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1.  Bone Marrow Aspiration Concentrate and Platelet Rich Plasma for Osteochondral Repair in a Porcine Osteochondral Defect Model 
PLoS ONE  2013;8(8):e71602.
Background
Bone marrow aspiration concentrate (BMAC) may possess a high potency for cartilage and osseous defect healing because it contains stem cells and multiple growth factors. Alternatively, platelet rich plasma (PRP), which contains a cocktail of multiple growth factors released from enriched activated thrombocytes may potentially stimulate the mesenchymal stem cells (MSCs) in bone marrow to proliferate and differentiate.
Methods
A critical size osteochondral defect (10×6 mm) in both medial femoral condyles was created in 14 Goettinger mini-pigs. All animals were randomized into the following four groups: biphasic scaffold alone (TRUFIT BGS, Smith & Nephew, USA), scaffold with PRP, scaffold with BMAC and scaffold in combination with BMAC and PRP. After 26 weeks all animals were euthanized and histological slides were cut, stained and evaluated using a histological score and immunohistochemistry.
Results
The thrombocyte number was significantly increased (p = 0.049) in PRP compared to whole blood. In addition the concentration of the measured growth factors in PRP such as BMP-2, BMP-7, VEGF, TGF-β1 and PDGF were significantly increased when compared to whole blood (p<0.05). In the defects of the therapy groups areas of chondrogenic tissue were present, which stained blue with toluidine blue and positively for collagen type II. Adding BMAC or PRP in a biphasic scaffold led to a significant improvement of the histological score compared to the control group, but the combination of BMAC and PRP did not further enhance the histological score.
Conclusions
The clinical application of BMAC or PRP in osteochondral defect healing is attractive because of their autologous origin and cost-effectiveness. Adding either PRP or BMAC to a biphasic scaffold led to a significantly better healing of osteochondral defects compared with the control group. However, the combination of both therapies did not further enhance healing.
doi:10.1371/journal.pone.0071602
PMCID: PMC3741121  PMID: 23951201
2.  In vivo animal study and clinical outcomes of autologous atelocollagen-induced chondrogenesis for osteochondral lesion treatment 
Background
Collagen acts as a scaffold for healing damaged cartilage. This study evaluated the results of an in vivo animal study and provides short-term clinical results on a mixture of atelocollagen and fibrin glue-enhanced microfracture techniques in patients with osteochondral lesions (OCL) of the talus.
Methods
This paper contains animal in vivo data and clinical outcomes on the effectiveness of atelocollagen. An in vivo animal study was conducted with full-thickness cartilage defects created in the femoral condyle of 12 rabbits equally divided into 4 groups evaluated at 2, 4, 8, and 12 weeks. Four chondral lesions were created according to one procedure on each rabbit with each lesion treated as follows: (1) microfracture, (2) microfracture and the lesion covered with atelocollagen, (3) microfracture and the lesion covered with mixture of atelocollagen and fibrin glue, and (4) microfracture and the lesion covered with fibrin glue. In the clinical evaluation, 17 patients were treated with a combination of microfracture and atelocollagen injection for symptomatic full-thickness OCL of the talus. They were evaluated by the American Orthopedic Foot and Ankle Society Ankle-Hindfoot Score (AOFAS), Hannover Ankle Score System (HSS), visual analog scale (VAS), and magnetic resonance imaging (MRI) at baseline and at 12-months follow-up. Magnetic Resonance Observation of Cartilage Repair Tissue (MOCART) score of the post-op status was compared with the MOCART score and a modified Anderson’s score of the pre-op status.
Results
In the animal study, subchondral bone and cartilage were generated completely in groups 2 and 3 microscopically. Hyaline-like cartilage was found in the repair tissue. In the clinical evaluation, mean AOFAS improved from 62 to 88, mean HSS improved from 62 to 87, and mean VAS score improved from 64 to 18, respectively (p <0.001). Fifteen patients (89 %) reported good or excellent satisfaction. We defined the improvement of most of the subchondral bone edema and bone cyst as well as a chondral lesion by radiologic evaluation.
Conclusions
Rapid regeneration of cartilage was demonstrated in the in vivo animal study, and patients showed significant clinical improvement. Atelocollagen-enhanced microfracture enabled a reasonable treatment of cartilage defects.
doi:10.1186/s13018-015-0212-x
PMCID: PMC4449973  PMID: 26018619
Talus; Cartilage disease; Subchondral arthroplasty; Atelocollagen; CartiFil
3.  CAN OSTEOCHONDRAL GRAFTING BE AUGMENTED WITH MICROFRACTURE IN AN EXTENDED SIZED LESION OF ARTICULAR CARTILAGE 
BACKGROUND
Both microfracture and osteochondral autografting procedures have been useful in treating osteochondral lesions.
HYPOTHESIS
Combining microfracture and osteochondral autografting procedures can extend the size of lesions which can be treated with either technique.
STUDY DESIGN
Descriptive laboratory study.
METHODS
Eight adult goats underwent osteochondral autograft transfer of a 4.5mm femoral trochlea plug into an 8mm full thickness chondral defect in the weight bearing portion of the medial femoral condyle. In the gap region surrounding the autograft, microfracture was performed. The animals were allowed normal activity until the end of the experiment at 6 months, at which time the knees were harvested. At harvest the knees were assessed grossly, and then evaluation was performed by histology and histomorphometry, biochemistry and biomechanics. One animal died at 6 wks from gastroenteritis.
