Celeste Scotti

Mesenchymal stem/stromal cells (MSC) are typically used to generate bone tissue by a process resembling intramembranous ossification, i.e., by direct osteoblastic differentiation. However, most bones develop by endochondral ossification, i.e., via remodeling of hypertrophic cartilaginous templates. To date, endochondral bone formation has not been reproduced using human, clinically compliant cell sources. Here, we aimed at engineering tissues from bone marrow-derived, adult human MSC with an intrinsic capacity to undergo endochondral ossification. By analogy to embryonic limb development, we hypothesized that successful execution of the endochondral program depends on the initial formation of hypertrophic cartilaginous templates. Human MSC, subcutaneously implanted into nude mice at various stages of chondrogenic differentiation, formed bone trabeculae only when they had developed in vitro hypertrophic tissue structures. Advanced maturation in vitro resulted in accelerated formation of larger bony tissues. The underlying morphogenetic process was structurally and molecularly similar to the temporal and spatial progression of limb bone development in embryos. In particular, Indian hedgehog signaling was activated at early stages and required for the in vitro formation of hypertrophic cartilage. Subsequent development of a bony collar in vivo was followed by vascularization, osteoclastic resorption of the cartilage template, and appearance of hematopoietic foci. This study reveals the capacity of human MSC to generate bone tissue via an endochondral program and provides a valid model to study mechanisms governing bone development. Most importantly, this process could generate advanced grafts for bone regeneration by invoking a "developmental engineering" paradigm.

Embryonic development, lengthening, and repair of most bones proceed by endochondral ossification, namely through formation of a cartilage intermediate. It was previously demonstrated that adult human bone marrow-derived mesenchymal stem/stromal cells (hMSCs) can execute an endochondral program and ectopically generate mature bone. Here we hypothesized that hMSCs pushed through endochondral ossification can engineer a scaled-up ossicle with features of a "bone organ," including physiologically remodeled bone, mature vasculature, and a fully functional hematopoietic compartment. Engineered hypertrophic cartilage required IL-1β to be efficiently remodeled into bone and bone marrow upon subcutaneous implantation. This model allowed distinguishing, by analogy with bone development and repair, an outer, cortical-like perichondral bone, generated mainly by host cells and laid over a premineralized area, and an inner, trabecular-like, endochondral bone, generated mainly by the human cells and formed over the cartilaginous template. Hypertrophic cartilage remodeling was paralleled by ingrowth of blood vessels, displaying sinusoid-like structures and stabilized by pericytic cells. Marrow cavities of the ossicles contained phenotypically defined hematopoietic stem cells and progenitor cells at similar frequencies as native bones, and marrow from ossicles reconstituted multilineage long-term hematopoiesis in lethally irradiated mice. This study, by invoking a "developmental engineering" paradigm, reports the generation by appropriately instructed hMSC of an ectopic "bone organ" with a size, structure, and functionality comparable to native bones. The work thus provides a model useful for fundamental and translational studies of bone morphogenesis and regeneration, as well as for the controlled manipulation of hematopoietic stem cell niches in physiology and pathology.

OBJECTIVE: The purpose of our study was to determine the effectiveness of cartilage repair utilizing 1-step surgery with bone marrow aspirate concentrate (BMAC) and a collagen I/III matrix (Chondro-Gide, Geistlich, Wolhusen, Switzerland). MATERIALS AND METHODS: We prospectively followed up for 2 years 15 patients (mean age, 48 years) who were operated for grade IV cartilage lesions of the knee. Six of the patients had multiple chondral lesions; the average size of the lesions was 9.2 cm(2). All patients underwent a mini-arthrotomy and concomitant transplantation with BMAC covered with the collagen matrix. Coexisting pathologies were treated before or during the same surgery. X-rays and MRI were collected preoperatively and at 1 and 2 years' follow-up. Visual analog scale (VAS), International Knee Documentation Committee (IKDC), Knee injury and Osteoarthritis Outcome Score (KOOS), Lysholm, Marx, SF-36 (physical/mental), and Tegner scores were collected preoperatively and at 6, 12, and 24 months' follow-up. Four patients gave their consent for second-look arthroscopy and 3 of them for a concomitant biopsy. RESULTS: Patients showed significant improvement in all scores at final follow-up (P < 0.005). Patients presenting single lesions and patients with small lesions showed higher improvement. MRI showed coverage of the lesion with hyaline-like tissue in all patients in accordance with clinical results. Hyaline-like histological findings were also reported for all the specimens analyzed. No adverse reactions or postoperative complications were noted. CONCLUSION: This study showed that 1-step surgery with BMAC and collagen I/III matrix could be a viable technique in the treatment of grade IV knee chondral lesions.

