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I. Roato,D. C. Belisario, M.Compagno, A. Lena, A. Bistolfi, L. Maccari, F. Mussano, T. Genova, L. Godio, G. Perale, M. Formica, I. Cambieri, C. Castagnoli, T. Robba, L. Felli, R. Ferracini
Osteoarthritis (OA) is characterized by articular cartilage degeneration and subchondral bone sclerosis. OA can benefit of non-surgical treatments with collagenase-isolated stromal vascular fraction (SVF) or cultured-expanded mesenchymal stem cells (ASCs). To avoid high manipulation of the lipoaspirate needed to obtain ASCs and SVF, we investigated whether articular infusions of autologous concentrated adipose tissue are an effective treatment for knee OA patients.
G. Perale, C. F. Grottoli, S. Molinari, G. Pertici, A. Bistolfi, R. Ferracini
Bone grafts for reconstructive surgery should ensure both volumetric stability and adequate strength. Moreover, their intimate structure should have an adequate open and interconnected porous network for cell migration and proliferation and vessel ingrowth, with a distributed pore size ranging between 50 to 350 m, while also providing specific signals for bone regeneration and remodelling [1,2,3].
An innovative composite solution, inspired by natural bone architecture and bearing cues from both mineral components and polymeric ones, was here followed to develop a three-dimensional bone scaffold, SmartBone®: a bovine derived mineral matrix is used to provide adequate solid structure and porosity, while resorbable polymers are used to reinforce it. RGD-exposing collagen fragments are finally added to promote cell colonization and proliferation. Previously published clinical results indicate that SB is osteoconductive and osteoinductive, promoting remodelling to mature bone formation in about 8-12 months .
Results and Discussion
These composite bone substitutes have been successfully grafted onto more than 50’000 patients up-to-day: the high performances of this biomaterial allow its current use in different specialities, including orthopaedic reconstructive applications.
Above pictures present an example of a reconstruction case: a twin tibial and fibula traumatic injury in an adult male. Capability to withstand heavy surgical manoeuvres, allowed SmartBone® blocks to be easily adapted to fit the residual defect and perfectly located inside the gap, being finally firmly fixed with osteosynthesis devices.
Surgery was fast and precise, allowing to obtain satisfactory results both in terms of anatomical reconstruction and functionality preservation. The post-operative follow-up recorded no issues of any kind and proceeded 2
optimally, evidencing a faster healing and rapidly decreasing patient pain together with mobility recovery: restored anatomy and functionality found confirmation from 6 months post-op the radiographic images, which showed complete volume stability and already ongoing graft remodelling process.
Radiologically evaluated bone density analysis indicates, in extremely good agreement with past histological studies, that SmartBone is osteoinductive and osteoconductive: it promotes fast bone regeneration, finally leading to mature bone formation in shorter time-windows with respect to alternative solutions such as synthetic materials and allografts, thus confirming the validity of the endogenous tissue restoration principle.
R. Piana, M. Boffano, P. Pellegrino, N. Ratto, L. Rossi, G. Perale
INTRODUCTION – Chondrosarcomas (CS) are bone and less frequently soft tissues tumors, composed of pathologically transformed chondrocytes. CS represent about 30% of all bone cancers and are known to be aggressive and poorly responsive to chemotherapy and radiotherapy. Surgery is hence the election approach, which, in big limb-located masses, might in some cases lead to amputation (1). Within a clinical study, we developed a fixation–free surgical technique to treat femoral CS, ensuring both immediate loading and robust bone regeneration.
METHODS – A 44-yrs old female was diagnosed with I grade CS of left proximal femur that had spared the external cortical lamina (fig. 1). A window made with the intact cortical lamina, opened as a flap, was used to access tumor, where a deep lesion curettage was performed. The accurately cleaned cavity was then filled with SmartBone® (SB) blocks (I.B.I. SA, Switzerland) and finally the cortical lamina was closed back in position (fig 2). SB is a biohybrid bone graft, composed of a bovine-derived mineral porous matrix, reinforced with resorbable polymers and functionalized with RGD-containing collagen fragments (2). Compact positioning of duly shaped SB blocks within void volume, along major stress directions, together with SB high mechanical properties, allowed avoiding fixation devices.
