An engineered periosteum for efficient delivery of rhBMP-2 and mesenchymal progenitor cells during bone regeneration.

During bone regeneration, the periosteum acts as a carrier for key regenerative cues, delivering osteochondroprogenitor cells and crucial growth factors to the injured bone. We developed a biocompatible, 3D polycaprolactone (PCL) melt electro-written membrane to act as a mimetic periosteum. Poly (ethyl acrylate) coating of the PCL membrane allowed functionalization, mediated by fibronectin and low dose recombinant human BMP-2 (rhBMP-2) (10-25 µg/ml), resulting in efficient, sustained osteoinduction in vitro. In vivo, rhBMP-2 functionalized mimetic periosteum demonstrated regenerative potential in the treatment of rat critical-size femoral defects with highly efficient healing and functional recovery (80%-93%). Mimetic periosteum has also proven to be efficient for cell delivery, as observed through the migration of transplanted periosteum-derived mesenchymal cells to the bone defect and their survival. Ultimately, mimetic periosteum demonstrated its ability to deliver key stem cells and morphogens to an injured site, exposing a therapeutic and translational potential in vivo when combined with unprecedentedly low rhBMP-2 doses.

CC-Chemokine Receptor-2 Expression in Osteoblasts Contributes to Cartilage and Bone Damage during Post-Traumatic Osteoarthritis.

In osteoarthritis (OA), bone changes are radiological hallmarks and are considered important for disease progression. The C-C chemokine receptor-2 (CCR2) has been shown to play an important role in bone physiology. In this study, we investigated whether Ccr2 osteoblast-specific inactivation at different times during post-traumatic OA (PTOA) progression improves joint structures, bone parameters, and pain. We used a tamoxifen-inducible Ccr2 inactivation in Collagen1α-expressing cells to obtain osteoblasts lacking Ccr2 (CCR2-Col1αKO). We stimulated PTOA changes in CCR2-Col1αKO and CCR2+/+ mice using the destabilization of the meniscus model (DMM), inducing recombination before or after DMM (early- vs. late-inactivation). Joint damage was evaluated at two, four, eight, and twelve weeks post-DMM using multiple scores: articular-cartilage structure (ACS), Safranin-O, histomorphometry, osteophyte size/maturity, subchondral bone thickness and synovial hyperplasia. Spontaneous and evoked pain were assessed for up to 20 weeks. We found that early osteoblast-Ccr2 inactivation delayed articular cartilage damage and matrix degeneration compared to CCR2+/+, as well as DMM-induced bone thickness. Osteophyte formation and maturation were only minimally affected. Late Collagen1α-Ccr2 deletion led to less evident improvements. Osteoblast-Ccr2 deletion also improved static measures of pain, while evoked pain did not change. Our study demonstrates that Ccr2 expression in osteoblasts contributes to PTOA disease progression and pain by affecting both cartilage and bone tissues.

Sustained inhibition of CC-chemokine receptor-2 via intraarticular deposition of polymeric microplates in post-traumatic osteoarthritis.

Posttraumatic osteoarthritis (PTOA) is mostly treated via corticosteroid administration, and total joint arthroplasty continues to be the sole effective intervention in severe conditions. To assess the therapeutic potential of CCR2 targeting in PTOA, we used biodegradable microplates (µPLs) to achieve a slow and sustained intraarticular release of the CCR2 inhibitor RS504393 into injured knees and followed joint damage during disease progression. RS504393-loaded µPLs (RS-µPLs) were fabricated via a template-replica molding technique. A mixture of poly(lactic-co-glycolic acid) (PLGA) and RS504393 was deposited into 20 × 10 µm (length × height) wells in a polyvinyl alcohol (PVA) square-patterned template. After physicochemical and toxicological characterizations, the RS504393 release profile from µPL was assessed in PBS buffer. C57BL/6 J male mice were subjected to destabilization of the medial meniscus (DMM)/sham surgery, and RS-µPLs (1 mg/kg) were administered intraarticularly 1 week postsurgery. Administrations were repeated at 4 and 7 weeks post-DMM. Drug free-µPLs (DF-µPLs) and saline injections were performed as controls. Mice were euthanized at 4 and 10 weeks post-DMM, corresponding to the early and severe PTOA stages, respectively. Knees were evaluated for cartilage structure score (ACS, H&E), matrix loss (safranin O score), osteophyte formation and maturation from cartilage to bone (cartilage quantification), and subchondral plate thickness. The RS-µPL architecture ensured the sustained release of CCR2 inhibitors over several weeks, with ~ 20% of RS504393 still available at 21 days. This prolonged release improved cartilage structure and reduced bone damage and synovial hyperplasia at both PTOA stages. Extracellular matrix loss was also attenuated, although with less efficacy. The results indicate that local sustained delivery is needed to optimize CCR2-targeted therapies.

