Carlo Ferretti
University of the Witwatersrand
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Featured researches published by Carlo Ferretti.
Journal of Anatomy | 2006
Ugo Ripamonti; Carlo Ferretti; Manolis Heliotis
The osteogenic molecular signals of the transforming growth factor‐β (TGF‐β) superfamily, the bone morphogenetic/osteogenic proteins (BMPs/OPs) and uniquely in primates the TGF‐β isoforms per se, pleiotropic members of the TGF‐β supergene family, induce de novo endochondral bone formation as a recapitulation of embryonic development. Naturally derived BMPs/OPs and gamma‐irradiated human recombinant osteogenic protein‐1 (hOP‐1) delivered by allogeneic and xenogeneic insoluble collagenous matrices initiate de novo bone induction in heterotopic and orthotopic sites of the primate Papio ursinus, culminating in complete calvarial regeneration by day 90 and maintaining the regenerated structures by day 365. The induction of bone by hOP‐1 in P. ursinus develops as a mosaic structure with distinct spatial and temporal patterns of gene expression of members of the TGF‐β superfamily that singly, synergistically and synchronously initiate and maintain tissue induction and morphogenesis. The temporal and spatial expressions of TGF‐β1 mRNA indicate a specific temporal transcriptional window during which expression of TGF‐β1 is mandatory for successful and optimal osteogenesis. Highly purified naturally derived bovine BMPs/OPs and hOP‐1 delivered by human collagenous bone matrices and porous hydroxyapatite, respectively, induce bone formation in mandibular defects of human patients. By using healthy body sites as bioreactors it is possible to recapitulate embryonic developments by inducing selected biomaterials combined with recombinant proteins to transform into custom‐made prefabricated bone grafts for human reconstruction. The osteogenic proteins of the TGF‐β superfamily, BMPs/OPs and TGF‐βs, the last endowed with the striking prerogative of inducing endochondral bone formation in primates only, are helping to engineer skeletal reconstruction in molecular terms.
Journal of Craniofacial Surgery | 2009
Ugo Ripamonti; Carlo Ferretti; June Teare; Leandra Blann
Craniofacial skeletal reconstruction remains a challenging problem despite major molecular and surgical developments in the understanding of bone formation by induction. The induction of bone formation has been a critical topic of research across the planet. The bone induction principle identified important cues for tissue engineering of bone, namely, osteogenic soluble molecular signals, the bone morphogenetic and osteogenic proteins, and insoluble signals or substrata including biomimetic bioactive matrices and responding stem cells. In primates, and in primates only, the osteogenic soluble molecular signals that initiate the induction of bone formation additionally include the 3 mammalian transforming growth factor-beta (TGF-beta) isoforms, members of the TGF-beta supergene family. The mammalian TGF-beta isoforms, when implanted in the rectus abdominis muscle of the nonhuman primate Papio ursinus, induce rapid and substantial endochondral bone formation resulting in large corticalized ossicles by day 30 after heterotopic implantation; in calvarial defects of the same nonhuman primates, identical or higher doses of the TGF-beta protein do not induce bone formation because of the overexpression of Smad-6 and Smad-7, gene product inhibitors of the TGF-beta signaling pathway. The addition of minced fragments of autogenous rectus abdominis muscle partially restores the osteoinductive activity of the human TGF-beta3 isoform resulting in the induction of bone formation in the treated calvarial defects. Recombinant human TGF-beta3 delivered by Matrigel matrix and implanted in class II and III furcation defects of mandibular molars of P. ursinus induce periodontal tissue regeneration. The addition of minced fragments of autogenous rectus abdominis muscle significantly enhances cementogenesis. This review highlights the induction of bone formation by the osteogenic proteins of the TGF-beta superfamily in the nonhuman primate P. ursinus and reviews combinatorial applications of myoblastic/myogenic stem cell-based therapeutics for bone induction and morphogenesis. The recruitment of myoendothelial cells is also discussed in the light of the intrinsic and spontaneous induction of bone formation by smart biomaterial matrices that induce bone differentiation in heterotopic extraskeletal sites of P. ursinus without the exogenous application of the osteogenic soluble molecular signals of the TGF-beta superfamily.
