Fibrin Hydrogel Based Bone Substitute Tethered with BMP-2 and BMP-2/7 Heterodimers

Karfeld-Sulzer, Lindsay S.; Siegenthaler, Barbara; Ghayor, Chafik; Weber, Franz E.

doi:10.3390/ma8030977

Cited by 16 publications

(28 citation statements)

References 43 publications

(67 reference statements)

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“…Although the biochemical analysis revealed higher matrix synthesis and content after incorporation of growth factor compared to pure hydrogel delivery, these results did not reach statistical significance. An explanation might be the relatively short observation time in combination with a delivery system that requires hydrogel degradation for growth factor release . Longer culture periods may be needed to detect a significant impact of sustained release BMP‐2/7 delivery on the tissue matrix level.…”

Section: Discussionmentioning

confidence: 99%

“…BMP‐2/7 heterodimer was produced as described previously . The BMP‐2/7 contained extra amino acids for transglutaminase crosslinking and plasmin cleavage sites at the N terminus.…”

Section: Methodsmentioning

confidence: 99%

“…The BMP‐2/7 contained extra amino acids for transglutaminase crosslinking and plasmin cleavage sites at the N terminus. This manipulation facilitates covalent binding of BMP‐2/7 to fibrin or fibrin‐like materials and cell‐demanded growth factor release . Recombinant human BMP‐2 including amino acids for transglutaminase and plasmin cleavage sites (TG‐BMP‐2) and BMP‐7 were cloned and expressed in E. coli .…”

Section: Methodsmentioning

confidence: 99%

“…ß METHODS BMP-2/7 Heterodimer Production BMP-2/7 heterodimer was produced as described previously. 23 The BMP-2/7 contained extra amino acids for transglutaminase crosslinking and plasmin cleavage sites at the N terminus. This manipulation facilitates covalent binding of BMP-2/7 to fibrin or fibrin-like materials and cell-demanded growth factor release.…”

mentioning

confidence: 99%

“…An explanation might be the relatively short observation time in combination with a delivery system that requires hydrogel degradation for growth factor release. 23 Longer culture periods may be needed to detect a significant impact of sustained release BMP-2/7 delivery on the tissue matrix level. Furthermore, combinations of different growth factors might show superior efficacy.…”

mentioning

confidence: 99%

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Heterodimeric BMP‐2/7 for nucleus pulposus regeneration—In vitro and ex vivo studies

Lang

Karfeld-Sulzer

et al. 2016

Journal Orthopaedic Research

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Intervertebral disc (IVD) degeneration is the leading trigger of low back pain, which causes disability and leads to enormous healthcare toll worldwide. Biological treatment with growth factors has evolved as potential therapy for IVD regeneration. Bone morphogenetic protein 2 (BMP-2) and BMP-7 have shown promise in this regard. In the current study, we evaluated the effect of BMP-2/7 heterodimer for disc regeneration both in vitro and in organ culture. Nucleus pulposus (NP) cells isolated from bovine caudal disc were cultured in a fibrin-hyaluronan (FBG-HA) hydrogel for up to 14 days. BMP-2/7 heterodimer covalently incorporated within the hydrogel up-regulated the aggrecan and type II collagen gene expression, and glycosaminoglycan synthesis of NP cells. The activity of the BMP-2/7 heterodimer was dose dependent. The higher dose of BMP-2/7 was further assessed in an IVD whole organ system. After 14 days of culture with cyclic dynamic load, the BMP-2/7 heterodimer delivered into the nucleotomized region showed potential to stimulate the gene expression and synthesis of proteoglycan in the remaining NP tissue after partial nucleotomy. The gene expression level of type I collagen and alkaline phosphatase in the native disc tissue were not affected by BMP-2/7 treatment, indicating no adverse fibroblastic or osteogenic effect on the disc tissue. Intradiscal delivery of BMP-2/7 heterodimer may be a promising therapeutic approach for NP regeneration. The current IVD whole organ partial nucleotomy model may be utilized for screening of other biomaterials or drugs to treat early degenerative disc disorders. Keywords: BMP-2/7 heterodimer; nucleus pulposus regeneration; intervertebral disc; whole organ cultureThe intervertebral disc (IVD) is composed of the central gel-like nucleus pulposus (NP), the surrounding annulus fibrosus (AF), and the cartilaginous endplates that anchor the discs to the adjacent vertebrae. 1 The main functions of the IVD are to provide flexibility to the spine, and to transmit mechanical loads. Low back pain caused by IVD degeneration is the leading cause of disability worldwide. 2 Biological approaches for treatment of IVD degeneration have recently evolved, including the use of recombinant or natural proteins that can lead to the restoration of the disc. 3,4 Bone morphogenetic proteins (BMPs) are involved in a variety of developmental processes, including bone, cartilage and IVD formation. 5,6 In particular, BMP-2 and BMP-7 have been investigated in musculoskeletal research and have demonstrated promising potential for IVD regeneration. BMP-2 can up-regulate the gene expression and protein synthesis of extracellular matrix components in rabbit 7 and human NP cells 8,9 cultured in vitro. In a rabbit in vivo study, treatment with adeno-associated viral vector carrying the gene for BMP-2 delayed the degeneration process in annulotomized discs. 10 BMP-7 was found to stimulate matrix synthesis in NP and AF cells from rabbit 11,12 and human 13 origin. It also inhibited cellular apoptosis, in...