RESULTS
The osteochondral plugs healed well, with integration of the bone and preservation of the chondral cap. The chondral gap between the host site articular cartilage and the transferred plug had decreased from 3 mm at implant to less than 0.1 mm. Histological analysis demonstrated regions of variable cartilage repair, with integration of the cartilage layer at some sites but incomplete healing at others. Histomorphometry demonstrated filling of the chondral gap to 75–85% of the normal volume. Biochemical analysis revealed greater than 90% type II collagen at most sites with some areas containing 80% type II collagen. Biomechanical indentation testing, indicated that the repaired area had variable thickness and stiffness, with a trend of increased stiffness in the bulk graft and decreased softness at the proximal microfracture interface site.
CONCLUSIONS
The performance of a combined microfracture and osteochondral autograft transfer (OATS) procedure to resurface a large chondral defect appears promising. Transferred cartilage tissue can successfully be incorporated into a large recipient defect, and microfracture of the surrounding bone can lead to a repair process which remains variable. Attempts need to be made to improve consistency of the repair process. This is a potential treatment option for large chondral defects which does not require a large area of autogenous tissue to be harvested.
CLINICAL RELEVANCE TO SPORTS MEDICINE
This combined technique shows promise for treatment of large chondral defects with a single operative procedure with autogenous tissue which is safe, and potentially would have a shorter period of rehabilitation, similar to that of osteochondral transfers and microfracture in a cost effective setting.
doi:10.1177/0363546510363433
PMCID: PMC4111625  PMID: 20400750
Articular cartilage repair; osteochondral allograft; microfracture; knees
4.  Treatment principles for osteochondral lesions in foot and ankle 
International Orthopaedics  2013;37(9):1697-1706.
Osteochondral lesion of the talus (OLT) is a broad term used to describe an injury or abnormality of the talar articular cartilage and adjacent bone. A variety of terms have been used to refer to this clinical entity, including osteochondritis dissecans (OCD), osteochondral fracture and osteochondral defect. Whether OLT is a precursor to more generalised arthrosis of the ankle remains unclear, but the condition is often symptomatic enough to warrant treatment. In more than one third of cases, conservative treatment is unsuccessful, and surgery is indicated. There is a wide variety of treatment strategies for osteochondral defects of the ankle, with new techniques that have substantially increased over the last decade. The common treatment strategies of symptomatic osteochondral lesions include nonsurgical treatment, with rest, cast immobilisation and use of nonsteroidal anti-inflammatory drugs (NSAIDs). Surgical options are lesion excision, excision and curettage, excision combined with curettage and microfracturing, filling the defect with autogenous cancellous bone graft, antegrade (transmalleolar) drilling, retrograde drilling, fixation and techniques such as osteochondral transplantation [osteochondral autograft transfer system (OATS)] and autologous chondrocyte implantation (ACI). Furthermore, smaller lesions are symptomatic and when left untreated, OCDs can progress; current treatment strategies have not solved this problem. The target of these treatment strategies is to relieve symptoms and improve function. Publications on the efficacy of these treatment strategies vary. In most cases, several treatment options are viable, and the choice of treatment is based on defect type and size and preferences of the treating clinician.
doi:10.1007/s00264-013-2076-1
PMCID: PMC3764304  PMID: 23982639
Osteochondral lesions; Osteochondritis dissecans; Talus; Foot and ankle; Cartilage damage; Subchondral bone
5.  The Role of Erythropoietin and Bone Marrow Concentrate in the Treatment of Osteochondral Defects in Mini-Pigs 
PLoS ONE  2014;9(3):e92766.
Background
All available treatment options for osteochondral and chondral defects do not restore hyaline cartilage and are limited to decreasing associated pain, and maintaining or improving joint function. The purpose of this study was to evaluate the potential of erythropoietin (EPO) in combination with bone marrow aspiration concentrate (BMAC) in the treatment of osteochondral defects of mini-pigs.
Methods
14 Goettinger mini-pigs, in which a 6×10 mm osteochondral defect in the medial femoral condyle of both knee joints was created, were randomized into four groups: biphasic scaffold alone, scaffold with EPO, scaffold with BMAC and scaffold in combination with EPO and BMAC. After 26 weeks all animals were euthanized and histological slides were evaluated using a modified ÓDriscoll Score.
Results
In the therapy groups, areas of chondrogenic tissue that contained collagen II were present. Adding EPO (p = 0.245) or BMAC (p = 0.099) alone to the scaffold led to a non-significant increase in the score compared to the control group. However, the combination of EPO and BMAC in the implanted scaffold showed a significant improvement (p = 0.02) in the histological score.
Conclusion
The results of our study show that in mini-pigs, the combination of EPO and BMAC leads to an enhanced osteochondral healing. However, additional research is necessary to further improve the repair tissue and to define the role of MSCs and EPO in cartilage repair.
doi:10.1371/journal.pone.0092766
PMCID: PMC3968023  PMID: 24676029
6.  The Augmentation of a Collagen/Glycosaminoglycan Biphasic Osteochondral Scaffold with Platelet-Rich Plasma and Concentrated Bone Marrow Aspirate for Osteochondral Defect Repair in Sheep 
Cartilage  2012;3(4):351-363.
Objective:
This study investigates the combination of platelet-rich plasma (PRP) or concentrated bone marrow aspirate (CBMA) with a biphasic collagen/glycosaminoglycan (GAG) osteochondral scaffold for the treatment of osteochondral defects in sheep.
Design:
Acute osteochondral defects were created in the medial femoral condyle (MFC) and the lateral trochlea sulcus (LTS) of 24 sheep (n = 6). Defects were left empty or filled with a 6 × 6-mm scaffold, either on its own or in combination with PRP or CBMA. Outcome measures at 6 months included mechanical testing, International Cartilage Repair Society (ICRS) repair score, modified O’Driscoll histology score, qualitative histology, and immunohistochemistry for type I, II, and VI collagen.