Biomaterials | 2010
Ugo Ripamonti; Roland M. Klar; Louise Renton; Carlo Ferretti
Thirty coral-derived calcium carbonate-based macroporous constructs with limited hydrothermal conversion to hydroxyapatite (7% HA/CC) were implanted in the rectus abdominis of three adult non-human primate Papio ursinus to investigate the intrinsic induction of bone formation. Macroporous constructs with 125 microg human recombinant osteogenic protein-1 (hOP-1) or 125 microg human recombinant transforming growth factor-beta(3) (hTGF-beta(3)) were also implanted. The potential synergistic interaction between morphogens was tested by implanting binary applications of hOP-1 and hTGF-beta(3) 5:1 by weight, respectively. To evaluate the role of osteoclastic activity on the implanted macroporous surfaces, coral-derived constructs were pre-loaded with 0.24 mg of bisphosphonate zoledronate (Zometa). To correlate the morphology of tissue induction with osteogenic gene expression and activation, harvested specimens on day 90 were analyzed for changes in OP-1 and TGF-beta(3) mRNA synthesis by quantitative real-time polymerase chain reaction (qRT-PCR). The induction of bone formation in 7% HA/CC solo correlated with OP-1 expression. Massive bone induction formed by binary applications of the recombinant morphogens. Single applications of hOP-1 and hTGF-beta(3) also resulted in substantial bone formation, not comparable however to synergistic binary applications. Zoledronate-treated macroporous constructs showed limited bone formation and in two specimens bone formation was altogether absent; qRT-PCR showed a prominent reduction of OP-1 gene expression whilst TGF-beta(3) expression was far greater than OP-1. The lack of bone formation by zoledronate-treated specimens indicates that osteoclastic activity on the implanted coral-derived constructs is critical for the spontaneous induction of bone formation. Indirectly, zoledronate-treated samples showing lack of OP-1 gene expression and absent or very limited bone formation by induction confirm that the spontaneous induction of bone formation by coral-derived macroporous constructs is initiated by secreted BMPs/OPs, in context the OP-1 isoform.
Journal of Cellular and Molecular Medicine | 2008
Ugo Ripamonti; L. Nathaniel Ramoshebi; June Teare; Louise Renton; Carlo Ferretti
Transforming growth factor‐β3 (TGF‐β3), a multi‐functional growth modulator of embryonic development, tissue repair and morphogenesis, immunoregulation, fibrosis, angiogenesis and carcinogenesis, is the third mammalian isoform of the TGF‐β subfamily of proteins. The pleiotropism of the signalling proteins of the TGF‐β superfamily, including the TGF‐β proteins per se, are highlighted by the apparent redundancy of soluble molecular signals initiating de novo endochondral bone induction in the primate only. In the heterotopic bioassay for bone induction in the subcutaneous site of rodents, the TGF‐β3 isoform does not initiate endochondral bone formation. Strikingly and in marked contrast to the rodent bioassay, recombinant human (h)TGF‐β3, when implanted in the rectus abdominis muscle of adult non‐human primates Papio ursinus at doses of 5, 25 and 125 μg per 100 mg of insoluble collagenous matrix as carrier, induces rapid endochondral bone formation resulting in large corticalized ossicles by day 30 and 90. In the same animals, the delivery of identical or higher doses of theTGF‐β3 protein results in minimal repair of calvarial defects on day 30 with limited bone regeneration across the pericranial aspect of the defects on day 90. Partial restoration of the bone induction cascade by the hTGF‐β3 protein is obtained by mixing the hTGF‐β3 device with minced fragments of autogenous rectus abdominis muscle thus adding responding stem cells for further bone induction by the hTGF‐β3 protein. The observed limited bone induction in hTGF‐β3/treated and untreated calvarial defects in Papio ursinus and therefore by extension to Homo sapiens, is due to the influence of Smad‐6 and Smad‐7 down‐stream antagonists of the TGF‐β signalling pathway. RT‐PCR, Western and Northern blot analyses of tissue specimens generated by the TGF‐β3 isoform demonstrate robust expression of Smad‐6 and Smad‐7 in orthotopic calvarial sites with limited expression in heterotopic rectus abdominis sites. Smad‐6 and ‐7 overexpression in hTGF‐β3/treated and untreated calvarial defects may be due to the vascular endothelial tissue of the arachnoids expressing signalling proteins modulating the expression of the inhibitory Smads in pre‐osteoblastic and osteoblastic calvarial cell lines controlling the induction of bone in the primate calvarium.