BACKGROUND: Rotator cuff repair typically results in a satisfactory, although variable, clinical outcome. However, anatomic failure of the repaired tendon often occurs. HYPOTHESIS: Patch augmentation can improve the results of open rotator cuff repair by supporting the healing process, protecting the suture, and reducing friction in the subacromial space. STUDY DESIGN: Cohort study; Level of evidence, 3. METHODS: A total of 152 patients with a posterosuperior massive rotator cuff tear were treated by open repair only (control group; n = 51; mean age, 67.06 ± 4.42 years), open repair together with collagen patch augmentation (collagen group; n = 49; mean age, 66.53 ± 5.17 years), or open repair together with polypropylene patch augmentation (polypropylene group; n = 52; mean age, 66.17 ± 5.44 years) and were retrospectively studied. Patients were evaluated preoperatively and after 36 months with a visual analog scale (VAS) and the University of California, Los Angeles (UCLA) shoulder rating scale and by measuring elevation of the scapular plane and strength with a dynamometer. The VAS and UCLA scores were also obtained 2 months postoperatively. Tendon integrity was assessed after 1 year by ultrasound. Patients were homogeneous as per the preoperative assessment. RESULTS: After 2 months, results (mean ± standard deviation) for the control, collagen, and polypropylene groups, respectively, were as follows: VAS scores were 6.96 ± 1.11, 6.46 ± 1.02, and 4.92 ± 0.90, while UCLA scores were 11.29 ± 1.46, 11.40 ± 1.51, and 19.15 ± 1.99. After 36 months, the mean scores for the respective groups were 3.66 ± 1.05, 4.06 ± 1.02, and 3.28 ± 1.10 for the VAS and 14.88 ± 1.98, 14.69 ± 1.99, and 24.61 ± 3.22 for the UCLA scale. In addition, after 36 months, elevation on the scapular plane was 140.68° ± 9.84°, 140.61° ± 12.48°, and 174.71° ± 8.18°, and abduction strength was 8.73 ± 0.54 kg, 9.03 ± 0.60 kg, and 13.79 ± 0.64 kg for the control, collagen, and polypropylene groups, respectively. The retear rate after 12 months was 41% (21/51) for the control group, 51% (25/49) for the collagen group, and 17% (9/52) for the polypropylene group. In particular, the reduced 12-month retear rate and the increased UCLA scores, abduction strength, and elevation at 3-year follow-up were statistically significant for patients treated with a polypropylene patch compared with those treated with repair only or with a collagen patch. CONCLUSION: Polypropylene patch augmentation of rotator cuff repair was demonstrated to significantly improve the 36-month outcome in terms of function, strength, and retear rate.

Background: Osteoarthritis is a common inflammatory disorder with no disease-modifying therapies. Whether inhibition of interleukin-1β (IL-1β) can reduce the consequences of large joint osteoarthritis is unclear. Objective: To determine whether IL-1β inhibition with canakinumab reduces incident total hip or knee replacement (THR/TKR). Design: Exploratory analysis of a randomized trial. (ClinicalTrials.gov: NCT01327846) Setting: 1091 clinical sites in 39 countries. Participants: 10 061 CANTOS (Canakinumab Anti-inflammatory Thrombosis Outcomes Study) participants. Intervention: Random allocation to placebo or canakinumab (50, 150, or 300 mg) subcutaneously once every 3 months. Measurements: The primary and secondary outcomes were time to first incident THR/TKR and time to first occurrence of an osteoarthritis-related adverse event (AE). Data were obtained through blinded ascertainment of trial clinical and safety databases. Results: Median follow-up was 3.7 years. For the individual canakinumab dose groups, compared with placebo, hazard ratios (HRs) for incident THR/TKR during follow-up were 0.60 (95% CI, 0.38 to 0.95) for the 50-mg group, 0.53 (CI, 0.33 to 0.84) for the 150-mg group, and 0.60 (CI, 0.38 to 0.93) for the 300-mg group. Thus, in the pooled canakinumab groups, compared with the placebo group, incidence rates for THR/TKR were 0.31 and 0.54 events per 100 person-years (HR, 0.58 [CI, 0.42 to 0.80]; P = 0.001), respectively. The HR for the secondary end point of osteoarthritis-related AEs was 0.73 (CI, 0.61 to 0.87). Similar findings were observed in analyses restricted to participants with a history of osteoarthritis. Limitation: Because the parent trial was not designed to examine the efficacy of IL-1β inhibitors in osteoarthritis, information on structural joint outcomes was not collected. Conclusion: Findings from this exploratory analysis of a randomized controlled trial support further investigation of IL-1β inhibition for treatment of large joint osteoarthritis. Primary Funding Source: Novartis Pharmaceuticals.