The morphogenesis of bone in replicas of porous hydroxyapatite obtained from conversion of calcium carbonate exoskeletons of coral

PKThe morphogenesis of bone in a porous hydroxyapatite substratum was studied after intramuscular implantation in adult primates. Replicas of porous hydroxyapatite that had been obtained after hydrothermal conversion of the calcium carbonate exoskeleton of coral (genus Goniopora) were implanted intramuscularly in twenty-four adult male baboons (Papio ursinus). Serial sections from specimens that had been harvested at three, six, and nine months showed that initially the formation of fibrous connective tissue was characterized by a prominent vascular component and by condensations of collagen fibers assembled at the interface of the hydroxyapatite. The morphogenesis of bone was intimately associated with the differentiation of the connective-tissue condensations. Bone formed without an intervening endochondral phase. Although the amount of bone varied considerably, in several specimens extensive bone developed, filling large portions of the porous spaces and culminating in total penetration by bone within the implants. The mean volume fraction composition of the specimens was 20.8 +/- 1.0 per cent (mean and standard error) for bone, 17.3 +/- 1.7 per cent for connective-tissue condensation, 31.9 +/- 1.0 per cent for fibrovascular tissue, 6.4 +/- 0.6 per cent for bone marrow, and 34.6 +/- 0.5 per cent for the hydroxyapatite framework. The amount of bone and marrow increased at each time-period, and the hydroxyapatite framework was significantly reduced between six and nine months. This indicated a moderate biodegradation over time, which was possibly a result of incomplete conversion of carbonate to hydroxyapatite. Linear regression analysis showed a negative correlation between the hydroxyapatite framework and the magnitude of bone formation within the porosities of the hydroxyapatite (p = 0.0001). Biochemical coating of the hydroxyapatite substratum with an allogeneic fibrin-fibronectin protein concentrate prepared from baboon plasma did not significantly increase the amount of bone formation within the porous spaces. The hydroxyapatite substratum may have functioned as a solid-phase domain for anchorage of bone morphogenetic proteins

Growth and morphogenetic factors in bone induction: role of osteogenin and related bone morphogenetic proteins in craniofacial and periodontal bone repair.

Bone has considerable potential for repair as illustrated by the phenomenon of fracture healing. Repair and regeneration of bone recapitulate the sequential stages of development. It is well known that demineralized bone matrix has the potential to induce new bone formation locally at a heterotopic site of implantation. The sequential development of bone is reminiscent of endochondral bone differentiation during bone development. The collagenous matrix-induced bone formation is a prototype model for matrix-cell interactions in vivo. The developmental cascade includes migration of progenitor cells by chemotaxis, attachment of cells through fibronectin, proliferation of mesenchymal cells, and differentiation of bone. The bone inductive protein, osteogenin, was isolated by heparin affinity chromatography. Osteogenin initiates new bone formation and is promoted by other growth factors. Recently, the genes for osteogenin and related bone morphogenetic proteins were cloned and expressed. Recombinant osteogenin is osteogenic in vivo. The future prospects for bone induction are bright, and this is an exciting frontier with applications in oral and orthopaedic surgery.TS2016

The Induction of Bone Formation by the recombinant human transforming growth Factor-β3 : From preclinical studies in Papio ursinus to translational research in Homo sapiens

Skeletal bone defects of the axial or the craniomaxillofacial skeletons still present formidable challenges to skeletal reconstructionists, tissue biologists and modern medicine. In systematic research experiments in the Chacma baboon Papio ursinus our laboratories have shown the previously unreported osteoinductive activity of the three mammalian transforming growth factor-β (TGF-β) isoforms. This review discusses the induction of bone formation by the mammalian TGF-βs with particular reference to the substantial and rapid induction of bone by the recombinant hTGF-β3 from the laboratory benches, to pre-clinical studies in heterotopic and orthotopic mandibular sites of Papio ursinus to clinical translation in human patients. Design and MethodsA series of systematic research experiments in Papio ursinus using the hTGF-β3 together with earlier experiments using the -β1 and β2 isoforms are reviewed and re-analyzed molecularly nd morphologically to provide the basic research data for the reported clinical translation in human patients. Results The three mammalian hTGF-β isoforms and notably hTGF-β3 induce rapid and substantial induction of heterotopic bone in intramuscular sites of Papio ursinus. Relatively low doses of hTGF-β1or hTGF-β3 in binary application with hBMP-7 synergize to induce massive corticalized ossicles in the rectus abdominis muscle. In orthotopic mandibular sites, 125 and250 µg doses of hTGF-β3 induce bone formation across large mandibular defects in Papio ursinus with corticalized buccal and lingual plates by day 30, with modeling and maintenance of corticalized bone by 9 to 12 months after implantation of the 250 µg dose in 3 cm mandibular defects Papio ursinus. Discussion hTGF-β3 significantly up-regulates RUNX-2 and Osteocalcin expression on day 15 controlling the differentiation of progenitor stem cells into the osteoblastic lineage. The induction of bone by the hTGF-β3 is via the bone morphogenetic proteins pathway; hTGF-β3 controls theinduction of bone by regulating the expression of BMPs gene and gene products via Noggin expression, eliciting bone induction by up-regulating exogenous BMPs

Neoplastic tissue transfiguration in vivo by recombinant human transforming growth factor-β3

Human oral squamous cell carcinomas (hSCCs) are the most common head and neck cancers now presenting with more aggressive biological and clinical features due to smoking and alcohol together with widespread viremia. Transforming growth factor-β (TGF-β) proteins are powerful morphogens that induce rapid and substantial induction of endochondral bone formation but in primates only

The conundrum of human osteoinduction : is the bone induction principle failing clinical translation?

