Bone Marrow Stimulation Group Research Articles

Losartan in Combination With Bone Marrow Stimulation Showed Synergistic Effects on Load to Failure and Tendon Matrix Organization in a Rabbit Model

To investigate the effects of combining bone marrow stimulation (BMS) with oral losartan to block transforming growth factor β1 (TGF-β1) on biomechanical repair strength in a rabbit chronic injury model. Forty rabbits were randomly allocated into 4 groups (10 in each group). The supraspinatus tendon was detached and left alone for 6 weeks to establish a rabbit chronic injury model and was then repaired in a surgical procedure using a transosseous, linked, crossing repair construct. The animals were divided into the following groups: control group (group C), surgical repair only; BMS group (group B), surgical repair with BMS of the tuberosity; losartan group (group L), surgical repair plus oral losartan (TGF-β1 blocker) for 8 weeks; and BMS-plus-losartan group (group BL), surgical repair plus BMS plus oral losartan for 8 weeks. At 8 weeks after repair, biomechanical and histologic evaluations were performed. The biomechanical testing results showed significantly higher ultimate load to failure in group BL than in group B (P= .029) but not compared with group C or group L. A 2× 2 analysis-of-variance model found that the effect of losartan on ultimate load significantly depended on whether BMS was performed (interaction term F1,28= 5.78, P= .018). No difference was found between the other groups. No difference in stiffness was found between any groups. On histologic assessment, groups B, L, and BL showed improved tendon morphology and an organized type I collagen matrix with less type III collagen compared with group C. Group BL showed the most highly organized tendon matrix with more type I collagen and less type III collagen, which indicates less fibrosis. Similar results were found at the bone-tendon interface. Rotator cuff repair combined with oral losartan and BMS of the greater tuberosity showed improved pullout strength and a highly organized tendon matrix in this rabbit chronic injury model. Tendon healing or scarring is accompanied by the formation of fibrosis, which has been shown to result in compromised biomechanical properties, and is therefore a potential limiting factor in healing after rotator cuff repair. TGF-β1 expression has been shown to play an important role in the formation of fibrosis. Recent studies focusing on muscle healing and cartilage repair have found that the downregulation of TGF-β1 by losartan intake can reduce fibrosis and improve tissue regeneration in animal models.

Bone marrow stimulation in arthroscopic rotator cuff repair is a cost-effective and straightforward technique to reduce retear rates: A systematic review and meta-analysis.

Bone marrow stimulation (BMS) has been considered a well-established method for treating knee and ankle osteochondral lesions. Some studies have also shown that BMS can promote healing of the repaired tendon and enhance biomechanical properties during rotator cuff repair. Our purpose was to compare the clinical outcomes of arthroscopic repair rotator cuff (ARCR) with and without BMS. A systematic review with meta-analysis was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). PubMed, Embase, Web of Science, Google scholar, ScienceDirect, and the Cochrane Library were searched from inception to March 20, 2022. Data on retear rates, shoulder functional outcomes, visual analog score and range of motion were pooled and analyzed. Dichotomous variables were presented as odds ratios (OR), and continuous variables were presented as mean differences (MD). Meta-analyses were conducted with Review Manager 5.3. Eight studies involving 674 patients were included, with mean follow-up period ranging from 12 to 36.8 months. Compared to ARCR alone, the intraoperative combination of the BMS resulted in lower retear rates (P < 0.0001), but showed similar results in Constant score (P = 0.10), University of California at Los Angeles (UCLA) score (P = 0.57), American Shoulder and Elbow Surgeons (ASES) score (P = 0.23), Disabilities of the Arm, Shoulder and Hand (DASH) score (P = 0.31), VAS (visual analog score) score (P = 0.34), and range of motion (ROM) (forward flexion, P = 0.42; external rotation, P = 0.21). After sensitivity analyses and subgroup analyses, no significant changes in statistical results were observed. Compared to ARCR alone, the combination of intraoperative BMS can significantly reduce the retear rates, but showed similar short-term results in functional outcomes, ROM and pain. Better clinical outcomes are anticipated in the BMS group by improving structural integrity during long-term follow-up. Currently, BMS may be a viable option in ARCR based on its straightforward and cost-effective advantages. https://www.crd.york.ac.uk/prospero/, identifier: CRD42022323379.

Clinical Outcomes of Osteochondral Fragment Fixation Versus Microfracture Even for Small Osteochondral Lesions of the Talus

Background: The bone marrow stimulation (BMS) technique is performed for osteochondral lesions of the talus (OLTs) with a lesion size of <100 mm2. The lesion defect is covered with fibrocartilage, and the clinical outcomes deteriorate over time. In contrast, the osteochondral fragment fixation can restore the native articular surface. The difference in clinical outcomes between these procedures is unclear. Purpose: To compare the clinical outcomes of BMS and osteochondral fragment fixation for OLTs and examine the characteristics of patients with poor clinical outcomes of BMS. Study Design: Cohort study; Level of evidence, 3. Methods: In total, 62 ankles in 59 patients with OLTs were included. BMS was performed for 26 ankles, and fixation was performed for 36 ankles. Clinical outcomes, including the American Orthopaedic Foot & Ankle Society (AOFAS) Ankle Hindfoot Scale and bone marrow edema (BME) as identified on magnetic resonance imaging, were compared between the 2 groups. On computed tomography scans, the lesion location was compared with or without BME in each group. Results: The AOFAS scores in the fixation group (97.3 ± 4.3 points) were significantly higher than those in the BMS group (91.3 ± 7.7 points), even when the lesion size was <100 mm2 (P < .05). When comparing the ankles with or without BME in each group, the AOFAS scores at the final follow-up were significantly lower for the ankles with BME (88.6 ± 7.8 points) than for those without BME (95.0 ± 6.1 points) in the BMS group (P < .05). Lesions with BME in the sagittal plane were located more centrally than those without BME in the BMS group. In the fixation group, there were no significant differences in AOFAS scores and location of the lesion in ankles with or without BME. Conclusion: The clinical outcomes of osteochondral fragment fixation are superior to those of BMS in OLTs, even for lesions sized <100 mm2. Fixation is recommended even for small lesions, especially for more centralized lesions in the medial and lateral sides of the talus.