Results:
No differences in mechanical properties, ICRS repair score, or modified O’Driscoll score were detected between the 4 groups. However, qualitative assessments of the histological architecture, Safranin O content, and collagen immunohistochemistry indicated that in the PRP/scaffold groups, there was a more hyaline cartilage–like tissue repair. In addition, the addition of CBMA and PRP to the scaffold reduced cyst formation in the subchondral bone of healed lesions.
Conclusion:
There was more hyaline cartilage–like tissue formed in the PRP/scaffold group and less subchondral cystic lesion formation in the CBMA and PRP/scaffold groups, although there were no quantitative differences in the repair tissue formed.
doi:10.1177/1947603512444597
PMCID: PMC4297149  PMID: 26069645
cartilage repair; osteochondral scaffold; platelet rich plasma
7.  One-step bone marrow-derived cell transplantation in talarosteochondral lesions: mid-term results 
Joints  2014;1(3):102-107.
Purpose
to verify the capability of scaffold-supported bone marrow-derived cells to be used in the repair of osteochondral lesions of the talus.
Methods
using a device to concentrate bone marrow-derived cells, a scaffold (collagen powder or hyaluronic acid membrane) for cell support and platelet gel, a one-step arthroscopic technique was developed for cartilage repair. In a prospective clinical study, we investigated the ability of this technique to repair talar osteochondral lesions in 64 patients. The mean follow-up was 53 months. Clinical results were evaluated using the American Orthopaedic Foot and Ankle Society (AOFAS) scale score. We also considered the influence of scaffold type, lesion area, previous surgery, and lesion depth.
Results
the mean preoperative AOFAS scale score was 65.2 ± 13.9. The clinical results peaked at 24 months, before declining gradually to settle at a score of around 80 at the maximum follow-up of 72 months.
Conclusions
the use of bone marrow-derived cells supported by scaffolds to repair osteochondral lesions of the talus resulted in significant clinical improvement, which was maintained over time.
Level of Evidence
level IV, therapeutic case series.
PMCID: PMC4295704  PMID: 25606518
bone marrow-derived cells; cartilage; osteochondral defect; repair; talus
8.  Clinical Cartilage Restoration: Evolution and Overview 
Background
Clinical cartilage restoration is evolving, with established and emerging technologies. Randomized, prospective studies with adequate power comparing the myriad of surgical techniques used to treat chondral injuries are still lacking and it remains a challenge for the surgeon treating patients to make evidence-based decisions.
Questions/purposes
We reviewed the history of the major cartilage repair/restorative procedures, indications for currently available repair/restorative procedures, and postoperative management.
Methods
We performed searches using MEDLINE and cartilage-specific key words to identify all English-language literature. Articles were selected based on their contributions to our current understanding of the basic science and clinical treatment of articular cartilage lesions or historical importance. We then selected 77 articles, two of which are articles of historical importance.
Results
Current cartilage restorative techniques include débridement, microfracture, osteochondral fragment repair, osteochondral allograft, osteochondral autograft, and autologous chondrocyte transplantation. Pending techniques include two-staged cell-based therapies integrated into a variety of scaffolds, single-stage cell-based therapy, and augmentation of marrow stimulation, each with suggested indications including lesion size, location, and activity demands of the patient. The literature demonstrates variable improvements in pain and function contingent upon multiple variables including indications and application.
Conclusions
For the patient with symptomatic chondral injury, numerous techniques are available to the surgeon to relieve pain and improve function. Until rigorous clinical trials (prospective, adequately powered, randomized control) are available, treatment decisions should be guided by expert extrapolation of the available literature based in historically sound principles.
doi:10.1007/s11999-010-1764-z
PMCID: PMC3171560  PMID: 21240578
9.  No Effect of Hole Geometry in Microfracture for Talar Osteochondral Defects 
Background
Débridement and bone marrow stimulation is an effective treatment option for patients with talar osteochondral defects. However, whether surgical factors affect the success of microfracture treatment of talar osteochondral defects is not well characterized.
Questions/purposes
We hypothesized (1) holes that reach deeper into the bone marrow-filled trabecular bone allow for more hyaline-like repair; and (2) a larger number of holes with a smaller diameter result in more solid integration of the repair tissue, less need for new bone formation, and higher fill of the defect.
Methods
Talar osteochondral defects that were 6 mm in diameter were drilled bilaterally in 16 goats (32 samples). In eight goats, one defect was treated by drilling six 0.45-mm diameter holes in the defect 2 mm deep; in the remaining eight goats, six 0.45-mm diameter holes were punctured to a depth of 4 mm. All contralateral defects were treated with three 1.1-mm diameter holes 3 mm deep, mimicking the clinical situation, as internal controls. After 24 weeks, histologic analyses were performed using Masson-Goldner/Safranin-O sections scored using a modified O’Driscoll histologic score (scale, 0–22) and analyzed for osteoid deposition. Before histology, repair tissue quality and defect fill were assessed by calculating the mean attenuation repair/healthy cartilage ratio on Equilibrium Partitioning of an Ionic Contrast agent (EPIC) micro-CT (μCT) scans. Differences were analyzed by paired comparison and Mann-Whitney U tests.
Results
Significant differences were not present between the 2-mm and 4-mm deep hole groups for the median O’Driscoll score (p = 0.31) and the median of the μCT attenuation repair/healthy cartilage ratios (p = 0.61), nor between the 0.45-mm diameter and the 1.1-mm diameter holes in defect fill (p = 0.33), osteoid (p = 0.89), or structural integrity (p = 0.80).
Conclusions
The results indicate that the geometry of microfracture holes does not influence cartilage healing in the caprine talus.