Osteosintesis asistida con navegación 2D con tornillos iliacosacros percutáneos en lesiones del anillo pélvico posterior / Assisted osteosynthesis with 2D navigation with percutaneous iliacosacral screws in posterior pelvic ring injuries

Introducción: La osteosíntesis percutánea sacroiliaca guiada por radioscopia en lesiones del anillo pélvico posterior sigue siendo la técnica de referencia. Sin embargo, el desarrollo de técnicas como la cirugía asistida por navegación 2D/3D o por tomografía han mejorado la facilidad y seguridad en la colocación de los tornillos. Objetivo: Presentar la técnica de fijación asistida por navegación en 2D y los resultados clínicos y radiológicos obtenidos. Materiales y métodos: Se revisaron 23 pacientes con disrupción del anillo pélvico posterior (luxación y/o fractura sacroiliaca) intervenidos mediante fijación percutánea asistida por navegación 2D (Sistema Synergy de Medtronic®) en el hospital desde 2017 hasta la actualidad. Se recogieron variables demográficas, de clasificación, terapéuticas y las complicaciones derivadas. Se utilizó la escala modificada de valoración POS (Multicenter Study Group Pelvis Outcome Scale) para evaluar el resultado clínico, radiológico y social. Resultados: Ocho pacientes presentaban luxación sacro-iliaca y 15 tenían fractura a través del sacro. Se implantaron 40 tornillos iliacosacros. El tiempo quirúrgico medio fue de 20 minutos para cada tornillo. Fueron necesarios ocho pulsos de radioscopia de media por intervención. Hubo tres tornillos (7.5%) mal posicionados. 15 pacientes obtuvieron un resultado bueno o excelente en el formulario POS. Conclusiones: La técnica asistida por navegación es una alternativa con buenos resultados. Facilita al cirujano la colocación correcta de los tornillos en el corredor óseo sacro, acortando el tiempo quirúrgico y con una menor exposición a radiaciones ionizantes. Es útil para todo tipo de lesiones del anillo y cuando son necesarias maniobras de reducción.

Introduction: Radioscopy-guided percutaneous sacroiliac osteosynthesis in posterior pelvic ring lesions continues to be the reference technique. However, the development of techniques such as surgery assisted by 2D/3D navigation or tomography have improved the ease and safety in screw placement. Objective: To present the 2D navigation-assisted fixation technique and the clinical and radiological results obtained. Materials and methods: 23 patients with disruption of the posterior pelvic ring (dislocation and/or sacroiliac fracture) who underwent percutaneous fixation assisted by 2D navigation (Medtronic® Synergy System) at the hospital from 2017 to the present were reviewed. Demographic, classification, therapeutic variables and resulting complications were collected. The modified POS (Multicenter Study Group Pelvis Outcome Scale) assessment scale was used to evaluate the clinical, radiological and social outcome. Results: Eight patients had sacro-iliac dislocation and 15 had a fracture through the sacrum. 40 iliacosacral screws were implanted. The average surgical time was 20 minutes for each screw. An average of eight fluoroscopy pulses were necessary per intervention. There were three screws (7.5%) incorrectly positioned. 15 patients had a good or excellent result on the POS form. Conclusions: The navigation-assisted technique is an alternative with good results. It makes it easier for the surgeon to correctly place the screws in the sacral bone corridor, shortening surgical time and with less exposure to ionizing radiation. It is useful for all types of ring injuries and when reduction maneuvers are necessary.

Molecular and Cellular Mechanisms of Delayed Fracture Healing in Mmp10 (Stromelysin 2) Knockout Mice.

The remodeling of the extracellular matrix is a central function in endochondral ossification and bone homeostasis. During secondary fracture healing, vascular invasion and bone growth requires the removal of the cartilage intermediate and the coordinate action of the collagenase matrix metalloproteinase (MMP)-13, produced by hypertrophic chondrocytes, and the gelatinase MMP-9, produced by cells of hematopoietic lineage. Interfering with these MMP activities results in impaired fracture healing characterized by cartilage accumulation and delayed vascularization. MMP-10, Stromelysin 2, a matrix metalloproteinase with high homology to MMP-3 (Stromelysin 1), presents a wide range of putative substrates identified in vitro, but its targets and functions in vivo and especially during fracture healing and bone homeostasis are not well defined. Here, we investigated the role of MMP-10 through bone regeneration in C57BL/6 mice. During secondary fracture healing, MMP-10 is expressed by hematopoietic cells and its maximum expression peak is associated with cartilage resorption at 14 days post fracture (dpf). In accordance with this expression pattern, when Mmp10 is globally silenced, we observed an impaired fracture-healing phenotype at 14 dpf, characterized by delayed cartilage resorption and TRAP-positive cell accumulation. This phenotype can be rescued by a non-competitive transplant of wild-type bone marrow, indicating that MMP-10 functions are required only in cells of hematopoietic linage. In addition, we found that this phenotype is a consequence of reduced gelatinase activity and the lack of proMMP-9 processing in macrophages. Our data provide evidence of the in vivo function of MMP-10 during endochondral ossification and defines the macrophages as the lead cell population in cartilage removal and vascular invasion. © 2021 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