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Section: Discussionmentioning

confidence: 99%

“…BMP‐2/7 heterodimer was produced as described previously . The BMP‐2/7 contained extra amino acids for transglutaminase crosslinking and plasmin cleavage sites at the N terminus.…”

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

See 3 more Smart Citations

Heterodimeric BMP‐2/7 for nucleus pulposus regeneration—In vitro and ex vivo studies

Lang

Karfeld-Sulzer

et al. 2016

Journal Orthopaedic Research

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Biomaterials for Sequestration of Growth Factors and Modulation of Cell Behavior

Teixeira

Domingues

Shevchuk

et al. 2020

Adv Funct Materials

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Growth factors (GFs) are proteins secreted by cells that regulate a variety of biological processes. Although they have long been proposed as potent therapeutic agents, their administration in a soluble form has proven costly and ineffective due to their short half-lives in biological environments. Biomaterial-based approaches are increasingly sought as alternatives to improve the efficacy or, ideally, replace the need for exogenous administration of GFs in regenerative medicine strategies. The means by which these systems evolve from biomaterials for conventional controlled release of GFs to the recent extracellular matrix (ECM)-inspired approaches for sequestering these labile molecules and regulating their spatiotemporal activity and presentation are reviewed. Focus is placed on biomaterials functionalized either with ECM components, which show promiscuous GF binding, or with targeted GF ligands (antibodies, aptamers, or peptides). The potential of synthetic platforms with abiotic affinity as cost-effective alternatives to the current biological ligands is also discussed. Overall, the various GF sequestering systems developed so far have remarkably improved the activity of GFs at reduced doses and, in some cases, completely avoided the need for their exogenous administration to guide cell fates. These bioinspired concepts thus enable the rational exploration of the full therapeutic potential of GFs in regenerative medicine.

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Spatiotemporal Control Strategies for Bone Formation through Tissue Engineering and Regenerative Medicine Approaches

White

Olabisi

2018

Adv Healthcare Materials

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Global increases in life expectancy drive increasing demands for bone regeneration. The gold standard for surgical bone repair is autografting, which enjoys excellent clinical outcomes; however, it possesses significant drawbacks including donor site morbidity and limited availability. Although collagen sponges delivered with bone morphogenetic protein, type 2 (BMP2) are a common alternative or supplement, they do not efficiently retain BMP2, necessitating extremely high doses to elicit bone formation. Hence, reports of BMP2 complications are rising, including cancer promotion and ectopic bone formation, the latter inducing complications such as breathing difficulties and neurologic impairments. Thus, efforts to exert spatial control over bone formation are increasing. Several tissue engineering approaches have demonstrated the potential for targeted and controlled bone formation. These approaches include biomaterial scaffolds derived from synthetic sources, e.g., calcium phosphates or polymers; natural sources, e.g., bone or seashell; and immobilized biofactors, e.g., BMP2. Although BMP2 is the only protein clinically approved for use in a surgical device, there are several proteins, small molecules, and growth factors that show promise in tissue engineering applications. This review profiles the tissue engineering advances in achieving control over the location and onset of bone formation (spatiotemporal control) toward avoiding the complications associated with BMP2.

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Fibrin Hydrogel Based Bone Substitute Tethered with BMP-2 and BMP-2/7 Heterodimers

Cited by 16 publications

References 43 publications

Heterodimeric BMP‐2/7 for nucleus pulposus regeneration—In vitro and ex vivo studies

Heterodimeric BMP‐2/7 for nucleus pulposus regeneration—In vitro and ex vivo studies

Biomaterials for Sequestration of Growth Factors and Modulation of Cell Behavior

Spatiotemporal Control Strategies for Bone Formation through Tissue Engineering and Regenerative Medicine Approaches

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