RESULTS – Surgical follow-up proceeded well and neither complications nor pain nor site morbidity were recorded. Clinical recovery allowed immediate progressive load bearing until reaching complete functional restoration in short time. SB grafts osteointegration and bone remodelling process were well evidenced by X-rays imagining already after 3 months follow-up (fig. 3): increasing bone density and good mineralization were visible and comparable to control healthy district.
DISCUSSION & CONCLUSIONS – This new approach to low invasiveness bone reconstruction post CS curettage in the proximal femur was made possible thanks to surgical approach saving healthy cortical lamina and precise positioning of SB within cavity along major stress directions, together with biomaterial high mechanical performances. Moreover, preserving the closed environment of the clean cavity acted as a “living bioreactor”, enhancing SB integration and remodelling, favoured by immediate load bearing. This meant faster overall recovery, already evident after 3 months post-op, and better patient outcome, also for the avoidance of a second surgery for osteosynthesis removal.
E. Facciuto, C. F. Grottoli, M. Mattarocci, F. Illiano, G. Pertici, G. Perale
Objectives: custom-made bone grafting to reconstruct cranio-facial defect due to past osteoma removal
Methods: Grafts for bone reconstruction should ensure both mechanical strength and volumetric stability. Their structure should have adequate interconnected porosity for cell migration and proliferation, while providing specific signals for bone remodeling and regeneration.
An innovative composite solution, bearing cues from both mineral components and polymeric ones, was here followed to develop a new three-dimensional bone scaffold, SmartBone® (SB): a bovine derived mineral matrix is used to provide adequate solid structure and porosity, while resorbable polymers are used to reinforce it. RGD-exposing collagen fragments are finally added to promote cell colonization and proliferation. Previously published results indicate that SB is osteoconductive and osteoinductive, promoting remodeling to mature bone formation in about 8-12 months av.
High performances of this biomaterial allowed developing custom-made products (a.k.a. SmartBone® On Demand™, SBoD), solving single specific cases of bone reconstruction: starting from CT scan, personalized grafts can be provided for every kind of defects.
This technology was successfully applied to a custom reconstruction of frontal bone and supraorbital foramen in a 30-years old male: twelve customized grafts were designed in order to fill the complex cavity of the defect, using a puzzle technique with SBoD . During surgery, each piece was perfectly located inside the gap and firmly fixed with small osteosynthesis titanium screws. Surgery was fast (<3 hrs) and very precise, allowing to obtain very satisfactory results both in terms of anatomical reconstruction and functionality. The post-operative follow-up recorded no issues of any kind and proceeded optimally.
Results: CT scan after 10 months showed impressive osteointegration and massive volume stability (>95%).
Conclusion: SBoD custom made bone grafting technique allows complete restoration of wide defects.
A. Schiavo, M. Samorì, C. Apicella
La colocación de implantes, en caso de reabsorción alveolar horizontal avanzada, es un desafío bien comprendido y reconocido que influye significativamente en el exito del tratamiento. Las técnicas de aumento del reborde alveolar toman en cuenta de principios mecánicos y físicos básicos para mejorar el potencial regenerativo del huésped. Estudios clínicos y experimentales han evaluado la colocación de diversos materiales de injerto óseo para aumentar los rebordes alveolares atróficos a fin de permitir la instalación de implantes y se han convertido en los tratamientos vectores de la odontología implantaria. En casos de defectos óseos de clase I por Seibert (pérdida de la dimensión vestibulolingual, conservando una dimensión corono apical normal de la cresta) está indicado un procedimiento de regeneración diferida y suele aconsejarse un injerto en bloque con membrana de barrera para asegurar el mantenimiento de suficiente espacio que permita un aumento horizontal importante. El utilizo de Injertos autologos ha sido y sigue siendo el “GOLD STANDARD” en los procedimientos de aumento del reborde alveolar en las técnicas de ROG, debido a sus potenciales propiedades osteogenicas, osteoinductivas y osteoconductivas. Actualmente pero el uso de autoinjertos esta limitado debido a la morbilidad asociada a su recolección, las posibles complicaciones asociadas al sitio donante, la dimensión limitada del injerto y su tasa elevada de reabsorción que requiere la colocación temprana de los implantes.