International Journal of Oral and Maxillofacial Surgery | 2008
Carlo Ferretti
The aim of this study was to test the performance of poly-L-lactic/polyglycolic acid (PLLA/PGA) co-polymer plates and screws in the fixation of mandibular fractures. Following clinical and radiographic examination, internal fixation was achieved with PLLA/PGA co-polymer plates and screws in 31 patients. Elastic maxillomandibular fixation was maintained for 4 weeks and a blenderized diet for 6 weeks. Patients were followed up at 1 week, 6 weeks, and 3, 6 and 12 months post surgery, and evaluated clinically for swelling, pain, mucosal discoloration and occlusal relation. Segment stability, fracture healing and screw-hole ossification were assessed radiographically. Of the 29 patients who completed the trial, 20 had an uncomplicated postoperative period, resulting in complete bone union. Radiographic evidence of screw-hole ossification was noted in several patients, with considerable site-dependent rate variation. Nine patients developed complications ranging from minor dehiscence (4 patients) to frank sepsis requiring plate removal (5 patients), resulting in a 22.5% complication rate. There were no cases of non-union at the end of the fixation period. The reported complication rate following titanium internal fixation of mandibular fractures is 13.7%-43%. PLLA/PGA co-polymer plate and screw fixation of mandibular fractures, although technically more challenging and costly, is a viable alternative to traditional metal devices in selected patients.
Journal of Craniofacial Surgery | 2002
Carlo Ferretti; Ugo Ripamonti
Bone induction with extracted and partially purified, naturally derived bone morphogenetic proteins (BMPs) has been demonstrated repeatedly in heterotopic and orthotopic sites of non-human primates. This spawned the investigation of bone regeneration in mandibular defects of human patients with naturally derived BMPs and was compared with osteogenesis in patients treated with autologous bone grafts (ABGs). The osteogenic device (OD) was formulated as a combination of human demineralized bone matrix as delivery system reconstituted with naturally derived BMPs. BMPs were extracted from bovine bone with chaotropic agents and purified by sequential chromatography. Thirteen patients with segmental mandibular defects were enrolled in the trial, 6 of whom received the OD and 7 the ABGs. Defects were reconstructed with a preformed titanium mesh. The OD was combined with sterile saline and applied to the defects as a paste. Autologous bone from the iliac crest was prepared as a cortico-cancellous bone graft and loaded into the titanium mesh. Patients were followed-up clinically and radiographically at 1 and 6 weeks, 3, 6, and 12-month post-implantation. A trephine biopsy of the implants was performed at 3 months post-implantation and the specimens examined on serial undecalcified sections. Histological examination showed that the OD induced bone in 2 of 6 patients treated. Histological examination of successful implanted OD exhibited mineralized bone trabeculae with copious osteoid seams lined by contiguous osteoblasts. Bone deposition directly onto non-vital matrix provided unequivocal evidence of osteoinduction. Of the 7 patients grafted with ABGs, 5 had histological evidence of osteogenesis. Morphometric analysis of the histological sections showed that, when successful, OD-treated defects had highly active osteogenesis compared with ABGs. Whilst this trial provides valuable insights for the use of BMPs in mandibular reconstruction further work is required to produce an OD that will perform reliably in clinical contexts.