Clinical Relevance
Bone marrow stimulation technique does not appear to be improved by changing the depth or diameter of the holes.
doi:10.1007/s11999-013-3189-y
PMCID: PMC3792274  PMID: 23893362
10.  Hip Microfracture 
Cartilage  2010;1(2):127-136.
Microfracture is a marrow-stimulating technique used in the hip to treat cartilage defects associated with femoro-acetabular impingement, instability, or traumatic hip injury. These defects have a low probability of healing spontaneously and therefore often require surgical intervention. Originally adapted from the knee, microfracture is part of a spectrum of cartilage repair options that include palliative procedures such as debridement and lavage, reparative procedures such as marrow-stimulating techniques (abrasion arthroplasty and microfracture), and restorative procedures such as autologous chondrocyte implantation and osteochondral allograft/autografts. The basic indications for microfracture of the hip include focal and contained lesions typically less than 4 cm in diameter, full-thickness (Outerbridge grade IV) defects in weightbearing areas, unstable lesions with intact subchondral bone, and focal lesions without evidence of surrounding chondromalacia. Although not extensively studied in the hip, there are some small clinical series with promising early outcomes. Although the widespread use of microfracture in the hip is hindered by difficulties in identifying lesions on preoperative imaging and instrumentation to circumvent the femoral head, this technique continues to gain acceptance as an initial treatment for small, focal cartilage defects.
doi:10.1177/1947603510366028
PMCID: PMC4297043  PMID: 26069544
marrow stimulation; hip; arthroscopy; cartilage repair
11.  One-step Bone Marrow-derived Cell Transplantation in Talar Osteochondral Lesions 
The ideal treatment of osteochondral lesions is debatable. Although autologous chondrocyte implantation provides pain relief, the need for two operations and high costs has prompted a search for alternatives. Bone marrow-derived cells may represent the future in osteochondral repair. Using a device to concentrate bone marrow-derived cells and collagen powder or hyaluronic acid membrane as scaffolds for cell support and platelet gel, a one-step arthroscopic technique was developed for cartilage repair. We performed an in vitro preclinical study to verify the capability of bone marrow-derived cells to differentiate into chondrogenic and osteogenic lineages and to be supported onto scaffolds. In a prospective clinical study, we investigated the ability of this technique to repair talar osteochondral lesions in 48 patients. Minimum followup was 24 months (mean, 29 months; range, 24–35 months). Clinical results were evaluated using the American Orthopaedic Foot and Ankle Society (AOFAS) score and the influence of scaffold type, lesion area, previous surgeries, and lesion depth was considered. MRI and histologic evaluation were performed. The AOFAS score improved from 64.4 ± 14.5 to 91.4 ± 7.7. Histologic evaluation showed regenerated tissue in various degrees of remodeling although none showed entirely hyaline cartilage. These data suggest the one-step technique is an alternative for cartilage repair, permitting improved functional scores and overcoming the drawbacks of previous techniques.
Level of Evidence: Level IV, therapeutic study. See Guidelines for Authors for a complete description of levels of evidence.
doi:10.1007/s11999-009-0885-8
PMCID: PMC2772930  PMID: 19449082
12.  Platelet autologous growth factors decrease the osteochondral regeneration capability of a collagen-hydroxyapatite scaffold in a sheep model 
Background
Current research aims to develop innovative approaches to improve chondral and osteochondral regeneration. The objective of this study was to investigate the regenerative potential of platelet-rich plasma (PRP) to enhance the repair process of a collagen-hydroxyapatite scaffold in osteochondral defects in a sheep model.
Methods
PRP was added to a new, multi-layer gradient, nanocomposite scaffold that was obtained by nucleating collagen fibrils with hydroxyapatite nanoparticles. Twenty-four osteochondral lesions were created in sheep femoral condyles. The animals were randomised to three treatment groups: scaffold, scaffold loaded with autologous PRP, and empty defect (control). The animals were sacrificed and evaluated six months after surgery.
Results
Gross evaluation and histology of the specimens showed good integration of the chondral surface in both treatment groups. Significantly better bone regeneration and cartilage surface reconstruction were observed in the group treated with the scaffold alone. Incomplete bone regeneration and irregular cartilage surface integration were observed in the group treated with the scaffold where PRP was added. In the control group, no bone and cartilage defect healing occurred; defects were filled with fibrous tissue. Quantitative macroscopic and histological score evaluations confirmed the qualitative trends observed.
Conclusions
The hydroxyapatite-collagen scaffold enhanced osteochondral lesion repair, but the combination with platelet growth factors did not have an additive effect; on the contrary, PRP administration had a negative effect on the results obtained by disturbing the regenerative process. In the scaffold + PRP group, highly amorphous cartilaginous repair tissue and poorly spatially organised underlying bone tissue were found.
doi:10.1186/1471-2474-11-220
PMCID: PMC2954989  PMID: 20875101
13.  Osteochondral Allograft of the Talus 
Osteochondral lesions of the talus are being recognized as an increasingly common injury. They are most commonly located postero-medially or antero-laterally, while centrally located lesions are uncommon. Large osteochondral lesions have significant biomechanical consequences and often require resurfacing with osteochondral autograft transfer, mosaicplasty, autologous chondrocyte implantation (or similar methods) or osteochondral allograft transplantation. Allograft procedures have become popular due to inherent advantages over other resurfacing techniques. Cartilage viability is one of the most important factors for successful clinical outcomes after transplantation of osteochondral allografts and is related to storage length and intra-operative factors. While there is abundant literature about osteochondral allograft transplantation in the knee, there are few papers about this procedure in the talus. Failure of non-operative management, initial debridement, curettage or microfractures are an indication for resurfacing. Patients should have a functional ankle motion, closed growth plates, absence of cartilage lesions on the tibial side. This paper reviews the published literature about osteochondral allograft transplantation of the talus focusing on indications, pre-operative planning, surgical approaches, postoperative management, results and complications of this procedure.