G. Pertici, D. D’Alessandro, S. Danti, M. Milazzo and G. Perale
Lo scaffold ideale per la rigenerazione ossea deve essere altamente poroso, non immunogenico, osteoconduttivo, bioriassorbibile ma sufficientemente stabile fino alla formazione di neo-tessuto osseo. Questo studio ha avuto come obiettivo quello di indagare, attraverso l’analisi istologica, il processo di neoformazione ossea in pazienti trattati con SmartBone granulare a seguito di interventi di aumento del seno mascellare. Sono state raccolte cinque biopsie in un intervallo da 4 a 9 mesi dopo l’impianto dello scaffold; successivamente sono state processate per analisi istochimica ed immunoistochimica, ed infine analisi istomorfometrica. Il Bone-particle conductivity index (BPCi) è stato utilizzato per valutare l’osteoconduttività dello scaffold. A 4 mesi, erano presenti sia lo scaffold (12%), che nuova matrice ossea (43,9%), entrambi circondati da tessuto connettivo vascolarizzato (37,2%). E’ stata evidenziata generazione di nuovo osso è in contatto con lo scaffold (BPCi = 0,22). A 6 mesi, SmartBone risultava quasi completamente riassorbito (0,5%) e il nuovo osso era visibile in maniera massiccia (80,8%). A 7 e 9 mesi il neo-osso formato rappresentava una grande porzione volumetrica (rispettivamente 79,3% e 67,4%), mentre il riassorbimento dello scaffold è stato pressoché totale (rispettivamente 0,5% e 0%). Si osservavano infatti lamelle ben orientate e cicatrici ossee tipiche dell’osso maturo. In tutte le biopsie, erano presenti biomolecole della matrice ossea ed osteoblasti visibilmente attivi. L’assenza di cellule infiammatorie ha confermato la biocompatibilità e la non-immunogenicità di SmartBone. Questi dati indicano che SmartBone è osteoconduttivo, che promuove una veloce rigenerazione ossea e che porta alla formazione di osso maturo in circa 7 mesi.
B. Michele, R. Nicola, P. Pietro, M. Stefano, F. Andrea, B. Elena. A.Ugo, P. Raimondo
OBJECTIVE Several synthetic bone grafts are now available. Each graft has its own specific properties. SmartBone ®(IBI, S.A., Switzerland) is produced by combining natural bovine bone mineral structures with bioresorbable polymers and cell nutrients. The aim of the study is to evaluate both structural and biological short term properties and its reliability in orthopedic oncology
STUDY DESIGN retrospective study
METHODS In the period October 2016-October 2017 in an Italian Reference centre for bone and soft tissue tumors 11 patients (age range 19-68ys) with bone tumors were treated and the bone gap was filled in with Smartbone. The diagnosis were: chondrosarcoma (3), giant cell tumor (GCT,1), enchondroma (3), benign fibrous histiocytoma (1), bone cyst (3). A follow up was conducted for a minimum of 4 months (range 4-16 months) with X-ray to evaluate graft integration and eventually with CT or MRI in case of possible local recurrence. Complications (infection, recurrence, fracture, early resorption) were also investigated.
RESULTS No infection and no fractures were observed. One local recurrence in a patellar GCT occurred after 12 months. Two cases of wound dehiscence occurred requiring advanced dressing or flap covering with no further secondary complications. The periodic X-ray showed a good to excellent graft integration in all patients within 10 weeks.
CONCLUSIONS Preliminary results of grafting bone lesions with Smartbone are satisfying. Graft integration occurred with no complications or inflammatory reaction in the surrounding tissues. Smartbone has also a structural function allowing an early weight-bearing in lower limb lesions. Prospective and multicentric studies are mandatory to confirm these results.
C. Stacchi, T. Lombardi, R. Ottonelli, F. Bertoni, G. Perinetti, T. Traini
Objective: The aim of this multicenter prospective study was to analyze clinically and histologically the influence of sinus cavity dimensions on new bone formation after transcrestal sinus floor elevation (tSFE).