Periosteum-derived mesenchymal progenitor cells in engineered implants promote fracture healing in a critical-size defect rat model.

An attractive alternative to bone autografts is the use of autologous mesenchymal progenitor cells (MSCs) in combination with biomaterials. We compared the therapeutic potential of different sources of mesenchymal stem cells in combination with biomaterials in a bone nonunion model. A critical-size defect was created in Sprague-Dawley rats. Animals were divided into six groups, depending on the treatment to be applied: bone defect was left empty (CTL); treated with live bone allograft (LBA); hrBMP-2 in collagen scaffold (CSBMP2 ); acellular polycaprolactone scaffold (PCL group); PCL scaffold containing periosteum-derived MSCs (PCLPMSCs ) and PCL containing bone marrow-derived MSCs (PCLBMSCs ). To facilitate cell tracking, both MSCs and bone graft were isolated from green fluorescent protein (GFP)-transgenic rats. CTL group did not show any signs of healing during the radiological follow-up (n = 6). In the LBA group, all the animals showed bone bridging (n = 6) whereas in the CSBMP2 group, four out of six animals demonstrated healing. In PCL and PCLPMSCs groups, a reduced number of animals showed radiological healing, whereas no healing was detected in the PCLBMSCs group. Using microcomputed tomography, the bone volume filling the defect was quantified, showing significant new bone formation in the LBA, CSBMP2 , and PCLPMSCs groups when compared with the CTL group. At 10 weeks, GFP positive cells were detected only in the LBA group and restricted to the outer cortical bone in close contact with the periosteum. Tracking of cellular implants demonstrated significant survival of the PMSCs when compared with BMSCs. In conclusion, PMSCs improve bone regeneration being suitable for mimetic autograft design.

Alteraciones electroencefalográficas en la enfermedad de Parkinson / Electroencefalographic changes in Parkinson's disease

Se estudió un grupo de 55 pacientes con enfermedad de Parkinson, de ambos sexos, con edad media de 62,9 años, largo tiempo de evolución de su enfermedad y todos en estadio II. Se dividió la muestra en 2 grupos (1 y 2), según estuvieran o no tratados con L-Dopa. No se encontraron diferencias globales en la aparición de alteraciones electroencefalográficas entre ambos, a excepción de una mayor incidencia del ritmo alfa en los pacientes del grupo 1 y la presencia de artefactos mecanográficos del temblor sólo en el 2. Hubo alteraciones del EEG en el 54,9 % de los pacientes, dadas por actividad lenta difusa en el 13,7, actividad theta focal en el 25,5, activida theta generalizada en el 9,8 y actividad paroxística sólo en el 5,9 %. Hubo cambios patológicos con la hiperventilación (HPV) en el 23,5 % de los pacientes. Se discuten las capacidades de la L-Dopa en la estabilización del ritmo alfa y en el control del temblor en los pacientes estudiados (AU)

Alteraciones electroencefalográficas en la enfermedad de Parkinson / Electroencefalographic changes in Parkinson's disease

Se estudió un grupo de 55 pacientes con enfermedad de Parkinson, de ambos sexos, con edad media de 62,9 años, largo tiempo de evolución de su enfermedad y todos en estadio II. Se dividió la muestra en 2 grupos (1 y 2), según estuvieran o no tratados con L-Dopa. No se encontraron diferencias globales en la aparición de alteraciones electroencefalográficas entre ambos, a excepción de una mayor incidencia del ritmo alfa en los pacientes del grupo 1 y la presencia de artefactos mecanográficos del temblor sólo en el 2. Hubo alteraciones del EEG en el 54,9 % de los pacientes, dadas por actividad lenta difusa en el 13,7, actividad theta focal en el 25,5, activida theta generalizada en el 9,8 y actividad paroxística sólo en el 5,9 %. Hubo cambios patológicos con la hiperventilación (HPV) en el 23,5 % de los pacientes. Se discuten las capacidades de la L-Dopa en la estabilización del ritmo alfa y en el control del temblor en los pacientes estudiados