Treatment of Osteochondral Lesions of the Talus in the Skeletally Immature Population: A Systematic Review.

Introduction:Skeletally immature osteochondral lesions of the talus (OLTs) are underreported and little is known about the clinical efficacy of different treatment options. The primary aim of the present study was to investigate the clinical efficacy of different conservative and surgical treatment options. The secondary aim was to assess return to sports (RTS) and radiologic outcomes for the different treatment options.Methods:An electronic literature search was carried out in the databases PubMed, EMBASE, Cochrane, CDSR, CENTRAL, and DARE from January 1996 to September 2021 to identify suitable studies for this review. The authors separately screened the articles for eligibility and conducted the quality assessment using the Methodological Index for Non-Randomized Studies (MINORS). Clinical success rates were calculated per separate study and pooled per treatment strategy. Radiologic outcomes and sports outcomes for the different treatment strategies were assessed.Results:Twenty studies with a total of 381 lesions were included. The mean MINORS score of the included study was 7.6 (range: 5 to 9). The pooled success rate was 44% [95% confidence interval (CI): 37%-51%] in the conservative group (n=192), 77% (95% CI: 68%-85%) in the bone marrow stimulation (BMS) group (n=97), 95% (95% CI: 78%-99%) in the retrograde drilling (RD) group (n=22), 79% (95% CI: 61%-91%) in the fixation group (n=33) and 67% (95% CI: 35%-88%) in the osteo(chondral) autograft group (n=9). RTS rates were reported in 2 treatment groups: BMS showed an RTS rate of 86% (95% CI: 42%-100%) without specified levels and an RTS rate to preinjury level of 43% (95% CI: 10%-82%). RD showed an RTS rate of 100% (95% CI: 63%-100%) without specified levels, an RTS rate to preinjury level was not given. RTS times were not given for any treatment option. The radiologic success according to magnetic resonance imaging were 29% (95% CI: 16%-47%) (n=31) in the conservative group, 81% (95% CI: 65%-92%) (n=37) in the BMS group, 41% (95% CI: 18%-67%) (n=19) in the RD group, 87% (95% CI: 65%-97%) (n=19) in the fixation group, and were not reported in the osteo(chondral) transplantation group. Radiologic success rates based on computed tomography scans were 62% (95% CI: 32%-86%) (n=13) in the conservative group, 30% (95% CI: 7%-65%) (n=10) in the BMS group, 57% (95% CI: 25%-84%) (n=7) in the RD group, and were not reported for the fixation and the osteo(chondral) transplantation groups.Conclusions:This study showed that for skeletally immature patients presenting with symptomatic OLTs, conservative treatment is clinically successful in 4 out of 10 children, whereas the different surgical treatment options were found to be successful in 7 to 10 out of 10 children. Specifically, fixation was clinically successful in 8 out of 10 patients and showed radiologically successful outcomes in 9 out of 10 patients, and would therefore be the primary preferred surgical treatment modality. The treatment provided should be tailor-made, considering lesion characteristics and patient and parent preferences.Level of Evidence:Level IV—systematic review and meta-analysis.

Use of Extracellular Matrix Cartilage Allograft May Improve Infill of the Defects in Bone Marrow Stimulation for Osteochondral Lesions of the Talus

Category:AnkleIntroduction/Purpose:The purpose of this study is to evaluate the effectiveness of Extracellular Matrix Cartilage Allograft (EMCA) as an adjuvant to bone marrow stimulation (BMS) compared to BMS alone in the treatment of osteochondral lesions of the talus (OLT).Methods:A retrospective cohort study comparing patients treated with BMS with EMCA (BMS-EMCA group) and BMS alone (BMS group) between 2013 and 2019 was undertaken. Clinical outcome was evaluated with the Foot and Ankle Outcome Score (FAOS) pre-and postoperatively. Postoperative MRIs were evaluated using a modified Magnetic Resonance Observation of Cartilage Tissue (MOCART) score. Comparisons between groups were made with the Man-Whitney U test for continuous variables and the χ2 or Fisher exact test for categorical variables.Results:Twenty-four patients underwent BMS with EMCA (BMS-EMCA group) and 24 patients underwent BMS alone (BMS group). The mean age was 40.8 years (range, 19 to 60 years) in BMS-EMCA group and 47.8 years (range, 24 to 60 years) in BMS group (p=0.060). The mean follow-up time was 20.0 months (range, 12-36 months) in BMS-EMCA group and 26.9 months (range, 12 to 55 months) in BMS group (p=0.031). Both groups showed significant improvements in all FAOS subscales. No significant differences between groups were found in all postoperative FAOS. The mean MOCART score in BMS-EMCA group was higher (76.3 vs 66.3), but not statistically significant (p=0.176). The MRI analysis showed that 87.5% of BMS-EMCA group had complete infill of the defect with repair tissue, however less than half (46.5%) of BMS group had complete infill (p=0.015).Conclusion:BMS with EMCA is an effective treatment strategy for the treatment of OLT and provides better cartilage infill in the defect on MRI. However, this did not translate to improved functional outcomes compared with BMS alone in the short-term.

