Global morphogenesis regulating tissue architecture and organogenesis.

This perspective article proposes that the induction of bone by recombinant human bone morphogenetic proteins (hBMPs), and by the recombinant human transforming growth factor-β (hTGF-β), the latter only in primates, recapitulates embryonic development, whereby large ossicles de novo form in heterotopic intramuscular sites, where several responding cells are available with marked vascular invasion. The induction of bone initiates with the induction of cartilage' anlages recapitulating development. Selected recombinant hBMPs, hBMP-2 and hOP-1 (hBMP-7) on the other hand, fail to induce significant osteoinduction in orthotopic intraskeletal sites in clinical contexts.

Mechanistic insights into the spontaneous induction of bone formation.

The grand discovery of morphogens, or "form-generating substances", revealed that tissue morphogenesis is initiated by soluble molecular signals or morphogens primarily belonging to the transforming growth factor-β (TGF-β) supergene family. The regenerative potential of bone rests on its extracellular matrix, which is the repository of several morphogens that tightly control cellular differentiating pathways, cellular matrix deposition and remodeling. Alluringly, the matrix also contains specific factors transferred from the heterotopic implanted bone matrices initiating "Tissue Induction", as provocatively described in Nature in 1945.

Pediatric Mandibular Defect Rehabilitation by Human Transforming Growth Factor-β3 with an Implant-Supported Prosthesis.

Large mandibular defects in children are an uncommon but challenging problem for surgeons to solve. The time-honored options of autologous bone grafts are seldom a viable option, as suitable donor sites are unavailable. Osteoinductive morphogens may yet provide a solution in these cases.

Osteogenic Competence and Potency of the Bone Induction Principle: Inductive Substrates That Initiate "Bone: Formation by Autoinduction".

The de novo induction of bone has always been a fascinating phenomenon, keeping skeletal reconstructionists and cellular developmental biologists continuously engaged to finally provide a molecular and cellular approach to the induction of bone formation. A significant advancement was made by the purification and cloning of the human recombinant bone morphogenetic proteins, members of the transforming growth factor-β supergene family. Human bone morphogenetic proteins are powerful inducers of bone in animal models including nonhuman primates.

Long Term Follow-Up of Pediatric Mandibular Reconstruction With Human Transforming Growth Factor-β3.

Translating bone regeneration induced by recombinant human bone morphogenetic proteins from animal models to human patients has proven inexplicably inconsistent. This prompted us to test in 5 pediatric patients, an alternative osteoinductive morphogen, recombinant human transforming growth factor β3 (hTGF-β3), to reconstruct mandibular defects of such a size to preclude reconstruction with autologous bone. An osteoinductive implant of human demineralized bone matrix (DBM) loaded with 125 μg hTGF-β3 per gram of DBM was implanted into one defect, and 250 μg hTGF-β3 per gram of DBM in another.

A mass guide for the harvest of cortico-cancellous bone from the posterior iliac crest for mandibular reconstruction.

This study sought to find the mass of particulate cortico-cancellous bone graft required per 1 cm continuity defect of the mandible. Harvested bone was weighed, milled and maximally compressed in a syringe. The defect length (DL) was measured in centimetres, and the compressed bone volume (CBV) used was recorded.

Developmental pathways of periodontal tissue regeneration: Developmental diversities of tooth morphogenesis do also map capacity of periodontal tissue regeneration?

Nothing is known on the impact of developmental divergence on periodontal tissue regeneration in vertebrate animals. Molecularly, the induction of tooth morphogenesis is highly conserved deploying across animal phyla a constant and reproducible set of gene pathways, which result in morphogenesis of multiple odontode forms and shapes. Genetic mutations positively affect animal speciation via evolving biting and masticatory forces as well as dietary habits selectively imprinted in animal phyla during evolutionary speciation.

New technique for endoscopically-assisted particulate graft reconstruction of the mandible.

The reconstruction of mandibular defects using particulate grafts is a proven technique that restores the osseous anatomy effectively. Secondary osseous reconstruction can be accomplished with endoscopic assistance and reduced-access incisions if an intermediate spacer is placed during resection. Two patients required reconstruction after resection of mandibular ameloblastomas.

Functionalized Surface Geometries Induce: ".

The induction of tissue formation, and the allied disciplines of tissue engineering and regenerative medicine, have flooded the twenty-first century tissue biology scenario and morphed into high expectations of a fulfilling regenerative dream of molecularly generated tissues and organs in assembling human tissue factories. The grand conceptualization of deploying soluble molecular signals, first defined by Turing as forms generating substances, or morphogens, stemmed from classic last century studies that hypothesized the presence of morphogens in several mineralized and non-mineralized mammalian matrices. The realization of morphogens within mammalian matrices devised dissociative extractions and chromatographic procedures to isolate, purify, and finally reconstitute the cloned morphogens, found to be members of the transforming growth factor-β (TGF-β) supergene family, with insoluble signals or substrata to induce tissue induction and morphogenesis.