Material and Methods: Patients needing maxillary sinus augmentation (residual crest height <5 mm) were treated with tSFE using xenogeneic granules. Six months later, bone-core biopsies were retrieved for histological analysis in implant insertion sites. Bucco-palatal sinus width (SW) and contact between graft and bone walls (WGC) were evaluated on cone beam computed tomography, and correlations between histomorphometric and anatomical parameters were quantified by means of forward multiple linear regression analysis.
Results: Fifty consecutive patients were enrolled and underwent tSFE procedures, and forty-four were included in the final analysis. Mean percentage of newly formed bone (NFB) at 6 months was 21.2 ± 16.9%. Multivariate analysis showed a strong negative correlation between SW and NFB (R2 = .793) and a strong positive correlation between WGC and NFB (R2 = .781). Furthermore, when SW was stratified into three groups (<12 mm, 12 to 15 mm, and >15 mm), NFB percentages (36%, 13% and 3%, respectively) resulted significantly different.
Conclusions: This study represented the first confirmation based on histomorphometric data that NFB after tSFE was strongly influenced by sinus width and occurred consistently only in narrow sinus cavities (SW <12 mm, measured between buccal and palatal walls at 10-mm level, comprising the residual alveolar crest).
I. Roato, A. Lena, D.C. Belisario, M. Compagno, F. Mussano, T. Genova, L. Godio, F. Veneziano, G. Perale, A. Bistolfi, M. Formica, I. Cambieri, C. Castagnoli, T. Robba, L. Felli, R. Ferracini
Osteoarthritis (OA) is characterized by articular cartilage degeneration and subchondral bone sclerosis. Early OA begins as a focal damage; thus, its repair is envisioned to spare the joints from further degeneration and resume pain free movement. OA may benefit from non-surgical treatments based on articular infusions of adipose tissue derived-Stromal Vascular Fraction (SVF) or -mesenchymal stem cells (ASCs). Since both
cultured-expanded ASCs and collagenase-isolated SVF need manipulation in laboratory setting, we investigated the possibility to reduce lipoaspirate manipulation using autologous concentrated adipose tissue, injected intra-articularly in the knee.
The infusion of concentrated adipose tissue resulted safe, and all patients reported an improvement in term of pain reduction and function increase (VAS and WOMAC scores), even though the MRI evaluation was unable to detect augment in the thickness of cartilage. SVF and ASCs isolated from adipose tissue samples were cultured in vitro in standard conditions and plated on a composite bone scaffold, showing capabilities to differentiate into osteoblasts and chondrocytes upon stimulation. Immunohistochemistry performed both on bone scaffold and on knee joint intra-operative biopsies of patients, who underwent joint prosthesis, showed new tissue formation close to the osteochondral lesions. Overall our data indicate that concentrated adipose tissue infusion can stimulate tissue regeneration and might be considered an innovative and safe treatment for knee osteoarthritis, to place side by side to arthroscopy.
G. Perale, I. Roato, D. C. Belisario, M. Compagno, F. Mussano, T. Genova, F. Veneziano, G. Pertici, R. Ferracini
Intra-articular infusions of adipose tissue-derived stem cells (ASCs) are a promising tool for bone regenerative medicine, thanks to their multilineage differentiating ability. One major limitation of ASCs is represented by the necessity to be isolated and expanded through in vitro culture, thus a strong interest was generated by the adipose stromal vascular fraction (SVF), the non-cultured fraction of ASCs. Besides the easiness of retrieval, handling and good availability, SVF is a heterogeneous populations able to differentiate in vitro into osteoblasts, chondrocytes and adipocytes, according to the different stimuli received.
We investigated and compared the bone regenerative potential of SVF and ASCs, through their ability to grow on SmartBone®, a composite xenohybrid bone scaffold. SVF plated on SmartBone® showed better osteoinductive capabilities than ASCs.
Collagen I, osteocalcin and TGF markedly stained the new tissue on SmartBone®; microCT analysis indicated a progressive increase in mineralised tissue apposition by quantification of newly formed trabeculae (3391 ± 270,5 vs 1825 ± 133,4, p˂ 0,001); an increased secretion of soluble factors stimulating osteoblasts, as VEGF (153,5 to 1278,1 pg/ml) and endothelin 1 (0,43 to 1,47 pg/ml), was detected over time.