Arthroscopic Bone Marrow Stimulation or Non-Operative Treatment for Osteochondral Lesions of the Tibial Plafond

Category:Ankle; ArthroscopyIntroduction/Purpose:A paucity of clinical results from osteochondral lesion of the tibial plafond (OLTP) treatment exists in the literature. The primary purpose of this study was therefore to compare the patient reported outcomes of OLTPs treated with arthroscopic bone marrow stimulation (BMS) and non-operative treatment. The secondary purpose was to compare the reintervention- and complication rates.Methods:Patients treated either with BMS (BMS group) or any form of non-operative treatment (non-operative group) at a minimum follow-up of 12 months were selected from a retrospective database query of patients treated between 1990 and 2020. Eligible patients were contacted by phone and cross-sectionally included. The primary outcome was the Numeric Rating Scale (NRS) during weightbearing. Secondary outcomes included; the NRS in rest, the Foot and Ankle Outcome Score (FAOS), and the Short Form Health Survey (SF-36) general health questionnaire. Additionally, the reintervention- and complication rates were collected.Results:A total of 55 patients were included, which consisted of 15 patients for the non-operative group and 40 patients for the BMS group were analyzed at a mean 73.2 +- 62.9 and 100.5 +- 72.1 months respectively (Table 1). The median NRS during weightbearing was 2 (IQR: 1-5) for the non-operative group and 1.5 (IQR: 0-4) for the BMS group (P= 0.43). The NRS in rest was, similarly, not significantly different between groups. None of the FAOS subscales were found to be significantly different between treatment groups. No reoperations or major complications after follow-up treatment were recorded.Conclusion:Clinical outcomes following arthroscopic BMS and non-operative treatment yield moderate to good clinical results in this cross-sectional cohort OLTP patients. Although this study was the first to report outcomes of non-operative treatment of OLTPs and to compare these to BMS, prospective studies are highly needed for these understudied lesions.

Effect of bone marrow stimulation on arthroscopic repair of anterior talofibular ligament

Objective: To investigate the effect of simultaneous bone marrow stimulation in the treatment of osteochondral lesions of the talus (OLTs) on arthroscopic repair of anterior talofibular ligament. Methods: The clinical data of 33 patients with ankle instability treated by operation in Sun Yat-Sen Memorial Hospital from January 2018 to December 2019 were retrospectively analyzed. There were 20 males and 13 females with a mean age of (31±9) years. According to the type of surgery, the patients were divided into two groups: ligament repair group (arthroscopic anterior talofibular ligament repair) and bone marrow stimulation group (arthroscopic anterior talofibular ligament repair+talus microfracture). Visual analogue scale (VAS), American Orthopedic Foot And Ankle Society (AOFAS) score, time to return to work and time to return to sport were compared between the two groups. Results: In the ligament repair group, the preoperative VAS score and the AOFAS score was 5.0±1.9 and 72.4±9.0, respectively, and it was 1.1±1.6 and 95.5±5.2 at the last follow-up, respectively. In the bone marrow stimulation group, the preoperative VAS score and the AOFAS score was 5.8±1.9 and 64.8±12.6, respectively, and it was 1.8±1.5 and 93.1±5.6 at the last follow-up, respectively. The scores of VAS and AOFAS were significantly improved in both groups after the operation, but there was no significant difference between the two groups (both P>0.05). There was no significant difference in time to return to work and return to sport between the two groups (both P>0.05). Conclusion: When repairing the anterior talofibular ligament under arthroscopy, simultaneous bone marrow in the treatment of osteochondral lesions of the talus does not affect the postoperative functional recovery and the time to return to work/sport, and satisfactory clinical results also can be obtained.

Effect of Systemic Administration of Granulocyte Colony-Stimulating Factor on a Chronic Partial-Thickness Cartilage Defect in a Rabbit Knee Joint.

Cartilage lesions in the knee joint can lead to joint mechanics changes and cause knee pain. Bone marrow stimulation (BMS) promotes cartilage regeneration by perforating the subchondral bone just below the injury and inducing bone marrow cells. This study aimed to investigate whether systemic administration of granulocyte colony-stimulating factor (G-CSF) with BMS improves repair of chronic partial-thickness cartilage defects (PTCDs). Eighteen 6-month-old New Zealand white rabbits were divided into 3 groups: control (C, n = 6), BMS alone (n = 6), and BMS + G-CSF (n = 6). Partial cartilage defects with 5 mm diameter were created in the trochlear region of both knees; after 4 weeks, the BMS alone and BMS + G-CSF groups underwent BMS; G-CSF (50 µg/kg) or saline was administered subcutaneously for 5 days starting from 3 days before BMS. At 8 and 16 weeks after cartilage defect creation, the area of cartilage defects was macroscopically and histologically evaluated. International Cartilage Repair Society (ICRS) grades for macroscopic assessment were 0, 0.7, and 0.7 at 8 weeks and 0, 1.2, and 1.3 at 16 weeks in the C, BMS, and BMS + G-CSF groups, respectively. Wakitani scores for histological assessment were 9.8, 8.7, and 8.2 at 8 weeks and 9.5, 9, and 8.2 at 16 weeks in the C, BMS, and BMS + G-CSF groups, respectively. The BMS + G-CSF group showed significantly more repair than the C group, but there was no difference from the BMS group. The effect of BMS and G-CSF on chronic PTCDs in mature rabbit knees was limited.

