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Riccardo Ferracini , Alessandro Bistolfi Riccardo Garibaldi , Vanessa Furfaro , Agnese Battista and Giuseppe Perale
Introduction: Tibial plateau fractures represent a common challenge for orthopaedic surgeons, sometimes representing complex cases to manage, where augmentation using bone grafts is required for stabilisation. Autologous iliac bone graft (AIBG) is the current gold standard for bone grafting. In order to overcome limitations related to the procedure, alternative strategies, like allogenic and xenogeneic bone substitutes have been investigated. Here, within the framework of an observational clinical study, we report clinical and radiological outcomes of patients treated for tibial plateau fractures with a composite xenohybrid bone graft, aiming at assessing clinical and radiological outcomes. Materials and Methods: We performed a cohort retrospective study of patients treated for tibial plateau fractures from May 2017 to January 2018. Thirty-four patients, i.e. 100% of those having received the bone graft under investigation for tibial plateaux fracture treatment, met the inclusion criteria and were enrolled in the study. Patients were assessed at 2 weeks, and then at a 1-, 3-, and 6-months, and 1-year follow-up. At each evaluation patients filled a visual analogue scale (VAS) for the level of pain during the day life activities and underwent physical exam and anteroposterior and lateral projection radiographs of the knee. At 1 year the Tegner Lysholm Scoring Scale, International Knee Document Committee 2000 (IKDC 2000), and Short Form (36) Health Survey (SF-36) were administered. Results: At 1-year, mean VAS decreased from 6.33 ± 1.40 to 1 ± 0.79 (P < 0.0001); Tegner Lysholm Scoring Scale was 89 ± 4.10 and mean IKDC 2000 was 78.67 ± 3.31. No infections, neurovascular complications or adverse effects related to implants were reported during the clinical exams at follow-up. Mean ROM was 124 ± 6°. Radiographs did not show defects of consolidation or progressive post-surgical subsidence and demonstrated a good grade of integration of the implant. Conclusions: Clinical and radiological outcomes, and scores of questionnaires, were good. The xenograft has demonstrated to be a safe biomaterial, with satisfactory mechanical and biological performances in the mid-term period. It also showed a high grade of osteointegration and remodelling
Enzo Facciuto, MD, Carlo Francesco Grottoli, MSE, Maurizio Mattarocci, MD, Fausto Illiano, MD, Mara Compagno, PhD, Riccardo Ferracini, MD, PhD, and Giuseppe Perale, MSE, PhD
This is a report of a 34-year-old male lacking of bone development in the frontal and orbital part of
the skull due to a surgical removal of a right orbital-front osteoma at the age of five. The integrity of the
craniofacial district was important for the young patient also for social acceptance and self-esteem.
Based on computed tomography patient images, a skull model was reconstructed, both digitally and on 3D real
model, to best design the needed bone graft. Defect wide extension and surface curvature called for the use of the
puzzle technique, where the whole graft is composed by several elements, mechanically slotting into each other. The
realization was made possible thanks to the use of a composite xenohybrid bone substitute specifically developed
for reconstructive surgery (SmartBone@, by Industrie Biomediche Insubri SA). SmartBone® technology allowed the
realization of custom-made grafts which perfectly joined each other and fitted the bone defect thanks to mechanical
strength, also at low thicknesses and wide extensions.
The postoperative course was uneventful and computed tomography scans showed new bone formation and
complete calvaria continuity already ten months after surgery, with no signs of inflammation over the entire follow
This case study represents a proof of concept that SmartBone® On Demand ™ custom-made bone grafts, together
with puzzle technique, are effective, easy to handle and provide final excellent functional and aesthetic results.
C. F. Grottoli, R. Ferracini, M. Compagno, A. Tombolesi, O. Rampado, L. Pilone, A. Bistolfi, A. Borrè, A. Cingolani
and G. Perale
(1) Background: Bone tissue engineering is a promising tool to develop new smart solutions
for regeneration of complex bone districts, from orthopedic to oral and maxillo-facial fields. In this
respect, a crucial characteristic for biomaterials is the ability to fully integrate within the patient
body. In this work, we developed a novel radiological approach, in substitution to invasive histology,
for evaluating the level of osteointegration and osteogenesis, in both qualitative and quantitative
manners. (2) SmartBone®, a composite xeno-hybrid bone graft, was selected as the base material
because of its remarkable effectiveness in clinical practice. Using pre- and post-surgery computed
tomography (CT), we built 3D models that faithfully represented the patient’s anatomy, with special
attention to the bone defects. (3) Results: This way, it was possible to assess whether the new
bone formation respected the natural geometry of the healthy bone. In all cases of the study (four
dental, one maxillo-facial, and one orthopedic) we evaluated the presence of new bone formation
and volumetric increase. (4) Conclusion: The newly established radiological protocol allowed the
tracking of SmartBone®effective integration and bone regeneration. Moreover, the patient’s anatomy
was completely restored in the defect area and functionality completely rehabilitated without foreign
body reaction or inflammation.
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 dierentiating 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 population able to dierentiate in vitro into
osteoblasts, chondrocytes and adipocytes, according to the dierent 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 scaold. 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 quantication 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 denitively represent
a benet for a larger use in clinical applications. Our data strongly support an innovative idea for a bone
regenerative medicine based on resorbable scaold seeded with SVF, which will improve the precision of stem
cells implant and the quality of new bone formation.