PMCID: PMC4127728  PMID: 25328456
14.  Dynamic Regulation of Bone Morphogenetic Proteins in Engineered Osteochondral Constructs by Biomechanical Stimulation 
Tissue Engineering. Part A  2012;19(5-6):783-792.
Osteochondral tissue-engineered grafts are proposed to hold greater potential to repair/regenerate damaged cartilage through enhanced biochemical and mechanical interactions with underlying subchondral bone as compared to simple engineered cartilage. Additionally, biomechanical stimulation of articular chondrocytes (ACs) or osteoblasts (OBs) was shown to induce greater morphogenesis of the engineered tissues composed of these cells. In this report, to define the advantages of biomechanical stimulation to osteochondral grafts for tissue engineering, we examined whether (1) ACs and OBs in three-dimensional (3D) osteochondral constructs support functional development of each other at the molecular level, and (2) biomechanical stimulation of osteochondral constructs further promotes the regenerative potential of such grafts. Various configurations of cell/scaffold assemblies, including chondral, osseous, and osteochondral constructs, were engineered with mechano-responsive electrospun poly(ɛ-caprolactone) scaffolds. These constructs were subjected to either static or dynamic (10% cyclic compressive strain at 1 Hz for 3 h/day) culture conditions for 2 weeks. The expression of bone morphogenetic proteins (BMPs) was examined to assess the regenerative potential of each treatment on the cells. Biomechanical stimulation augmented a marked upregulation of Bmp2, Bmp6, and Bmp7 as well as downregulation of BMP antagonist, Bmp3, in a time-specific manner in the ACs and OBs of 3D osteochondral constructs. More importantly, the presence of biomechanically stimulated OBs was especially crucial for the induction of Bmp6 in ACs, a BMP required for chondrocytic growth and differentiation. Biomechanical stimulation led to enhanced tissue morphogenesis possibly through this BMP regulation, evident by the improved effective compressive modulus of the osteochondral constructs (710 kPa of dynamic culture vs. 280 kPa of static culture). Similar BMP regulation was observed in the femoral cartilages of the rats subjected to gentle exercise, demonstrating the physiological relevance of in vitro biomechanical stimulation of osteochondral constructs. Overall, our findings show that biomechanical stimulation may be critical for cross signaling between ACs and OBs to support chondrocytic growth in 3D osteochondral tissues.
doi:10.1089/ten.tea.2012.0103
PMCID: PMC3568965  PMID: 23198877
15.  Reconstruction of Osteochondral Defects by Combined Bone Grafting and a Bilayer Collagen Membrane as a Sandwich Technique 
Orthopedic Reviews  2013;5(4):e36.
Treatment of osteochondral lesions of the knee remains a major challenge in orthopedic surgery. Recently established procedures like autologous chondrocyte implantation or matrix-associated chondrocyte implantation yield good results, but include the disadvantage of two-step procedures. The purpose of this study was to evaluate the clinical and magnetic resonance imaging outcome of repairs of osteochondral defects of the knee by a combined procedure of bone grafting and covering with a bilayer collagen membrane in a sandwich technique. Seven male patients with a mean age of 42 (range 30-55) years and symptomatic focal osteochondral lesions of the knee grade IV according to the International Cartilage Repair Society classification were included. The mean diameter of defects was 28.6 (range 15-40) mm. Results were evaluated at a minimum of 24 months after surgery by International Knee Documentation Committee score, Lysholm-score, visual analogue scale, and magnetic resonance imaging with specific cartilage sequences, evaluating the ICRS score and the Magnetic Observation of Cartilage Repair Tissue (MOCART) score. All patients judged the operation as successful. Among the patients available for the long-term follow-up, mean visual analogue scale value was 1.3 (range 0-3) out of 10 points. Mean International Knee Documentation Committee score was 80.8 (range 63.2-88.5) out of 100 points. Mean Lysholm score was 85 (range 55-95) out of 100 points. None of the patients had to be reoperated until today. Evaluation of magnetic resonance imaging using the MOCART score revealed a good correlation to the clinical outcome. This is the first study reporting results after reconstruction of osteochondral defects of the knee joint by bone grafting and a bilayer collagen membrane. This new method offers the advantage of a one-step-procedure and yields both good clinical and magnetic resonance findings. We conclude that this procedure can be a valuable tool to improve joint function after osteochondral defects, trauma, and in joints with local arthritic lesions.
doi:10.4081/or.2013.e36
PMCID: PMC3883077  PMID: 24416480
knee; osteochondral defects; cartilage repair; regenerative joint surgery; magnetic resonance imaging; MOCART score