Intra-articular Injection of Bevacizumab Enhances Bone Marrow Stimulation–Mediated Cartilage Repair in a Rabbit Osteochondral Defect Model

Background: Bone marrow stimulation (BMS) via microfracture historically has been a first-line treatment for articular cartilage lesions. However, BMS has become less favorable because of resulting fibrocartilage formation. Previous studies have shown that angiogenesis blockade promotes cartilage repair. Bevacizumab is a Food and Drug Administration–approved medication used clinically to prevent angiogenesis. Hypothesis: The intra-articular injection of bevacizumab would prevent angiogenesis after BMS and lead to improved cartilage repair with more hyaline-like cartilage. Study Design: Controlled laboratory study. Methods: The dose of bevacizumab was first optimized in a rabbit osteochondral defect model with BMS. Then, 48 rabbits (n = 8/group/time point) were divided into 3 groups: osteochondral defect (defect), osteochondral defect + BMS (BMS group), and osteochondral defect + BMS + bevacizumab intra-articular injection (bevacizumab group). Rabbits were sacrificed at either 6 or 12 weeks after surgery. Three-dimensional (3D) micro–computed tomography (microCT), macroscope score, modified O’Driscoll histology scores, collagen type 2, Herovici staining, and hematoxylin and eosin staining were performed. Angiogenesis markers were also evaluated. Results: The intra-articular dose of 12.5 mg/0.5 mL bevacizumab was found to be effective without deleteriously affecting the subchondral bone. Intra-articular injection of bevacizumab resulted in significantly improved cartilage repair for the bevacizumab group compared with the BMS or the defect group based on 3D microCT, the macroscope score (both P < .05), the modified O’Driscoll histology score (P = .0034 and P = .019 vs defect and BMS groups, respectively), collagen type 2, Herovici staining, and hematoxylin and eosin staining at 6 weeks. Cartilage in the bevacizumab group had significantly more hyaline cartilage than did that in other groups. At 12 weeks, the cartilage layer regenerated in all groups; however, the bevacizumab group showed more hyaline-like morphology, as demonstrated by microCT, histology scores (P < .001 and .0225 vs defect and BMS groups, respectively), histology, and immunohistochemistry. The bevacizumab injection did not significantly change mRNA expressions of smooth muscle actin, vascular endothelial growth factor, or hypoxia-inducible factor-1 alpha. Conclusion: Intra-articular injection of bevacizumab significantly enhanced the quality and quantity of hyaline-like cartilage after BMS in a rabbit model. Future large-animal and human studies are necessary to evaluate the clinical effect of this therapy, which may lead to improved BMS outcomes and thus the durability of the regenerated cartilage. Clinical Relevance: The use of bevacizumab may be an important clinical adjunct to improve BMS-mediated cartilage repair.

Use of Extracellular Matrix Cartilage Allograft May Improve Infill of the Defects in Bone Marrow Stimulation for Osteochondral Lesions of the Talus

To evaluate the effectiveness of extracellular matrix cartilage allograft (EMCA) as an adjuvant to bone marrow stimulation (BMS) compared with BMS alone in the treatment of osteochondral lesions of the talus. A retrospective cohort study comparing patients treated with BMS with EMCA (BMS-EMCA group) and BMS alone (BMS group) between 2013 and 2019 was undertaken. Clinical outcomes were evaluated with the Foot and Ankle Outcome Score (FAOS) preoperatively and postoperatively. Postoperative magnetic resonance imaging (MRI) scans were evaluated using the modified Magnetic Resonance Observation of Cartilage Repair Tissue score. Comparisons between groups were made with the Mann-Whitney U test for continuous variables and the Fisher exact test for categorical variables. Twenty-four patients underwent BMS with EMCA (BMS-EMCA group), and 24 patients underwent BMS alone (BMS group). The mean age was 40.8 years (range, 19-60 years) in the BMS-EMCA group and 47.8 years (range, 24-60 years) in the BMS group (P= .060). The mean follow-up time was 20.0 months (range, 12-36 months) in the BMS-EMCA group and 26.9 months (range, 12-55 months) in the BMS group (P= .031). Both groups showed significant improvements in all FAOS subscales. No significant differences between groups were found in all postoperative FAOS values. The mean Magnetic Resonance Observation of Cartilage Repair Tissue score in the BMS-EMCA group was higher (76.3 vs 66.3) but not statistically significant (P= .176). The MRI analysis showed that 87.5% of the BMS-EMCA patients had complete infill of the defect with repair tissue; however, fewer than half of the BMS patients (46.5%) had complete infill (P= .015). BMS with EMCA is an effective treatment strategy for osteochondral lesions of the talus and provides better cartilage infill in the defect on MRI. However, this did not translate to improved functional outcomes compared with BMS alone in the short term. Additionally, according to analysis of the minimal clinically important difference, there was no significant difference in clinical function scoring between the 2 groups postoperatively. Level III, retrospective comparative study.