In conclusion, the usage of SVF, whose handling doesn’t require manipulation in an in vitro culture, could definitively represent a benefit for a larger use in clinical applications. Our data strongly support an innovative idea for a bone regenerativemedicine based on resorbable scaffold seeded with SVF, which will improve the precision of stem cells implant and the quality of new bone formation.
I. Roato, D. C. Belisario, M. Compagno, L.Verderio, A. Sighinolfi, F. Mussano, T. Genova, F. Veneziano, G. Pertici, G. Perale, R. Ferracini
Adipose tissue-derived stem cells (ASCs) are a promising tool for treatment of bone diseases or skeletal lesions, thanks to their multilineage differentiating ability. Osteoarthritis, a disease characterized by articular cartilage degeneration and subchondral bone sclerosis, may benefit from non-surgical treatments based on intra-articular infusions of ASCs. One of the major limitations of ASCs is represented by the necessity to be isolated and expanded through in vitro culture, thus a strong interest was generated by the adipose stromal vascular fraction (SVF), the non-cultured fraction of ASCs. We investigated and compared the bone regenerative potential of SVF and ASCs, taking advantage of their ability to grow on Smart-Bone” (SB), a xenohybrid bone scaffold. Both ASCs and SVF colonized and formed new tissue on SB, filling its periphery and bone lacunae over time. At 15, 30 and 60 days, we monitored the tissue growth through immunoistochemical staining: collagen I, osteocalcin and TGFb markedly stained the new tissue on SB. MicroCT analysis showed a progressive increase in mineralised tissue apposition by newly formed trabeculae. Indeed, their quantification analysis demonstrated that SVFs were significantly more efficient than ASCs (3391 ± 270.5 vs. 1825 ± 133.4, p\0.001) in inducing bone formation, when cultured on SB with osteogenic medium. In SVF cultures, we observed an increased secretion of soluble factors stimulating osteoblasts over time: VEGF (153.5–1278.1 pg/ml) and endothelin 1 (0.43–1.47 pg/ml). In conclusion, the absence of manipulation of SVF in an in vitro culture could definitively represent a benefit for a larger use in clinical applications. Moreover, our data strongly support an innovative idea for a regenerative medicine based on solid scaffold functionalised with SVF to improve the precision of stem cells implant and the quality of new bone formation.
I. Roato, D. C. Belisario, M. Compagno, L. Verderio, A. Sighinolfi, F. Mussano, T. Genova, F. Veneziano, G. Pertici, G. Perale and R. Ferracini
Regenerative medicine based on stem cell ability to potentially repair injured tissues is a promising treatment for many orthopaedic problems [1, 2]. Indeed, the availability of adult stem cells, such as mesenchymal stem cells (MSCs), which can be easily retrieved by adipose tissue, has dramatically enlarged their potential field of application [3–7]. One of the major limitations of MSCs is represented by the necessity to expand them through in vitro culturing, transforming them into a pharmaceutical product with its restrictive regulatory clearance and connected difficulties for clinical routinary use. Thus, a strong interest was generated by the stromal vascular fraction (SVF), the noncultured fraction of MSCs, directly obtained after collagenase treatment of adipose tissue . SVF contains MSCs called adipose tissue-derived stem cells (ASCs), which are able to differentiate in bone, cartilage, and adipose tissue [7, 8] and have been successfully used in human patients without the need of a surgical procedure . In the last decade, many clinical trials tested infusion of ASCs or SVF alone or in combination with platelet-rich plasma (PRP): they not only showed encouraging results in regenerating cartilage in patients with large cartilage lesions or with osteoarthritis (OA)but also report improvement in orthopaedic scores for pain, function, range of motion, and MRI evidence of cartilage regeneration [9–11]. Often in OA, there is a concomitant subchondral bone damage; thus, a role of SVF in regeneration of bone is envisioned. Moreover, other pathological conditions (e.g., osteonecrosis of femoral head, bone fracture, and nonunion fractures) could benefit from the SVF ability to regenerate bone. In order to improve bone regeneration, different scaffolds have been generated, using different biomaterials, and recent trends point towards a composite approach for best mimicking the human bone structure . In this framework, SmartBone (SB), a xenohybrid bone graft , resulted to be particularly efficient: it is commercially available as a medical device, and it was initially developed as a bone substitute for reconstructive surgeries in the presence of bone losses, giving excellent results [13, 14]. SB is constituted of a bovine bone matrix reinforced by a micrometric thin poly(l-lacticco-ε-caprolactone) film embedding RGD-containing collagen fragments (extracted by purified bovine gelatin), which overall results in increased mechanical properties, hydrophilicity, cell adhesion, and osteogenicity . In order to deeply investigate the basic biological mechanisms beneath the recorded clinical performances of such a graft and to investigate the bone-regenerative potential of ASCs and SVF, we studied their ability to colonize SB and generate new tissue when cultured on it .