16.  Expression of proteoglycan epitopes in articular cartilage repair tissue. 
To determine if expression of specific proteoglycan epitopes distinguishes articular cartilage repair tissue from normal articular cartilage, we used seven monoclonal antibodies to examine normal articular cartilage and cartilage repair tissue from osteochondral defects 3.2 mm in diameter and 4.0 mm deep in the medial femoral condyles of 27 New Zealand white rabbits and seven cynomolgus monkeys. Following creation of the osteochondral defects, one limb of each animal was treated with cast immobilization while the other limb was treated with passive motion for two weeks. Rabbit knees were examined at eight (13 animals, 26 knees) and 36 weeks (14 animals, 28 knees) and monkey knees at eight weeks (seven animals, 14 knees) following surgery. Staining for six of the antibodies did not differ between repair cartilage and normal articular cartilage, but an antibody that recognizes atypical glycosaminoglycan structures in developing tissues (MAb 7D4) consistently distinguished repair cartilage from normal cartilage in rabbits and monkeys. Repair tissue consisting of hyaline toluidine blue-staining matrix containing chondrocytic cells uniformly showed strong 7D4 staining. In contrast, normal articular cartilage and fibrous repair tissue showed inconsistent weak 7D4 staining. At eight weeks following surgery, rabbit cartilage repair tissue stained more intensely for 7D4 than monkey cartilage repair tissue; in rabbits, cartilage repair tissue stained more intensely for 7D4 at eight weeks than at 36 weeks following surgery. Repair tissue staining for 7D4 did not differ between osteochondral defects treated with passive motion and those treated with immobilization in rabbits and monkeys. These results indicate that expression of a high level of proteoglycan epitope 7D4 distinguishes hyaline articular cartilage repair tissue from normal articular cartilage and fibrous cartilage repair tissue in the early stages of osteochondral healing, and that as hyaline articular cartilage repair tissue matures expression of 7D4 decreases. The ability to characterize repair cartilage proteoglycans with monoclonal antibodies may aid in the evaluation of the quality and maturity of cartilage repair tissue and thereby facilitate improvements in procedures for resurfacing joints.
Images
PMCID: PMC2378177  PMID: 9807703
17.  Scientific Evidence Base for Cartilage Injury and Repair in the Athlete 
Cartilage  2012;3(1 Suppl):11S-17S.
Soccer players and athletes in high-impact sports are frequently affected by knee injuries. Injuries to the anterior cruciate ligament and menisci are frequently observed in soccer players and may increase the risk of developing an articular cartilage lesion. In high-level athletes, the overall prevalence of knee articular cartilage lesions has been reported to be 36% to 38%. The treatment for athletic patients with articular cartilage lesions is often challenging because of the high demands placed on the repair tissue by impact sports. Cartilage defects in athletes can be treated with microfracture, osteochondral grafting, and autologous chondrocyte implantation. There is increasing scientific evidence for cartilage repair in athletes, with more extensive information available for microfracture and autologous chondrocyte implantation than for osteochondral grafting. The reported rates and times to return to sport at the preinjury level are variable in recreational players, with the best results seen in younger and high-level athletes. Better return to sport is consistently observed for all repair techniques with early cartilage repair. Besides minimizing sensorimotor deficits and addressing accompanying pathologies, the quality of the repair tissue may be a significant factor for the return to sport.
doi:10.1177/1947603511415841
PMCID: PMC4297168  PMID: 26069601
articular cartilage injury; cartilage repair; sports injury knee; return to sports; athletes; scientific evidence
18.  Integration of Tissue-engineered Cartilage With Host Cartilage: An In Vitro Model 
Background
We developed a tissue-engineered biphasic cartilage bone substitute construct which has been shown to integrate with host cartilage and differs from autologous osteochondral transfer in which integration with host cartilage does not occur.
Questions/purposes
(1) Develop a reproducible in vitro model to study the mechanisms regulating tissue-engineered cartilage integration with host cartilage, (2) compare the integrative properties of tissue-engineered cartilage with autologous cartilage and (3) determine if chondrocytes from the in-vitro formed cartilage migrate across the integration site.
Methods
A biphasic construct was placed into host bovine osteochondral explant and cultured for up to 8 weeks (n = 6 at each time point). Autologous osteochondral implants served as controls (n = 6 at each time point). Integration was evaluated histologically, ultrastructurally, biochemically and biomechanically. Chondrocytes used to form cartilage in vitro were labeled with carboxyfluorescein diacetate which allowed evaluation of cell migration into host cartilage.
Results
Histologic assessment demonstrated that tissue-engineered cartilage integrated over time, unlike autologous osteochondral implant controls. Biochemically there was an increase in collagen content of the tissue-engineered implant over time but was well below that for native cartilage. Integration strength increased between 4 and 8 weeks as determined by a pushout test. Fluorescent cells were detected in the host cartilage up to 1.5 mm from the interface demonstrating chondrocyte migration.
Conclusions
Tissue-engineered cartilage demonstrated improved integration over time in contrast to autologous osteochondral implants. Integration extent and strength increased with culture duration. There was chondrocyte migration from tissue-engineered cartilage to host cartilage.
Clinical Relevance
This in vitro integration model will allow study of the mechanism(s) regulating cartilage integration. Understanding this process will facilitate enhancement of cartilage repair strategies for the treatment of chondral injuries.
doi:10.1007/s11999-011-1856-4
PMCID: PMC3171526  PMID: 21403985
19.  Cartilage repair techniques of the talus: An update 
World Journal of Orthopedics  2014;5(3):171-179.
Symptomatic chondral or osteochondral defects of the talus reduce the quality of life of many patients. Although their pathomechanism is well understood, it is well known that different aetiologic factors play a role in their origin. Additionally, it is well recognised that the talar articular cartilage strongly differs from that in the knee. Despite this fact, many recommendations for the management of talar cartilage defects are based on approaches that were developed for the knee. Conservative treatment seems to work best in paediatric and adolescent patients with osteochondritis dissecans. However, depending on the size of the lesions, surgical approaches are necessary to treat many of these defects. Bone marrow stimulation techniques may achieve good results in small lesions. Large lesions may be treated by open procedures such as osteochondral autograft transfer or allograft transplantation. Autologous chondrocyte transplantation, as a restorative procedure, is well investigated in the knee and has been applied in the talus with increasing popularity and promising results but the evidence to date is poor. The goals of the current article are to summarise the different options for treating chondral and osteochondral defects of the talus and review the available literature.
doi:10.5312/wjo.v5.i3.171
PMCID: PMC4095009  PMID: 25035819
Cartilage defect; Talus; Repair techniques; Arthroscopy; Marrow stimulation; Mosaicplasty; Autologous chondrocyte implantation
20.  Cell-based approaches to joint surface repair: a research perspective 
Osteoarthritis and Cartilage  2013;21(7):892-900.