Primary Autologous Osteochondral Transfer Shows Superior Long-Term Outcome and Survival Rate Compared With Bone Marrow Stimulation for Large Cystic Osteochondral Lesion of Talus

To compare the results of bone marrow stimulation (BMS) versus autologous osteochondral transfer (AOT) as primary surgical option for large cystic osteochondral lesion of talus (OLT) and to further distinguish factors associated with clinical failures and overall survival. We retrospectively analyzed patients with symptomatic large cystic OLT (>300 mm3) who underwent either primary BMS or AOT between January 2001 and January 2016 with a minimum follow-up of 36 months. Lesion surface area and volume were measured on magnetic resonance imaging. Clinical outcomes were assessed using pain visual analog scale (VAS), American Orthopaedic Foot and Ankle Society (AOFAS) score, and Foot and Ankle Outcome Score (FAOS). Survival outcomes and factors associated with clinical failures were evaluated using Kaplan-Meier analysis and Cox regression analyses, respectively. Fifty of the total 853 patients had large cystic OLTs. Thirty-two patients underwent primary BMS, and 18 patients underwent primary AOT. Mean follow-up period was 118 months, and average lesion surface area and volume were 152.8 mm2 and 850.7 mm3, respectively. The primary AOT group showed significantly superior improvements in clinical outcomes compared with the BMS group at last follow-up (P= .001). Fourteen patients in the primary BMS group and 2 patients in the primary AOT group experienced clinical failure. Kaplan-Meier analysis showed a superior survival rate of primary AOT (P= .042). Syndesmosis widening (hazard ratio 12.361; P= .004) and large lesion surface area (hazard ratio 1.011; P= .014) were significant relative risks of clinical failure in the primary BMS group. However, lesion volume showed no significant relationship with clinical failure. Long-term results of primary AOT showed superior clinical improvements and survival rate in treating large cystic OLT. Risk factors for failure in the primary BMS group were large lesion surface area and syndesmosis widening. Retrospective comparative study LEVEL OF EVIDENCE: III.

Bone Marrow Stimulation in Arthroscopic Repair for Large to Massive Rotator Cuff Tears With Incomplete Footprint Coverage

Background: There is no research on incomplete footprint coverage with single-row repair related to bone marrow stimulation (BMS) in large to massive rotator cuff tears (RCTs). Purpose/Hypothesis: The purpose was to compare the clinical results and structural integrity between BMS and non-BMS groups that underwent arthroscopic repair of large to massive rotator cuff tears with <50% footprint coverage. It was hypothesized that both groups would exhibit improved clinical outcomes at 2 years after surgery but the BMS group would have significantly better clinical outcomes and structural integrity. Study Design: Cohort study; Level of evidence, 3. Methods: This study included 98 patients who underwent arthroscopic repair with <50% footprint coverage for large to massive RCTs with (BMS group; n = 56) or without (non-BMS group; n = 42) BMS. Functional outcomes at the 2-year follow-up were assessed using the visual analog scale for pain score, subjective shoulder value; American Shoulder and Elbow Surgeons score; University of California, Los Angeles, shoulder score; and active range of motion. Structural integrity was evaluated using magnetic resonance arthrography or computed tomography arthrography results at 6 months postoperatively. Results: At the 2-year follow-up, all functional outcomes significantly improved in both groups compared with preoperative values (P < .001). However, there were no significant postoperative differences between groups. On follow-up magnetic resonance arthrography or computed tomography arthrography, the overall retear rate was not significantly different between the BMS group (30.3%; 17/56) and the non-BMS group (35.7%; 15/42). Conclusion: While both groups exhibited functional improvement after single-row repair with <50% footprint coverage for large to massive RCTs, BMS did not produce better clinical outcomes or structural integrity.