British Journal of Oral & Maxillofacial Surgery | 2002
Johan P. Reyneke; Carlo Ferretti
PURPOSE To evaluate a method to identify condylar sag intraoperatively by clinical examination after bilateral sagittal split osteotomy (BSSO). METHODS We prospectively studied 184 patients (121 female, 63 male) who had BSSO. The same surgeon operated all patients over a period of 15 months using the same technique. All patients had mandibular advancements. A standard condylar seating technique was used. The occlusion was evaluated at operation and 1 week later. RESULTS Eighteen patients had an incorrect occlusion diagnosed during the operation after removal of the IMF. Peripheral condylar sag (type II) had developed in three of these patients. In 15 patients central sag was diagnosed. One-week postoperatively, three patients had a malocclusion as a result of condylar sag. CONCLUSION Meticulous examination of the occlusion and an understanding of the occlusal changes secondary to condylar sag can reliably identify condylar sag intraoperatively. The use of suitable corrective measures during the primary operation can substantially reduce the postoperative complication rate of condylar sag.
Journal of Cellular and Molecular Medicine | 2013
Roland M. Klar; Raquel Duarte; Therese Dix-Peek; Caroline Dickens; Carlo Ferretti; Ugo Ripamonti
Coral‐derived calcium carbonate/hydroxyapatite macroporous constructs of the genus Goniopora with limited hydrothermal conversion to hydroxyapatite (7% HA/CC) initiate the induction of bone formation. Which are the molecular signals that initiate pattern formation and the induction of bone formation? To evaluate the role of released calcium ions and osteoclastogenesis, 7% HA/CC was pre‐loaded with either 500 μg of the calcium channel blocker, verapamil hydrochloride, or 240 μg of the osteoclast inhibitor, biphosphonate zoledronate, and implanted in the rectus abdominis muscle of six adult Chacma baboons Papio ursinus. Generated tissues on days 15, 60 and 90 were analysed by histomorphometry and qRT‐PCR. On day 15, up‐regulation of type IV collagen characterized all the implanted constructs correlating with vascular invasion. Zoledronate‐treated specimens showed an important delay in tissue patterning and morphogenesis with limited bone formation. Osteoclastic inhibition yielded minimal, if any, bone formation by induction. 7% HA/CC pre‐loaded with the Ca++ channel blocker verapamil hydrochloride strongly inhibited the induction of bone formation. Down‐regulation of bone morphogenetic protein‐2 (BMP‐2) together with up‐regulation of Noggin genes correlated with limited bone formation in 7% HA/CC pre‐loaded with either verapamil or zoledronate, indicating that the induction of bone formation by coral‐derived macroporous constructs is via the BMPs pathway. The spontaneous induction of bone formation is initiated by a local peak of Ca++ activating stem cell differentiation and the induction of bone formation.
British Journal of Oral & Maxillofacial Surgery | 2009
Manolis Heliotis; Ugo Ripamonti; Carlo Ferretti; C. Kerawala; Athanasios Mantalaris; Eleftherios Tsiridis
The last few decades of basic science research have provided an increased understanding of the role of osteogenic glycoproteins in bone formation. The isolation of such molecules now permits de novo orthotopic induction with increasing evidence of the ability to also induce bone growth in heterotopic sites. The current editorial focuses on the basic science of bone induction with two subsequent issues dedicated to the translation of these principles into both animal subjects and human clinical applications.
British Journal of Oral & Maxillofacial Surgery | 2010
Carlo Ferretti; Ugo Ripamonti; Eleftherios Tsiridis; C. Kerawala; Athanasios Mantalaris; Manolis Heliotis
This review, the second in a series of three editorials, focuses on the problems of translating basic scientific research on induction of bone into reliable clinical applications.