Summary
Repair of lesions of the articular cartilage lining the joints remains a major clinical challenge. Surgical interventions include osteochondral autograft transfer and microfracture. They can provide some relief of symptoms to patients, but generally fail to durably repair the cartilage. Autologous chondrocyte implantation has thus far shown the most promise for the durable repair of cartilage, with long-term follow-up studies indicating improved structural and functional outcomes. However, disadvantages of this technique include the need for additional surgery, availability of sufficient chondrocytes for implantation, and maintenance of their phenotype during culture-expansion. Mesenchymal stem cells offer an attractive alternative cell-source for cartilage repair, due to their ease of isolation and amenability to ex vivo expansion while retaining stem cell properties. Preclinical and clinical studies have demonstrated the potential of mesenchymal stem cells to promote articular cartilage repair, but have also highlighted several key challenges. Most notably, the quality and durability of the repair tissue, its resistance to endochondral ossification, and its effective integration with the surrounding host tissue. In addition, challenges exist related to the heterogeneity of mesenchymal stem cell preparations and their quality-control, as well as optimising the delivery method. Finally, as our knowledge of the cellular and molecular mechanisms underlying articular cartilage repair increases, promising studies are emerging employing bioactive scaffolds or therapeutics that elicit an effective tissue repair response through activation and mobilisation of endogenous stem and progenitor cells.
doi:10.1016/j.joca.2013.04.008
PMCID: PMC3694304  PMID: 23598176
Cartilage; Osteoarthritis; Cell therapy; Mesenchymal stem cell; Chondrocyte
21.  Midterm results of biologic fixation or mosaicplasty and drilling in osteochondritis dissecans 
Indian Journal of Orthopaedics  2011;45(5):445-449.
Background:
Osteochondritis dissecans (OCD) primarily affects subchondral bone. Multiple drilling, fixation implant or autogenous osteochondral grafts are reported as treatment options. We present the midterm results of cases in which an OCD lesion was treated by osteochondral autograft transfer and drilling.
Materials and Methods:
Between 2002 and 2006, 14 knees with International Cartilage Repair Society (ICRS-OCD) type II and III lesions were treated in our clinic using osteochondral autograft transfer and drilling by arthroscopic or open surgery. The average age of our patients was 22.14 years (range 17-29 years) and average followup was of 24.3 months (range 11-40 months). Lesion type was ICRS type II in five patients (35.7%) and ICRS type III in nine patients (64.3%). In cases with ICRS-OCD type II lesions, in situ fixation was applied following circumferential multiple drilling, while mosaicplasty was done following debridement and multiple drilling in cases with ICRS-OCD type III lesion. Mosaicplasty was performed in the lesion area by an average of 2.5 (range 1-3) cylindrical osteochondral autografts. Patients were not allowed to perform loading activities for 3 weeks in the postoperative period; movement was initiated by using CPM device in the early phase; full range of motion was achieved in third week, and full weight bearing was permitted in 6 to 8 weeks
Results:
While 6 and 8 patients were classified preoperatively as fair and poor, respectively, according to Hughston scale, excellent and good results were obtained postoperatively in 10 and 4 patients, respectively. During the followup, no problems were detected in any of the patients in the regions where osteochondral graft was harvested.
Conclusion:
Biologic fixation or mosaicplasty and drilling as a technique to treatment of the lesion in OCD by osteochondral autograft transfer has resulted in good and excellent clinical outcomes in our patients and it is considered that providing blood flow to subchondral bone by circumferencial drilling leads to an increase in the robustness of biological internal fixation and shortens the duration of recovery.
doi:10.4103/0019-5413.83137
PMCID: PMC3162682  PMID: 21886927
Osteochondritis dissecans; Hughston scale; knee; mosaicplasty
22.  In Vivo Comparison of the Bone Regeneration Capability of Human Bone Marrow Concentrates vs. Platelet-Rich Plasma 
PLoS ONE  2012;7(7):e40833.
Background
Bone marrow aspirate concentrate (BMAC) including high densities of stem cells and progenitor cells may possess a stronger bone regenerative capability compared with Platelet-rich plasma (PRP), which contains enriched growth factors. The objective of this study was to evaluate the effects of human BMAC and PRP in combination with β-tricalcium phosphate (β-TCP) on promoting initial bone augmentation in an immunodeficient mouse model.
Methodology/Principal Findings
BMAC and PRP were concentrated with an automated blood separator from the bone marrow and peripheral blood aspirates. β-TCP particles were employed as a scaffold to carry cells. After cell counting and FACS characterization, three groups of nude mice (BMAC+TCP, PRP+TCP, and a TCP control) were implanted with graft materials for onlay placement on the cranium. Samples were harvested after 4 weeks, and serial sections were prepared. We observed the new bone on light microscopy and performed histomorphometric analysis. After centrifugation, the concentrations of nucleated cells and platelets in BMAC were increased by factors of 2.8±0.8 and 5.3±2.4, respectively, whereas leucocytes and platelets in PRP were increased by factors of 4.1±1.8 and 4.4±1.9, respectively. The concentrations of CD34-, CD271-, CD90-, CD105-, and CD146-positive cells were markedly increased in both BMAC and PRP. The percentage of new bone in the BMAC group (7.6±3.9%) and the PRP group (7.2±3.8%) were significantly higher than that of TCP group (2.7±1.4%). Significantly more bone cells in the new bone occurred in sites transplanted with BMAC (552±257) and PRP (491±211) compared to TCP alone (187±94). But the difference between the treatment groups was not significant.