Complex osteochondral tissue engineering

Purpose: Proper zonal organization of cartilage is important for maintaining proper functions of joint tissues. Complex tissue engineering approaches recapitulating the cartilage zonal organization have great potential in treating cartilage injuries and diseases particularly those with compromised osteochondral interface. Here, we aim to develop a stem cell-based biomaterial-assisted tissue engineered osteochondral tissue with proper zonal organization and evaluate its efficacy by comparing with bone marrow stimulation and autograft in a rabbit osteochondral defect model. Methods: Rabbit bone marrow mesenchymal stem cell were isolated and expanded before microencapsulating them in collagen biomaterials to form cell-matrix microspheres. The mesenchymal stem cells were induced to differentiate towards both the chondrogenic and the osteogenic lineages using chemically defined culture medium. The chondrogenic and the osteogenic micro-tissues so obtained were assembled to form an osteochondral tissue with proper zonal organization. A surgically induced osteochondral defect was created in the load-bearing femoral condyle of adult New Zealand rabbits before the autologous MSC-derived engineered osteochondral tissue was implanted. Osteochondral defect alone (bone marrow stimulation) and autograft were used as the control groups. The articular joint tissues were harvested at 1, 3 and 6 months post-operation for histological, biochemical and biomechanical analyses. Results: The engineered osteochondral tissue group and the autograft group showed full volume filling immediately after operation. At 1 month post-operation, the engineered osteochondral group showed excellent regeneration outcomes with type II collagen and glycosaminoglycan-rich hyaline cartilage and with partial regeneration of the tide-mark while the defect in the bone marrow stimulation (natural healing) group was still a big hole slightly filled with fibrous tissues without cartilage matrix. The autograft group showed some remodeling but was also positive for cartilage matrix. The histological characteristics of the engineered osteochondral tissues were similar to that of the autograft, with full thickness hyaline cartilage and proper osteochondral zonal organization throughout the 6 months follow up period while the natural healing group showed some regeneration particularly at 3 months post-operation but the nature of the repaired cartilage was still fibrocartilage with mixed type I and II collagen matrix. Moreover, at 6 months post-operation, the natural healing group showed obvious cartilage thinning while the engineered osteochondral tissue group and the autograft group showed nice hyaline cartilage. The O’Driscoll histological score of knees showed that the engineered osteochondral tissue group was the highest among all groups and was statistically significantly different from the bone marrow stimulation group. Biochemical compositional analysis of the cartilage tissues in various groups showed that the glycosaminoglycan to hydroxyproline (marker for collagen) ratio of the engineered osteochondral tissue group was increasing over time and was statistically similar to that of the autograft group throughout the 6 months follow up period but was statistically different than the natural healing group. Biomechanically, the aggregate modulus and the permeability of the engineered osteochondral tissues were statistically similar to that in autograft throughout the 6 months follow up period and the values were even within the 95% confidence interval of the mechanical properties of uninjured (healthy) rabbit cartilage. The natural healing group showed significantly different (lower) biomechanical properties as compared with the other groups. Conclusions: The engineered osteochondral tissue showed excellent regeneration outcomes histologically, biochemically and biomechanically and these outcomes were statistically comparable with the clinical gold standard the autograft group, throughout the 6 months follow up period. This work demonstrates the promising potential of using complex engineered osteochondral tissues for cartilage regeneration.

Biologically Regulated Marrow Stimulation by Blocking TGF-β1 With Losartan Oral Administration Results in Hyaline-like Cartilage Repair: A Rabbit Osteochondral Defect Model

Background: Microfracture or bone marrow stimulation (BMS) is often the first choice for clinical treatment of cartilage injuries; however, fibrocartilage, not pure hyaline cartilage, has been reported because of the development of fibrosis in the repair tissue. Transforming growth factor β1 (TGF-β1), which can promote fibrosis, can be inhibited by losartan and potentially be used to reduce fibrocartilage. Hypothesis: Blocking TGF-β1 would improve cartilage healing in a rabbit knee BMS model via decreasing the amount of fibrocartilage and increasing hyaline-like cartilage formation. Study Design: Controlled laboratory study. Methods: An osteochondral defect was made in the patellar groove of 48 New Zealand White rabbits. The rabbits were divided into 3 groups: a defect group (defect only), a BMS group (osteochondral defect + BMS), and a BMS + losartan group (osteochondral defect + BMS + losartan). For the rabbits in the BMS + losartan group, losartan was administrated orally from the day after surgery through the day of euthanasia. Rabbits were sacrificed 6 or 12 weeks postoperatively. Macroscopic appearance, microcomputed tomography, histological assessment, and TGF-β1 signaling pathway were evaluated at 6 and 12 weeks postoperatively. Results: The macroscopic assessment of the repair revealed that the BMS + losartan group was superior to the other groups tested. Microcomputed tomography showed superior healing of the bony defect in the BMS + losartan group in comparison with the other groups. Histologically, fibrosis in the repair tissue of the BMS + losartan group was significantly reduced when compared with the other groups. Results obtained with the modified O’Driscoll International Cartilage Repair Society grading system yielded significantly superior scores in the BMS + losartan group as compared with both the defect group and the BMS group (F value: 15.8, P < .001, P = .012, respectively). TGF-β1 signaling and TGF-β-activated kinase 1 of the BMS + losartan group were significantly suppressed in the synovial tissues. Conclusion: By blocking TGF-β1 with losartan, the repair cartilage tissue after BMS was superior to the other groups and consisted primarily of hyaline cartilage. These results should be easily translated to the clinic because losartan is a Food and Drug Administration–approved drug and it can be combined with the BMS technique for optimal repair of chondral defects. Clinical Relevance: Biologically regulated marrow stimulation by blocking TGF-β1 (oral intake of losartan) provides superior repair via decreasing fibrocartilage formation and resulting in hyaline-like cartilage as compared with outcomes from BMS only.

Evaluation of an Autologous Bone Mesenchymal Stem Cell-Derived Extracellular Matrix Scaffold in a Rabbit and Minipig Model of Cartilage Repair.

BackgroundThis study aimed to evaluate an autologous bone mesenchymal stem cell (MSC)-derived extracellular matrix (ECM) scaffold in two animal models of cartilage repair.Material/MethodsA rabbit model (n=16) and a minipig model (n=8) of cartilage repair were created with cartilage defects of the knee joints treated with bone marrow stimulation (BMS). In the ECM group, autologous bone MSC-derived ECM scaffolds were implanted into the cartilage defects after bone marrow stimulation. In the BMS group, the cartilage defects were treated by bone marrow stimulation only. The renewal capacity of bone MSCs was measured with a colony-forming unit fibroblast (CFU-F) in vitro assay. The extent of cartilage repair was as-sessed at 6 months after surgery.ResultsIn the rabbit model, the macroscopic appearance of the exudate of the healing wounds in the ECM group showed less fibrosis, and the histology showed more evenly distributed chondrocytes compared with the BMS group. The CFU-F assay showed that the number of bone MSCs in the ECM group was approximately was twice that of the BMS group. In the minipig model, the macroscopic appearance and magnetic resonance imaging (MRI) findings of the ECM group were improved when compared with the BMS group. The repaired tissue in ECM group had similar histological characteristics and biochemical content to normal hyaline cartilage.ConclusionsIn two animal models of knee joint cartilage repair, the use of an ECM scaffold increased the number of bone MSCs and improved the extent of cartilage repair.