Mohammed S. Abuelnaga, Nader N. Elbokle, Mohammed M. Khashaba
Aim: This study was to evaluate clinically and radiographically the volume changes of alveolar ridge grafting using
customized xenogenic bone graft.
Materials and Methods: A total of 12 patients with mandibular horizontal and vertical alveolar ridge defects ≥ 3 mm
were selected. They were divided into 2 groups: Group I (Test Group) included 6 patients in which mandibular alveolar
ridges were reconstructed with customized Xenogenic bone graft Smartbone (IBI S.A., Switzerland). Group II (Control
Group) included 6 patients in which mandibular alveolar ridges were reconstructed with particulate Xenogenic bone
(Smart bone, IBI S.A., Switzerland) grafting to posterior mandibular ridge with titanium mesh was performed. Volume
analysis of the changes in alveolar ridge in both Groups were obtained before and four months after the procedure using
CBCT. Densitometric analysis of the Postoperative bone formed and compared with native bone. .
Results: Four months postoperatively. Measurements made on cone-beam computerized tomograms, four months
postoperative showed significance increase in bone volume by 40 % in the area of newly formed bone in Group I
(Customized bone) compared with 23% in Control Group. Statistical significant changes was found in the density of
newly formed bone four months post-operatively in both Groups, however there was no significant difference in bone
density postoperatively between Group I (customized Bone) and Group II (Control).
Conclusion: According to the results, the treatment of defective alveolar ridge augmentation of the mandibular ridge with
customized xenogenic bone graft Smartbone (IBI S.A., Switzerland) is successful and produces results consistent with
the control Group.
A. Cingolani, C.F Grottoli, R. Esposito, T. Villa, F. Rossi, G. Perale
Background: The further functionalization of natural existing biomaterials is a very efficient method to introduce additional advanced characteristics on a unique structural composition and architecture.
Objective: As an example, different animal sources, if properly treated, can be used to develop bone xenograft active in hard tissues regeneration. In this sense, it is also important to consider that the selected process has to take into consideration the intrinsic variability of the base material itself and possibly being able to compensate for it.
Methods: In this work we characterize cancellous bovine bone treated by deposition of polymer and collagen and we show that the added components not only lead to a more resistant and more hydrophilic material, but also reduce the conventional correlation between apparent density and elastic modulus, which, in general, is a major source of uncertainty and risk in xenografts usage.
Results: Moreover, though intrinsically reinforcing the material, the deposition process leaves the specific open-porous structure, that allows cells proliferation and vessels ingrowth, basically unaltered.
Conclusion: The final material combines in a single piece and at the same time, mechanical resistance, homogeneous mechanical response and proper structural characteristics that allow further integration within the patient autochthonous tissues.
H. J. Haugen, S. P. Lyngstadaas, F. Rossi, G. Perale
Bovine xenograft materials, followed by synthetic biomaterials, which unfortunately still lack documented predictability and clinical performance, dominate the market for the cranio‐maxillofacial area. In Europe, new stringent regulations are expected to further limit the allograft market in the future
Within this narrative review, we discuss possible future biomaterials for bone replacement.
Although the bone graft (BG) literature is overflooded, only a handful of new BG substitutes are clinically available. Laboratory studies tend to focus on advanced production methods and novel biomaterial features, which can be costly to produce.
In this review, we ask why such a limited number of BGs are clinically available when compared to extensive laboratory studies. We also discuss what features are needed for an ideal BG.
We have identified the key properties of current bone substitutes and have provided important information to guide clinical decision‐making and generate new perspectives on bone substitutes. Our results indicated that different mechanical and biological properties are needed despite each having a broad spectrum of variations.
We foresee bone replacement composite materials with higher levels of bioactivity, providing an appropriate balance between bioabsorption and volume maintenance for achieving ideal bone remodelling.
F. Mandelli, G. Perale, S. Danti, D. D’Alessandro, P. Ghensi
Objectives.The aim of this case series study was to evaluate, clinically and histologically, the performances of a novel composite xenohybrid bone substitute.
Methods. Ten non-restorable teeth were extracted and socket preservation was performed with a bovine heterologous graft enriched with collagen and resorbable biopolymers (SmartBone®). The socket was covered with a collagen membrane firmly sutured. After five months of healing, implant site was prepared by means of a trephine bur and a dental implant was inserted. Specimens were sent for histological analysis. After three months of healing, patients received a provisional restoration followed by a definitive crown.
Results. All socket preservations healed uneventfully and, after five months, it was possible to insert implants with no additional bone augmentation procedures. All placed implants osseointegrated successfully and were in function after a minimum follow-up period of 30 months.
Conclusions. The tested biomaterial confirmed good clinical performance and, even if left exposed to the oral cavity covered with a collagen membrane, did not show signs of infection. Further research is desirable with a larger sample and variations of socket preservation technique to better understand the potential of this novel bone substitute.
G. Pertici, C. F. Grottoli
Biomaterials for bone tissue engineering should ensure both adequate strength and volumetric maintenance. Moreover, their intimate structure should have an interconnected porous network for cell 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. 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 (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.
SmartBone® technology was successfully applied for more than 55.000 cases.
CT scans 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.
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.