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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.
Milazzo M., D’Alessandro D., Stefanini C., Pertici G., Perale G., Danti S.
L’ingegneria tissutale ha, tra i suoi obiettivi, quello di sviluppare nuovi biomateriali in grado di sostituire e/o rigenerare i tessuti ossei colpiti da patologie o rimossi tramite chirurgia.Questo studio si è proposto di analizzare l’efficacia di un nuovo biomateriale, Smartbone®, costituito da osso bovino spongioso deproteinizzato e funzionalizzato con biopolimeri e frammenti peptidici con sequenza RGD esposta, nella chirurgia maxillofacciale.
E. Facciuto, C. F. Grottoli, M. Mattarocci, F. Illiano, G. Perale, G. Pertici
Grafts for bone reconstruction should ensure both mechanical stability and strength. Moreover, their structure should have an adequate interconnected porosity for cell migration and proliferation, while also providing specific signals for bone regeneration. A composite solution, based on a novel concept of biomaterial assembly, bearing cues from both mineral components and polymeric ones, was here followed to develop a new three-dimensional bone scaffold. A bovine derived mineral matrix was used to provide adequate three dimensional structure and porosity, while a combination of resorbable polymers were used to reinforce it. Bioactive agent was added to promote cell colonization and proliferation. Thanks to the very high performances of this material (SmartBone® ), particularly its impressively higher mechanical properties with respect to the other bone substitutes, Industrie Biomediche Insubri SA (IBI, Switzerland) developed custom-made products “SmartBone® On Demand™”, solving single specific cases of bone reconstruction: starting from CT scan, IBI can provide the adequate substitute for every kind of defects. Moreover, all data reported in previous scientific papers, indicate that SmartBone is osteoconductive, promotes fast bone regeneration, leading to mature bone formation in about 7 months. 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 adopting SmartBone® on demand™. During the surgery each piece were located perfectly inside the gap and fixed strongly adopting small osteosynthesis titanium screws. Surgery was fast and very precise allowing to obtain a very satisfactory results both in terms of anatomical reconstruction and functional. The surgical operation was no longer than two hours and forty-five minutes reducing dramatically the common timing for this kind of surgeries. The post-operative situation is optimal. The TC-scan after 10 months shows an impressive result. In conclusion, this technique permits a full complete restoration with custom made bone grafts.
Dr. Maurizio Martini, Dr. Anna Zazzetta (Macerata, Italy – Dubai, UAE)
Bone grafting has always been considered a challenge for dentists. Initially the diffusion of this procedure was conditioned by the need of invasive surgery, bone harvesting and the morbidity of the patient. Now its diffusion will be ever more necessary due to the spread of implantology. SmartBone allows dentists to reduce the patient’s morbidity, have an optimal osteointegration in order to achieve the best outcomes in implant surgery. In particular, the service “SmartBone on Demand” allows to obtain a custom-made graft to provide the exact required quantity of bone for the specific needs of the patient.
Mahesh L., Aran Shetty D., Shukla S.
Soon after tooth extraction a cascade of bone remodeling starts which result in bone resorption. Procedures such Socket Seal Surgery can be employed to preserve future implant site. There are various grafts which can used for the same purpose. The best method to observe a graft’s healing is surgical re-entry and or histopathology. The aim of this Case Report is to document the use of Smartbone® xenograft for socket preservation. After 5 months of healing, histopathological core sampling revealed good osteoconduction of the graft.
Poonia N, Morales H, Mahesh L.
A patient with failed implant in relation to 44 was being referred to the dental office. Site 44 was reimplanted with AB Dent dental implants, and guided bone regeneration was done with Smartbone® bone graft and resorbable collagen membrane. Root submerged technique was followed in relation to 45. One year postoperative follow-up shows stable bone levels in relation to 44, 45, and 46.