No abstract available.https://journals.lww.com/jcraniofacialsurgery/pages/default.aspxhj2022Maxillo-Facial and Oral Surger

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. Thereafter in 3 patients limited amounts of particulate cortico-cancellous bone graft harvested from the posterior iliac crest were combined with 250 μg hTGF-β3 per gram of DBM. Patients were followed up for 3 to 6 years. Three patients achieved clinically significant osteoinduction, 1 patient with hTGF-β3 only, and 2 by combining hTGF-β3 with a small supplement of autologous bone. One patient with hTGF-β3 only and followed up for 5 years retains a viable reconstruction but has had sub-optimal bone regeneration. One patient had osteoinductive failure due to sepsis although the plate reconstruction remains viable. Recombinant human TGF-β3 initiates osteoinduction in humans and potentiates autologous bone graft activity allowing the reconstruction of large mandibular defects in pediatric patients.The University of the Witwatersrand, Johannesburg and the National Research Foundation of South Africa.https://journals.lww.com/jcraniofacialsurgery/pages/default.aspxhj2021Maxillo-Facial and Oral Surger

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. We used a modified protocol that involved the implantation of a graft of particulate corticocancellous bone after removal of the spacer, and prepared the recipient site under endoscopic guidance with small extraoral incisions. The grafts healed uneventfully and matured into ossicles suitable for the placement of osseointegrated implants.http://bjoms.comhttp://www.journals.elsevier.com/british-journal-of-oral-and-maxillofacial-surgery2019-06-01hj2018Maxillo-Facial and Oral Surger

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. Translation in clinical contexts has however, proven to be surprisingly difficult. This review also describes the significant induction of bone formation by the human transforming growth factor-β3 when implanted in heterotopic intramuscular sites of the Chacma baboon Papio ursinus. Large mandibular defects implanted with 250 mg human transforming growth factor-β3 in human patients showed significant osteoinduction; however, the induction of bone was comparatively less than the induction of bone in P ursinus once again highlighting the conundrum of human osteoinduction: is the bone induction principle failing clinical translation?http://www.jcraniofacialsurgery.comhj2023Maxillo-Facial and Oral Surger

Soluble and insoluble signals sculpt osteogenesis in angiogenesis

The basic tissue engineering paradigm is tissue induction and morphogenesis by combinatorial molecular protocols whereby soluble molecular signals are combined with insoluble signals or substrata. The insoluble signal acts as a three-dimensional scaffold for the initiation of de novo tissue induction and morphogenesis. The osteogenic soluble molecular signals of the transforming growth factor-β (TGF-β) supergene family, the bone morphogenetic/osteogenic proteins (BMPs/OPs) and, uniquely in the non-human primate Papio ursinus (P. ursinus), the three mammalian TGF-β isoforms induce bone formation as a recapitulation of embryonic development. In this paper, I discuss the pleiotropic activity of the BMPs/OPs in the non-human primate P. ursinus, the induction of bone by transitional uroepithelium, and the apparent redundancy of molecular signals initiating bone formation by induction including the three mammalian TGF-β isoforms. Amongst all mammals tested so far, the three mammalian TGF-β isoforms induce endochondral bone formation in the non-human primate P. ursinus only. Bone tissue engineering starts by erecting scaffolds of biomimetic biomaterial matrices that mimic the supramolecular assembly of the extracellular matrix of bone. The molecular scaffolding lies at the hearth of all tissue engineering strategies including the induction of bone formation. The novel concept of tissue engineering is the generation of newly formed bone by the implantation of “smart” intelligent biomimetic matrices that per se initiate the ripple-like cascade of bone differentiation by induction without exogenously applied BMPs/OPs of the TGF-β supergene family. A comprehensive digital iconographic material presents the modified tissue engineering paradigm whereby the induction of bone formation is initiated by intelligent smart biomimetic matrices that per se initiate the induction of bone formation without the exogenous application of the soluble osteogenic molecular signals. The driving force of the intrinsic induction of bone formation by bioactive biomimetic matrices is the shape of the implanted substratum. The language of shape is the language of geometry; the language of geometry is the language of a sequence of repetitive concavities, which biomimetizes the remodelling cycle of the primate osteonic bone

Functionalized Surface Geometries Induce: “Bone: Formation by Autoinduction”

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 de novo tissue induction and morphogenesis. Can we however construct macroporous bioreactors per se capable of inducing bone formation even without the exogenous applications of the osteogenic soluble molecular signals of the TGF-β supergene family? This review describes original research on coral-derived calcium phosphate-based macroporous constructs showing that the formation of bone is independent of the exogenous application of the osteogenic soluble signals of the TGF-β supergene family. Such signals are the molecular bases of the induction of bone formation. The aim of this review is to primarily describe today's hottest topic of biomaterials' science, i.e., to construct and define osteogenetic biomaterials' surfaces that per se, in its own right, do initiate the induction of bone formation. Biomaterials are often used to reconstruct osseous defects particularly in the craniofacial skeleton. Edentulism did spring titanium implants as tooth replacement strategies. No were else that titanium surfaces require functionalized geometric nanotopographic cues to set into motion osteogenesis independently of the exogenous application of the osteogenic soluble molecular signals. Inductive morphogenetic surfaces are the way ahead of biomaterials' science: the connubium of stem cells on primed functionalized surfaces precisely regulates gene expression and the induction of the osteogenic phenotype