R. Piana, M. Boffano, P. Pellegrino, L. Rossi, G. Perale
Aneurysmal bone cysts (ABCs), a misnomer pathology, are osteolytic bone neoplasms characterized by several sponge-like spaces. ABCs commonly affect vertebral metaphyses, flat bones or long bones; frequently recorded in 10-30 yrs population, they are commonest pelvis benign tumor in pediatric population. Curettage, marginal resection and cell killing methods at cyst margins are most commonly used surgical approaches, but often cyst dimensions require bone filling and use of fixation devices to ensure load bearing capabilities of lesioned bone (1). Within a clinical study, we developed a fixation devices free surgical methodology to treat ABC, ensuring both immediate loading and robust bone regeneration.
S. Spinato, P. Galindo-Moreno, F. Bernardello, D. Zaffe
This retrospective study quantitatively analyzed the minimum prosthetic abutment height to eliminate bone loss after 4.7-mm-diameter implant placement in maxillary bone and how grafting techniques can affect the marginal bone loss in implants placed in maxillary areas. Materials and Methods: Two different implant types with a similar neck design were singularly placed in two groups of patients: the test group, with platform switched implants, and the control group, with conventional (non–platform-switched) implants. Patients requiring bone augmentation underwent unilateral sinus augmentation using a transcrestal technique with mineralized xenograft. Radiographs were taken immediately after implant placement, after delivery of the prosthetic restoration, and after 12 months of loading. Results: The average mesial and distal marginal bone loss of the control group (25 patients) was significantly more than twice that of the test group (26 patients), while their average abutment height was similar. Linear regression analysis highlighted a statistically significant inverse relationship between marginal bone loss and abutment height in both groups; however, the intercept of the regression line, both mesially and distally, was 50% lower for the test group than for the control group. The marginal bone loss was annulled with an abutment height of 2.5 mm for the test group and 3.0 mm for the control group. No statistically significant differences were found regarding marginal bone loss of implants placed in native maxillary bone compared with those placed in the grafted areas. Conclusion: The results suggest that the shorter the abutment height, the greater the marginal bone loss in cement-retained prostheses. Abutment height showed a greater influence in platform-switched than in non–platform-switched implants on the limitation of marginal bone loss.
F. Secondo, C.F. Grottoli, I. Zolino, G. Perale, D. Lauritano
During a sinus lift procedure the main requirement in order to position an implant is to have a maxillary sinus floor cortical bone thick enough to guarantee a primary stability in the implant inserted. In this way, the healing process is facilitated and osseointegration of the titanium surface may occur simultaneously, thus reducing the waiting time for the engraftment of the implant into the body. Unfortunately, these conditions are not always present. Hence, the need of developing an alternative approach that could simultaneously allow to perform sinus floor elevation along with an implant placement.
Here we present the case of a 62-year-old patient that requires implant-prosthetic rehabilitation from 1.2 to 1.6 at diagnosis.
In this study, we reported a novel application derived from the use of a heterologous bone scaffold (SmartBone@) in a sinus lift procedure. We showed the successful implant along with sinus lift with SmartBone@, both at the time of the surgery and after follow-up of the patient at 10 months from the implant. The possibility to perform simultaneously the contextual implant along with sinus lift dramatically reduced the waiting time for the patient of minimum 5-6 months required for osseointegration of the grafted biomaterials, before performing the implant procedure. This surgery represents an advance both in terms of medical technique and as life-benefit for the patient.