Delfo D’Alessandro, Giuseppe Perale, Mario Milazzo, Stefania Moscato, Cesare Stefanini, Gianni Pertici, Serena Danti
The ideal scaffold for bone regeneration is required to be highly porous, non-immunogenic, biostable until the new tissue formation, bioresorbable and osteoconductive. This study aimed at investigating the process of new bone formation in patients treated with granular SmartBone for sinus augmentation, providing an extensive histologic analysis. Five biopsies were collected at 4–9 months post SmartBone implantation and processed for histochemistry and immunohistochemistry. Histomorphometric analysis was performed. Bone-particle conductivity index (BPCi) was used to assess SmartBone osteoconductivity. At 4 months, SmartBone (12%) and new bone (43.9%) were both present and surrounded by vascularized connective tissue (37.2%). New bone was grown on SmartBone1 (BPCi = 0.22). At 6 months, SmartBone was almost completely resorbed (0.5%) and new bone was massively present (80.8%). At 7 and 9 months, new bone accounted for a large volume fraction (79.3% and 67.4%, respectively) and SmartBone1 was resorbed (0.5% and 0%, respectively). Well-oriented lamellae and bone scars, typical of mature bone, were observed. In all the biopsies, bone matrix biomolecules and active osteoblasts were visible. The absence of inflammatory cells confirmed SmartBone1 biocompatibility and nonimmunogenicity. These data indicate that SmartBone1 is osteoconductive, promotes fast bone regeneration, leading to mature bone formation in about 7 months.
Evidence of clinical needs related to bone reconstruction dates back to ancient Egypt. A more rigorous scientific approach has been followed since 1889, when “modern” scientists started to focus their efforts on what can be defined as the early bone tissue engineering . Nature here provides the key inspiration to new generation devices, where a composite approach is taking the lead by the smart combination of bio and nano-technologies to replicate the intimate bone structure. The goal of a new approach is hence to combine the biocompatibility and tissue integration of natural materials with the possibility to tune mechanical and physical properties typical of synthetic ones: composite grafts best mimic the real nature of healthy human bone, being rigid and elastic, compact but porous, dense but viable to cells and vessels .
E.C. Ekwueme, J.M. Patel, J.W. Freeman, S. Danti
The skeletal system provides structure, protection, and movement to the body through bones, cartilages, tendons, and ligaments. Many congenital, traumatic, and degenerative diseases may affect the function of skeletal tissues during the life span, leading to the necessity of very specific replacements and treatments. In the widespread and mechanically constraining scenario of skeletal pathologies, biodegradable polymers can play unique roles that should not only be confined to adjuvant bulk devices. Tissue engineering has recently renewed the attention towards this class of biomaterials, enchantingly exploiting their outstanding versatility to accomplish smart and biomimetic solutions to surgical and therapeutic needs. This chapter describes the most recent achievements in this field, focusing on tissue type- and subtype-specific replacements, while taking into account clinical applications and future trends.
Ilaria Zollino, Giorgio Carusi, Francesco Carinci, Giuseppe Perale
The present case reports the success rate after 8 months of follow-up in a sinus pneumatization case with maxillary sinus floor cortical bone loss due to 2.5 dental agenesis. Rehabilitation including the opportunity to insert a contextual implant during maxillary sinus lift surgery was planned, using SmartBone® Microchips heterologous bone inserted into the maxillary sinus. The newly developed bone substitute was designed starting from bovine bone derived mineral matrix, reinforced with bioresorbable aliphatic polymers and cell nutrients. SmartBone® Microchips showed a tight contact with the new bone and neither gaps nor fibrous tissues at the interface. No inflammation or foreign body reaction were observed, and these findings support the good biocompatibility of SmartBone® Microchips composite material. Moreover, new bone, thanks to its mechanical properties, consented to fix screw in combination with maxillary sinus floor elevation for a dental implant.
The newly developed bone substitute SmartBone® Microchips showed in a patient with jaw cortical pavement defect a tight contact with the new bone and neither gaps nor fibrous tissues at the interface. No inflammation or foreign body reaction were observed, and these findings support the good biocompatibility of SmartBone® Microchips composite material. Moreover, new bone, thanks to its mechanical properties, consented to fix one screw in combination with maxillary sinus floor elevation for the dental implant. All these statements showed the good suitability of SmartBone® Microchips for alveolar defect repair in sinus lift procedure
M. Milazzo, D. D’Alessandro, S. Danti, C. Stefanini, G. Pertici, nd G. Perale
The ideal scaffold for bone regeneration needs a number of requirements, such as biostability until the formation of mature tissue, high porosity for cell migration, extracellular matrix (ECM) deposition and vascularization, and non-immunogenicity. Moreover it should be bioresorbable, osteoconductive and possibly osteoinductive. Processed bovine spongy bone xenografts, coated with poly(L-lactic-co-ε-caprolactone) (PLCL) and added with gelatin are commercially available as a new class III medical device (SmartBone®, IBI S/A, Switzerland) . This study was aimed at investigating the process of new bone formation in patients treated with SmartBone® for sinus lift procedures prior to dental implants.