Biomimetic Functionalized Surfaces and the Induction of Bone Formation.

Tissue engineering still needs to assign the molecular basis of pattern formation, tissue induction, and morphogenesis: What next to morphogens and stem cells? Macroporous biomimetic matrices per se, without the addition of the soluble osteogenic molecular signals of the transforming growth factor-β (TGF-β) supergene family, remarkably initiate the induction of bone formation. Carving geometries within different calcium phosphate-based macroporous bioreactors we show that geometric cues imprinted within the macroporous spaces initiate the spontaneous induction of bone. Concavities biomimetize the remodeling cycle of the primate osteonic bone and are endowed with functionalized smart geometric cues that per se initiate osteoblasts' differentiation with the expression and secretion of osteogenic molecular signals that induce bone as a secondary response.

Cementogenesis and osteogenesis in periodontal tissue regeneration by recombinant human transforming growth factor-β : a pilot study in Papio ursinus.

Objectives: The aim of this study was to investigate cementogenesis and alveolar bone induction during in vivo periodontal tissue regeneration upon implantation of hTGF-β in furcation defects of Papio ursinus and to evaluate the feasibility of gene expression studies.

Materials And Methods: Class II furcation defects (day 0) were prepared in mandibular first and second molars of three P. ursinus and on day 30 implanted with and without 75 μg hTGF-β in Matrigel matrix.

Redundancy and Molecular Evolution: The Rapid Induction of Bone Formation by the Mammalian Transforming Growth Factor-β3 Isoform.

The soluble osteogenic molecular signals of the transforming growth factor-β (TGF-β) supergene family are the molecular bases of the induction of bone formation and postnatal bone tissue morphogenesis with translation into clinical contexts. The mammalian TGF-β3 isoform, a pleiotropic member of the family, controls a vast array of biological processes including the induction of bone formation. Recombinant hTGF-β3 induces substantial bone formation when implanted with either collagenous bone matrices or coral-derived macroporous bioreactors in the rectus abdominis muscle of the non-human primate Papio ursinus.

The synergistic induction of bone formation by the osteogenic proteins of the TGF-β supergene family.

The momentum to compose this Leading Opinion on the synergistic induction of bone formation suddenly arose when a simple question was formulated during a discussion session on how to boost the often limited induction of bone formation seen in clinical contexts. Re-examination of morphological and molecular data available on the rapid induction of bone formation by the recombinant human transforming growth factor-β3 (hTGF-β3) shows that hTGF-β3 replicates the synergistic induction of bone formation as invocated by binary applications of hOP-1:hTGF-β1 at 20:1 by weight when implanted in heterotopic sites of the rectus abdominis muscle of the Chacma baboon, Papio ursinus. The rapid induction of bone formation in primates by hTGF-β3 may stem from bursts of cladistic evolution, now redundant in lower animal species but still activated in primates by relatively high doses of hTGF-β3.

Tissue segregation restores the induction of bone formation by the mammalian transforming growth factor-β(3) in calvarial defects of the non-human primate Papio ursinus.

A diffusion molecular hypothesis from the dura and/or the leptomeninges below that would control the induction of calvarial membranous bone formation by the recombinant human transforming growth factor-β3 (hTGF-β3) was investigated. Coral-derived calcium carbonate-based macroporous constructs (25 mm diameter; 3.5/4 mm thickness) with limited hydrothermal conversion to hydroxyapatite (7% HA/CC) were inserted into forty calvarial defects created in 10 adult Chacma baboons Papio ursinus.

Redefining the induction of periodontal tissue regeneration in primates by the osteogenic proteins of the transforming growth factor-β supergene family.

The molecular bases of periodontal tissue induction and regeneration are the osteogenic proteins of the transforming growth factor-β (TGF-β) supergene family. These morphogens act as soluble mediators for the induction of tissues morphogenesis sculpting the multicellular mineralized structures of the periodontal tissues with functionally oriented ligament fibers into newly formed cementum. Human TGF-β (hTGF-β ) in growth factor-reduced Matrigel matrix induces cementogenesis when implanted in class II mandibular furcation defects surgically prepared in the non-human primate Chacma baboon, Papio ursinus.

Reconstruction of 56 mandibular defects with autologous compressed particulate corticocancellous bone grafts.

We retrospectively evaluated the results of particulate corticocancellous bone grafting of mandibular defects. Patients with deficits of mandibular continuity as a result of injuries or resection of disease had the affected segment debrided or resected, followed by placement of a patient-specific reconstruction plate. Eight weeks after resection, it was reconstructed with an autotransplant from the posterior iliac crest.

