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A. Cingolani, T. Casalini, S. Caimi, A.Klaue, M. Sponchioni, F. Rossi, G. Perale
In the last decades bioresorbable and biodegradable polymers have gained a very good reputation both in research and in industry thanks to their unique characteristics. They are able to ensure high performance and biocompatibility, at the same time avoiding post-healing surgical interventions for device removal. In the medical device industry, it is widely known that product formulation and manufacturing need to follow specific procedures in order to ensure both the proper mechanical properties and desired degradation profile. Moreover, the sterilization method is crucial and its impact on physical properties is generally underestimated. In this work we focused our attention on the effect of different terminal sterilization methods on two commercially available poly(L-lactide-co-“-caprolactone) with equivalent chemical composition (70% PLA and 30% PCL) and relatively similar initial molecular weights, but different chain arrangements and crystallinity. Results obtained show that crystallinity plays a key role in helping preserve the narrow distribution of chains and, as a consequence, defined physical properties. These statements can be used as guidelines for a better choice of the most adequate biodegradable polymers in the production of resorbable medical devices.
Y. Mayer, O. Ginesin, A. Khutaba, E. E. Machtei, H. Z. Giladi
Background: Cells, scaffolds, and growth factors are the key components in bone tissue engineering. Scaffold composition, topography, and architecture influence the amount of regenerated bone in the implantation site. The aims of the study were to compare viability and proliferation of mesenchymal stem cells (MSCs) seeded onto two commercial xenografts: Bio-Oss (BO) and bioactive bone bovine (BB). Next, these materials were compared for histomorphometric bone formation in a socket preservation model in rats.
Materials and Methods: MSCs were seeded onto monolayers of BO or BB granules. Cell viability and proliferation were evaluated after incubation of 0, 2, 20, and 48 h. A total of 24 Sprague Dawley rats underwent unilateral extraction of maxillary molars. Rats were randomly divided into three groups: natural healing (nongrafted socket) or socket preservation with either BO or BB. Rats were sacrificed after 8 weeks, and histomorphometric analysis was done to evaluate bone formation and residual scaffold at the extraction site.
Results: Differences in the metabolic activity of MSCs that were seeded onto BO or BB was observed at 2 h after seeding: the metabolic activity was elevated compared to baseline in the BB (P 5 .046) and not changed in the BO wells (P 5 .84). After 20 h, the metabolic activity of MSCs seeded onto BO was decreasing (P 5 .005), while cell viability was not changed in the BB group (P 5 .356). Intergroup comparison revealed higher metabolic activity of MSCs seeded on BB after 48 h compared with BO (P 5 .016). The in vivo results demonstrated differences in socket healing between the groups: percentage of new bone was higher in the BB compared to BO group (39.1 6 14.3 vs. 23.7 6 10.8%, respectively, P 5 .096). Connective tissue portion was higher in the BO group compared with BB (73.7 6 11.1 vs. 49.6 6 13.7%, respectively, P 5 .018). Residual grafting martial was higher in the BB (11.34 6 4.18 vs. 2.62 6 1.23%, P 5 .011).
Conclusions: The results of this study demonstrating higher vitality and proliferation of MSCs seeded onto BB. Furthermore, following ridge preservation, higher percentage of new bone and lower residual scaffold were found in the BB compared with BO. This enhanced regenerative response might be the result of an enhancement of metabolic activity in cells attached to it. Further research will be needed to understand the precise mechanism.
I. Roato, D. C. Belisario, M. Compagno, F. Mussano, T. Genova, F. Veneziano, G. Pertici, G. Perale G and R. Ferracini
Regenerative medicine based on stem cell ability to potentially repair injured tissues is a promising treatment for many orthopaedic problems. Adipose tissue-derived stem cells (ASCs) have multi-lineage differentiating ability, thus they are useful for treatment of bone diseases or skeletal lesions. 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. In order to improve bone regeneration, different scaffolds have been generated. Excellent results were recently achieved by the usage of SmartBone®, a xenohybrid bone scaffold commercially available, initially developed as bone substitute for reconstructive surgeries in presence of bone losses.
G. Pertici, C. F. Grottoli, S. Molinari, G. Perale
Scaffolds for bone tissue engineering should ensure both volumetric stability and adequate strength. Moreover, their intimate structure should have an interconnected porous network for cell migration and proliferation, while also providing specific signals for bone remodelling and regeneration [1,2].
Results and Discussion
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 remodelling to mature bone formation in about 8-12 months . 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 around to 50.000 cases. In previous pictures a custom reconstruction of maxillary bone in a 70-years old male. During surgery, the piece was perfectly located inside the gap and firmly fixed with two osteosynthesis titanium screws. Surgery was fast (<2 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.
Conclusions and/or Outlook
CT scan after 8 months showed impressive osteointegration and massive volume stability (>95%). SBoD custom made bone grafting technique allows complete restoration of wide defects. Histological analysis indicates that SmartBone is osteoconductive, promotes fast bone regeneration, leading to mature bone formation in about 8 months.
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.