Conclusions/Significance
Both human BMACs and PRP may provide therapeutic benefits in bone tissue engineering applications. These fractions possess a similar ability to enhance early-phase bone regeneration.
doi:10.1371/journal.pone.0040833
PMCID: PMC3395629  PMID: 22808272
23.  In Vivo Efficacy of Fresh vs. Frozen Osteochondral Allografts in the Goat at 6 Months is Associated with PRG4 Secretion 
The long-term efficacy of osteochondral allografts is due to the presence of viable chondrocytes within graft cartilage. Chondrocytes in osteochondral allografts, especially those at the articular surface that normally produce the lubricant proteoglycan-4 (PRG4), are susceptible to storage-associated death. The hypothesis of this study was that the loss of chondrocytes within osteochondral grafts leads to decreased PRG4 secretion, after graft storage and subsequent implant. The objectives were to determine the effect of osteochondral allograft treatment (FROZEN vs. FRESH) on secretion of functional PRG4 after (i) storage, and (ii) 6months in vivo in adult goats. FROZEN allograft storage reduced PRG4 secretion from cartilage by ~85% compared to FRESH allograft storage. After 6months in vivo, the PRG4-secreting function of osteochondral allografts was diminished with prior FROZEN storage by ~81% versus FRESH allografts and by ~84% versus non-operated control cartilage. Concomitantly, cellularity at the articular surface in FROZEN allografts was ~96% lower than FRESH allografts and non-operated cartilage. Thus, the PRG4-secreting function of allografts appears to be maintained in vivo based on its state after storage. PRG4 secretion may be not only a useful marker of allograft performance, but also a biological process protecting the articular surface of grafts following cartilage repair.
doi:10.1002/jor.22319
PMCID: PMC4076778  PMID: 23362152
osteochondral allografts; animal models; proteoglycan-4; superficial zone
24.  Current Treatments of Isolated Articular Cartilage Lesions of the Knee Achieve Similar Outcomes 
Background
Many surgical techniques, including microfracture, periosteal and perichondral grafts, chondrocyte transplantation, and osteochondral grafts, have been studied in an attempt to restore damaged articular cartilage. However, there is no consensus regarding the best method to repair isolated articular cartilage defects of the knee.
Questions/purposes
We compared postoperative functional outcomes, followup MRI appearance, and arthroscopic examination after microfracture (MF), osteochondral autograft transplantation (OAT), or autologous chondrocyte implantation (ACI).
Methods
We prospectively investigated 30 knees with MF, 22 with OAT, and 18 with ACI. Minimum followup was 3 years (mean, 5 years; range, 3–10 years). We included only patients with isolated cartilage defects and without other knee injuries. The three procedures were compared in terms of function using the Lysholm knee evaluation scale, Tegner activity scale, and Hospital for Special Surgery (HSS) score; modified Outerbridge cartilage grades using MRI; and International Cartilage Repair Society (ICRS) repair grade using arthroscopy.
Results
All three procedures showed improvement in functional scores. There were no differences in functional scores and postoperative MRI grades among the groups. Arthroscopy at 1 year showed excellent or good results in 80% after MF, 82% after OAT, and 80% after ACI. Our study did not show a clear benefit of either ACI or OAT over MF.
Conclusions
Owing to a lack of superiority of any one treatment, we believe MF is a reasonable option as a first-line therapy given its ease and affordability relative to ACI or OAT.
Level of Evidence
Level II, therapeutic study. See Guidelines for Authors for a complete description of levels of evidence.
doi:10.1007/s11999-012-2304-9
PMCID: PMC3392395  PMID: 22422593
25.  Treatment of deep articular talus lesions by matrix associated autologous chondrocyte implantation—results at five years 
International Orthopaedics  2012;36(11):2279-2285.
Purpose
Treatment of focal full-thickness chondral or osteochondral defects of the talus remains a challenge. The aim of this study was to evaluate the postoperative success and the long-term efficacy of matrix associated autologous chondrocyte implantation in these defects.
Methods
Matrix associated autologous chondrocyte implantation (MACI) was applied in 22 consecutive patients (mean age 23.9 years) with full-thickness chondral or osteochondral lesions of the talus. The average defect-size was 1.94 cm² (range 1–6). In case of osteochondritis dissecans (n = 13) an autologous bone graft was performed simultaneously. Follow-ups were routinely scheduled up to 63.5 (±7.4) months, consisting of clinical evaluation and magnetic resonance imaging.
Results
The AOFAS score improved significantly from 70.1 to 87.9/92.6/93.5/95.0/95.5 and 95.3 points at three, six, 12, 24, 36 and 63.5 months, respectively. On a visual analogue scale, pain intensity decreased from 5.7 (±2.6) to 0.9 (±0.8) while subjective function increased from 5.3 (±2.3) to 8.9 (±0.9) at final follow-up (each p < 0.001). The Tegner score rose significantly from 2.4 (±1.2) to 4.7 (±0.6). The MOCART score improved from 62.6 (±19.4) at three months to 83.8 (±9.4) at final follow-up. No significant differences were found between lesions caused by osteochondritis dissecans or trauma and between first- or second-line treatments. For all scores, the most benefit was seen within the first 12 months with stable results afterwards. No major complications were noted.
Conclusions
Matrix associated autologous chondrocyte implantation is capable of significant and stable long-term improvement of pain and functional impairment caused by focal full-thickness chondral and osteochondral talus lesions.
doi:10.1007/s00264-012-1635-1
PMCID: PMC3479272  PMID: 22885840

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