Improvement of Cartilage Repair With Biologically Regulated Marrow Stimulation by Blocking TGF-β1 in A Rabbit Osteochondral Defect Model

Objectives: Application of growth factors for cartilage injury has been considered in recent studies; however, the effect of blocking detrimental growth factors for cartilage injury has not been well described. It is known that transforming growth factor beta 1 (TGF-β1) is overproduced in osteoarthritic joints. It has been reported that angiotensin II-induced activation of TGF-β1-pSmad2/3 signaling, which can result in fibrosis, can be inhibited by losartan (an FDA-approved hypertension drug). Although bone marrow stimulation (BMS) is often the first choice for clinical treatment of cartilage injuries, fibrocartilage, not pure hyaline cartilage, has been reported after BMS surgery. Our lab has shown that blocking TGF-β1 with losartan can decrease fibrosis in muscle injury models. We hypothesized that blocking TGF-β1 would improve cartilage healing in a rabbit osteochondral defect injury model via decreasing the amount of fibrocartilage formation, and increase hyaline-like cartilage formation, thus enhancing BMS-mediated cartilage repair. Methods: An osteochondral defect (diameter: 5 mm, depth: 2 mm) was made in the patellar groove of 48 New Zealand White rabbits. The rabbits were divided into 3 groups (N=8/group/time point) randomly: a control group (defect only), a BMS group (osteochondral defect + BMS), and a losartan-treated group (osteochondral defect + BMS + losartan). For the rabbits in the losartan-treated group, 10mg/kg/day dose of losartan was administrated orally from the day after surgery through the day of euthanasia. Rabbits were sacrificed 6 weeks and 12 weeks post-operatively, respectively. Macroscopic appearance, microcomputed tomography (microCT), histological assessment, and gene expression were evaluated. Results: The losartan-treated group scored highest in the International Cartilage Repair Society (ICRS) macroscopic assessment. MicroCT showed healing of the bony defect in the losartan-treated group, in comparison to no healing in the control group and partial healing in the BMS group. Histologically, results obtained using the Modified O’Driscoll ICRS grading system yielded significantly superior scores in the losartan-treated group compared to both the control group and the BMS group (12 weeks, mean [SD], control: 30.1 [3.6], BMS: 35.0 [3.7], losartan-treated: 41.4 [4.7]; p&lt; 0.001 compared to control group, p= 0.012 compared to BMS group, respectively). TGF-β1 signaling and TGF-β activated kinase-1 were suppressed in the fat pad tissues. Conclusion: Biologically regulated BMS by blocking TGF-β1 (oral intake of losartan) provided superior cartilage repair via decreasing fibrocartilage formation and resulting in hyaline-like cartilage, compared to outcomes from BMS only. FDA-approved blocking growth factor drugs will be a new frontier of biologically regulated BMS, which will be easily translatable into clinical settings as an off-label use. [Figure: see text]

Mosaic Osteochondral Autograft Transplantation Versus Bone Marrow Stimulation Technique as a Concomitant Procedure With Opening-Wedge High Tibial Osteotomy for Spontaneous Osteonecrosis of the Medial Femoral Condyle

To evaluate the effects of osteochondral autograft transplantation (OAT) mosaicplasty as a concomitant procedure with opening-wedge valgus high tibial osteotomy (HTO) for spontaneous osteonecrosis of the medial femoral condyle (MFC) on clinical outcomes and cartilage status in comparison with bone marrow stimulation (BMS) by drilling, and to assess the relation between lesion size and postoperative cartilage status. Fifty-eight patients with spontaneous osteonecrosis of the MFC were treated with opening-wedge HTO and a concomitant procedure of BMS (28 patients) or OAT (30 patients). Clinical evaluation was carried out using the Knee Society Score at postoperative 2years. Postoperative status of articular cartilage was assessed by arthroscopy according to the International Cartilage Repair Society (ICRS) grade at the time of plate removal. The Knee Society Score objective score and function score were improved at postoperative 2years compared with preoperative value in both groups, but no significant difference was found between the 2 groups. According to the ICRS overall repair grade, cartilage status was rated as normal or nearly normal (ICRS overall score ≥8) in 41% of the BMS group and 90% of the OAT group. The results suggested that cartilage repair in OAT was significantly better than that in BMS (P= .0015). Furthermore, the BMS group revealed that repair with normal or nearly normal was observed in all less than 4cm2 of lesion size, whereas the OAT group exhibited that repair with normal or nearly normal was independent of lesion size. This study suggested that OAT is superior to BMS as a concomitant procedure with opening-wedge valgus HTO for spontaneous osteonecrosis of the MFC in the success of cartilage repair. However, clinical outcomes were not significantly different between these 2 procedures. When treating the lesion larger than 4cm2 by joint-preserving surgery, OAT mosaicplasty is recommended as a concomitant procedure with HTO. Level III, therapeutic case-control study.