Profiling bone morphogenetic proteins and transforming growth factor-βs by hTGF-β3 pre-treated coral-derived macroporous bioreactors: the power of one.

To study the expression profile of bone morphogenetic proteins and transforming growth factor-βs (BMPs and TGFβs), coral-derived calcium carbonate-based macroporous bioreactors with limited conversion to hydroxyapatite (7% HA/CC) were pre-loaded with and without 250 μg hTGF-β3 and implanted in the rectus abdominis of 3 non-human primates Papio ursinus euthanized on day 60. To investigate the required dose of hNoggin, a BMPs antagonist that controls the induction of bone formation, 7% HA/CC were pre-loaded with 150 μg hNoggin, with 125 μg hTGF-β3/150 μg hNoggin, with or without 125 μg hTGF-β3 and implanted in the r. abdominis of 3 additional animals euthanized on day 90.

Re-evaluating the induction of bone formation in primates.

The molecular cloning of the osteogenic proteins of the transforming growth factor-β (TGF-β) supergene family and the results of numerous pre-clinical studies in several mammalian species including non-human primates, have prematurely convinced molecular biologists, tissue engineers and skeletal reconstructionists alike to believe that single recombinant human bone morphogenetic/osteogenic proteins (hBMPs/OPs) would result in tissue induction when translated in clinical contexts. This theoretical potential has not been translated to acceptable clinical results. Clinical trials in craniofacial and orthopedic applications such as mandibular reconstruction and sinus-lift operations have indicated that supra physiological doses of a single recombinant human protein are needed to induce unacceptable tissue regeneration whilst incurring significant costs without achieving equivalence to autogenous bone grafts.

The induction of bone formation by the recombinant human transforming growth factor-β3.

Implantation of recombinant human transforming growth factor-β3 (hTGF-β3) with coral-derived calcium carbonate-based macroporous bioreactors with limited conversion to hydroxyapatite (7% HA/CC) in the rectus abdominis muscle of the non-human primate Chacma baboon Papio ursinus induces endochondral bone formation. The exact mechanisms by which hTGF-β3 signalling induces bone in heterotopic sites of P. ursinus are not known.

Biological aspects of periodontal tissue regeneration: cementogenesis and the induction of Sharpey's fibres.

The realm of periodontal tissue regeneration has a plethora of unanswered questions and challenges due to the complexity of restoring mineralised and fibrous connective tissues ultimately to be covered by epithelium in a very specific spatial organisation. Wound healing of the periodontium follows a highly ordered sequence of events that guides cellular morphology, differentiation, migration and proliferation and comprises a series of cellular, extracellular and molecular reciprocal interactions. The prerequisite for regeneration of any structure is the trio of a soluble molecular signal, a scaffold and responding stem cells.

Calcium ions and osteoclastogenesis initiate the induction of bone formation by coral-derived macroporous constructs.

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.

A Macroporous Bioreactor Super Activated by the Recombinant Human Transforming Growth Factor-β(3).

Macroporous single phase hydroxyapatite (HA) and biphasic HA/β-tricalcium phosphate with 33% post-sinter hydroxyapatite (HA/β-TCP) were combined with 25 or 125 μg recombinant human transforming growth factor-β3 (hTGF-β(3)) to engineer a super activated bioreactor implanted in orthotopic calvarial and heterotopic rectus abdominis muscle sites and harvested on day 30 and 90. Coral-derived calcium carbonate fully converted (100%) and partially converted to 5 and 13% hydroxyapatite/calcium carbonate (5 and 13% HA/CC) pre-loaded with 125 and 250 μg hTGF-β(3), and 1:5 and 5:1 binary applications of hTGF-β(3): hOP-1 by weight, were implanted in the rectus abdominis and harvested on day 20 and 30, respectively, to monitor spatial/temporal morphogenesis by high doses of hTGF-β(3). Bone formation was assessed on decalcified paraffin-embedded sections by measuring the fractional volume of newly formed bone.

Osteoinductive hydroxyapatite-coated titanium implants.

Previous studies have shown that heterotopic induction of bone formation by calcium phosphate-based macroporous constructs is set into motion by the geometry of the implanted substrata, i.e. a sequence of repetitive concavities assembled within the macroporous spaces.

Synergistic induction of periodontal tissue regeneration by binary application of human osteogenic protein-1 and human transforming growth factor-β3 in Class II furcation defects of Papio ursinus.

Background And Objective: Binary applications of recombinant human osteogenic protein-1 (hOP-1) and transforming growth factor-β3 (hTGF-β3) synergize to induce pronounced bone formation. To induce periodontal tissue regeneration, binary applications of hOP-1 and hTGF-β(3) were implanted in Class II furcation defects of the Chacma baboon, Papio ursinus.

Material And Methods: Defects were created bilaterally in the furcation of the first and second mandibular molars of three adult baboons.