
		No. of Pts.	% of Pts.	No. of Pts.	% of Pts.	No. of Pts.	% of Pts.	No. of Pts.	No. of Pts.	No. of Pts.	% of Pts.	No. of Pts.	% of Pts.	No. of Pts.	% of Pts.	No. of Pts.	% of Pts.
Degree of defect repair	Complete	14	70%	0	0%	1	20%	3	19%	4	100%	9	35%	8	35%	2	20%
	Hypertrophy	4	20%	2	40%	2	40%	3	19%	0	0%	13	50%	12	52%	2	20%
	Incomplete	2	10%	3	60%	2	40%	10	63%	0	0%	4	15%	3	13%	6	60%
Integration to the Surrounding Cartilage	Complete	16	80%	4	80%	1	20%	8	50%	4	100%	9	35%	8	35%	4	40%
	Incomplete	2	10%	0	0%	4	80%	4	25%	0	0%	9	35%	0	0%	2	20%
	Defect visible	2	10%	1	20%	0	0%	4	25%	0	0%	8	31%	15	65%	4	40%
Surface of the Repaired tissue	Intact	14	70%	0	0%	1	20%	2	13%	3	75%	17	65%	15	65%	3	30%
	Damaged	6	30%	5	100%	4	80%	14	88%	1	25%	9	35%	8	35%	7	70%
Structure of the Repaired tissue	Homogeneous	6	30%	0	0%	0	0%	0	0%	1	25%	7	27%	6	26%	4	40%
	Inhomogeneous	14	70%	5	100%	5	100%	16	100%	3	75%	19	73%	17	74%	6	60%
Signal Intensity DPFSE	Isointense	13	65%	0	0%	2	40%	1	6%	2	50%	4	15%	3	13%	1	10%
	Hyperintense	7	35%	5	100%	2	40%	15	94%	1	25%	18	69%	17	74%	6	60%
	Hypointense	0	0%	0	0%	1	20%	0	0%	1	25%	4	15%	3	13%	3	30%
Subchondral lamina	Intact	6	30%	0	0%	0	0%	3	19%	1	25%	9	35%	8	35%	0	0%
	Not intact	14	70%	5	100%	5	100%	13	81%	3	75%	17	65%	15	65%	10	100%
Subchondral bone	Intact	6	30%	0	0%	1	20%	4	25%	2	50%	3	12%	3	13%	6	60%
	Not intact	14	70%	5	100%	4	80%	12	75%	2	50%	23	88%	20	87%	4	40%
Adhesions	No	20	100%	5	100%	5	100%	15	94%	3	75%	26	100%	23	100%	10	100%
	Yes	0	0%	0	0%	0	0%	1	6%	1	25%	0	0%	0	0%	0	0%
Effusion	No	17	85%	5	100%	3	60%	6	38%	4	100%	25	96%	22	96%	7	70%
	Yes	3	15%	0	0%	2	40%	10	63%	0	0%	1	4%	1	4%	3	30%

Table 5 Coleman methodology scores for the 15 reviewed studies reporting on autologous matrix-induced chondrogenesis

Ref.	Coleman methodology score
	Part A, maximum = 65						Part B, maximum = 35										Total, max = 100
	1	2	3	4	5	6	1				2				3
Buda et al[15]	0	4	0	10	10	5	2	2	3	3	5	4	3	3	5	5	64
Gille et al[26]	4	4	7	10	10	5	2	2	3	3	5	4	3	3	5	5	75
Dhollander et al[16]	0	4	10	10	10	5	2	2	3	3	5	0	3	0	5	5	67
Dhollander et al[13]	0	4	10	10	10	5	2	2	3	3	5	4	3	3	5	5	74
Kusano et al[22]	4	4	10	0	10	5	2	2	3	3	5	0	3	3	5	5	64
Leunig et al[23]	0	4	10	0	10	5	2	2	3	3	5	4	3	0	5	0	56
Pascarella et al[24]	0	4	10	10	0	5	0	2	3	0	5	0	3	0	5	5	52
Anders et al[3]	4	0	0	10	10	5	2	2	3	3	5	0	3	0	5	0	52
Gille et al[28]	7	4	10	0	0	0	2	2	3	3	5	0	3	0	5	5	49
Valderrabano et al[17]	0	4	10	10	10	5	2	2	3	3	5	0	3	0	5	5	67
Wiewiorski et al[25]	0	4	10	10	10	0	2	2	3	0	0	0	3	3	5	5	57
Dhollander et al[29]	0	4	10	0	10	5	2	2	3	3	5	0	3	3	5	5	60
Mancini et al[30]	4	7	0	10	5	5	2	2	3	0	5	0	3	3	5	5	59
Fontana et al[31]	7	7	0	10	5	5	2	2	3	0	5	0	3	3	5	5	62
Kubosch et al[32]	0	7	10	0	0	5	2	2	3	3	5	0	3	3	5	5	53
Shetty et al[34]	4	7	10	0	0	5	2	2	3	3	5	0	3	3	5	0	52

Table 6 Coleman methodology scores - mean, range and standard deviation for each section

Section score (maximum)	Mean	Range	SD
Part A (65)
Study size	2.1	0-7	2.6
Minimum follow-up	4.5	0-7	1.7
Number of different surgical treatment included	7.3	0-10	4.3
Study design	6.3	0-10	4.8
Description of surgical technique	6.9	0-10	4.3
Post-Op management described	4.4	0-5	1.7
Total part A	31.4	21-40	5.7
Part B (35)
Outcome measures clearly defined	1.9	0-2	0.5
Timing of outcome clearly stated	2	2	0
Use of reliable outcome criteria	3	3	0
General health measure inc.	2.2	0-3	1.3
Subjects recruited	4.7	0-5	1.2
Inv. independent of surgeon	1	0-4	1.7
Written assessment	3	3	0
Completion of assessment by patients with minimal investigator assistance	1.9	0-3	1.5
Selection criteria reported and unbiased	5	5	0
Recruitment rate reported	4.1	0-5	2
Total part B	28.9	23-35	3.9
Total, maximum = 100	60.2	49-75	7.7