A multilayer biomaterial for osteochondral regeneration shows superiority vs microfractures for the treatment of osteochondral lesions in a multicentre randomized trial at 2 years

PurposeThe increasing awareness on the role of subchondral bone in the etiopathology of articular surface lesions led to the development of osteochondral scaffolds. While safety and promising results have been suggested, there are no trials proving the real potential of the osteochondral regenerative approach. Aim was to assess the benefit provided by a nanostructured collagen–hydroxyapatite (coll-HA) multilayer scaffold for the treatment of chondral and osteochondral knee lesions.MethodsIn this multicentre randomized controlled clinical trial, 100 patients affected by symptomatic chondral and osteochondral lesions were treated and evaluated for up to 2 years (51 study group and 49 control group). A biomimetic coll-HA scaffold was studied, and bone marrow stimulation (BMS) was used as reference intervention. Primary efficacy measurement was IKDC subjective score at 2 years. Secondary efficacy measurements were: KOOS, IKDC Knee Examination Form, Tegner and VAS Pain scores evaluated at 6, 12 and 24 months. Tissue regeneration was evaluated with MRI MOCART scoring system at 6, 12 and 24 months. An external independent agency was involved to ensure data correctness and objectiveness.ResultsA statistically significant improvement of all clinical scores was obtained from basal evaluation to 2-year follow-up in both groups, although no overall statistically significant differences were detected between the two treatments. Conversely, the subgroup of patients affected by deep osteochondral lesions (i.e. Outerbridge grade IV and OCD) showed a statistically significant better IKDC subjective outcome (+12.4 points, p = 0.036) in the coll-HA group. Statistically significant better results were also found for another challenging group: sport active patients (+16.0, p = 0.027). Severe adverse events related to treatment were documented only in three patients in the coll-HA group and in one in the BMS group. The MOCART score showed no statistical difference between the two groups.ConclusionsThis study highlighted the safety and potential of a biomimetic implant. While no statistically significant differences were found compared to BMS for chondral lesions, this procedure can be considered a suitable option for the treatment of osteochondral lesions.Level of evidenceI.

Bone marrow stimulation at the footprint of arthroscopic surface-holding repair advances cuff repair integrity

Bone marrow stimulation (BMS) at the footprint of arthroscopic rotator cuff repair has not been fully evaluated according to the preoperative tear size and surgical technique. In this study, we investigated the effect of BMS on cuff repair integrity after an arthroscopic surface-holding (ASH) repair. A total of 111 patients (mean age, 64.5 years) with chronic rotator cuff tears who underwent treatment by the ASH method with BMS by drilling of multiple holes at the footprint (67 shoulders) or without BMS (44 shoulders) were studied, and all patients were observed prospectively. Sugaya's classification was used to evaluate cuff integrity by postoperative magnetic resonance imaging, with types IV and V classified as rotator cuff retears. The mean scores for cuff integrity were 2.2 ± 0.2 and 1.7 ± 0.2 in the non-BMS and BMS groups, respectively. The mean scores were similar between the 2 groups for medium tears; however, scores for large-massive tears were significantly lower in the BMS group. The overall retear rate was 23.9% in the non-BMS group and 9.1% in the BMS group, and the distribution of repair types differed significantly. For large-massive tears, the retear rate was much higher in the non-BMS group (28.6%) than in the BMS group (4.5%), although the rates for medium tears were comparable between the 2 groups. These findings demonstrate that applying BMS to the footprint during ASH repair results in improved cuff repair integrity, particularly in large-massive tears, and suggest the importance of biologic treatment for rotator cuff healing after arthroscopic rotator cuff repair.

An Autologous Bone Marrow Mesenchymal Stem Cell–Derived Extracellular Matrix Scaffold Applied with Bone Marrow Stimulation for Cartilage Repair

It is well known that implanting a bioactive scaffold into a cartilage defect site can enhance cartilage repair after bone marrow stimulation (BMS). However, most of the current scaffolds are derived from xenogenous tissue and/or artificial polymers. The implantation of these scaffolds adds risks of pathogen transmission, undesirable inflammation, and other immunological reactions, as well as ethical issues in clinical practice. The current study was undertaken to evaluate the effectiveness of implanting autologous bone marrow mesenchymal stem cell-derived extracellular matrix (aBMSC-dECM) scaffolds after BMS for cartilage repair. Full osteochondral defects were performed on the trochlear groove of both knees in 24 rabbits. One group underwent BMS only in the right knee (the BMS group), and the other group was treated by implantation of the aBMSC-dECM scaffold after BMS in the left knee (the aBMSC-dECM scaffold group). Better repair of cartilage defects was observed in the aBMSC-dECM scaffold group than in the BMS group according to gross observation, histological assessments, immunohistochemistry, and chemical assay. The glycosaminoglycan and DNA content, the distribution of proteoglycan, and the distribution and arrangement of type II and I collagen fibers in the repaired tissue in the aBMSC-dECM scaffold group at 12 weeks after surgery were similar to that surrounding normal hyaline cartilage. Implanting aBMSC-dECM scaffolds can enhance the therapeutic effect of BMS on articular cartilage repair, and this combination treatment is a potential method for successful articular cartilage repair.