Safety of recombinant human platelet-derived growth factor-BB in Augment(R) Bone Graft

Biomimetic Therapeutics Inc, Franklin, TN, USA.
Journal of Tissue Engineering 12/2012; 3(1):2041731412442668. DOI: 10.1177/2041731412442668
Source: PubMed


This article discusses nonclinical and clinical data regarding the safety of recombinant human platelet-derived growth factor-BB as a component of the Augment(®) Bone Graft (Augment). Augment is a bone graft substitute intended to be used as an alternative to autologous bone graft in the fusion of hindfoot and ankle joints. Nonclinical studies included assessment of the pharmacokinetic profile of intravenously administered recombinant human platelet-derived growth factor-BB in rat and dog, effects of intravenous administration of recombinant human platelet-derived growth factor-BB in a reproductive and development toxicity study in rats, and chronic toxicity and carcinogenicity of Augment in a 12-month implantation model. These studies showed that systemic exposure was brief and clearance was rapid. No signs of toxicity, carcinogenicity, or tumor promotion were observed even with doses far exceeding the maximum clinical dose. Results of clinical trials (605 participants) and commercial use of recombinant human platelet-derived growth factor-BB containing products indicate that these products are not associated with increased incidence of adverse events or cancer. The safety data presented provide evidence that recombinant human platelet-derived growth factor-BB is a safe therapeutic when used in combination products as a single administration during surgical procedures for bone repair and fusion. There is no evidence associating use of recombinant human platelet-derived growth factor-BB in Augment with chronic toxicity, carcinogenicity, or tumor promotion.

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Available from: Luis Solchaga, Sep 29, 2014
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    • "The potent stimulatory effects of PDGF as a chemoattractant [8], [9] and a mitogen [10], [11], along with its ability to promote angiogenesis [12], [13], position it as a key regulatory molecule in tissue repair. PDGF has been studied in a variety of preclinical models for safety [14], [15] and tissue regeneration as well as clinical trials in periodontal and orthopedic patients [13], [16], [17], [18]. These combined studies have confirmed the effectiveness of PDGF in the repair of musculoskeletal tissue defects. "
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    ABSTRACT: The recruitment of mesenchymal stem cells (MSCs) is a vital step in the bone healing process, and hence the functionalization of osteogenic biomaterials with chemotactic factors constitutes an important effort in the tissue engineering field. Previously we determined that bone-mimetic electrospun scaffolds composed of polycaprolactone, collagen I and nanohydroxyapatite (PCL/col/HA) supported greater MSC adhesion, proliferation and activation of integrin-related signaling cascades than scaffolds composed of PCL or collagen I alone. In the current study we investigated the capacity of bone-mimetic scaffolds to serve as carriers for delivery of an MSC chemotactic factor. In initial studies, we compared MSC chemotaxis toward a variety of molecules including PDGF-AB, PDGF-BB, BMP2, and a mixture of the chemokines SDF-1α, CXCL16, MIP-1α, MIP-1β, and RANTES. Transwell migration assays indicated that, of these factors, PDGF-BB was the most effective in stimulating MSC migration. We next evaluated the capacity of PCL/col/HA scaffolds, compared with PCL scaffolds, to adsorb and release PDGF-BB. We found that significantly more PDGF- BB was adsorbed to, and subsequently released from, PCL/col/HA scaffolds, with sustained release extending over an 8-week interval. The PDGF-BB released was chemotactically active in transwell migration assays, indicating that bioactivity was not diminished by adsorption to the biomaterial. Complementing these studies, we developed a new type of migration assay in which the PDGF-BB-coated bone-mimetic substrates were placed 1.5 cm away from the cell migration front. These experiments confirmed the ability of PDGF-BB-coated PCL/col/HA scaffolds to induce significant MSC chemotaxis under more stringent conditions than standard types of migration assays. Our collective results substantiate the efficacy of PDGF-BB in stimulating MSC recruitment, and further show that the incorporation of native bone molecules, collagen I and nanoHA, into electrospun scaffolds not only enhances MSC adhesion and proliferation, but also increases the amount of PDGF-BB that can be delivered from scaffolds.
    Preview · Article · Jul 2012 · PLoS ONE
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    ABSTRACT: Purpose: Repairing tendon injuries with recombinant human platelet-derived growth factor-BB has potential for improving surgical outcomes. Augmentation of sutures, a critical component of surgical tendon repair, by coating with growth factors may provide a clinically useful therapeutic device for improving tendon repair. Therefore, the purpose of this study was to (a) coat Vicryl sutures with a defined dose of recombinant human platelet-derived growth factor-BB without additional coating excipients (e.g. gelatin), (b) quantify the recombinant human platelet-derived growth factor-BB released from the suture, and (c) use the recombinant human platelet-derived growth factor-BB-coated sutures to enhance tendon repair in a rat Achilles tendon transection model.
    Full-text · Article · Dec 2012 · Journal of Tissue Engineering
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    ABSTRACT: Background Augment® Bone Graft is a bone graft substitute intended to be used as an alternative to autologous bone graft in the fusion of hindfoot and ankle joints. Augment® Bone Graft is a combination device comprised of beta-tricalcium phosphate (β-TCP) and recombinant human platelet-derived growth factor BB homodimer (rhPDGF-BB). Objective This human pharmacokinetic study was undertaken to assess the effect of Augment® Bone Graft implantation on the serum concentration of platelet-derived growth factors (PDGFs). Methods Under the terms of a Research Ethics Board-approved protocol, Augment® Bone Graft was implanted in patients (n = 7) undergoing hindfoot and ankle arthrodesis procedures requiring graft material. The control cohort of the study (n = 4) received autologous bone graft. The serum concentrations of PDGF isoforms AA, AB and BB in blood samples, obtained prior to and at ten time points (up to 7 days) after surgery, were measured using enzyme-linked immunosorbent assays (ELISA). Results The serum concentration of PDGF-BB did not vary significantly from baseline (median of the combined cohorts 3.89 ng/mL) throughout the course of the study. The serum concentrations of PDGF-AA, PDGF-AB and total PDGF did not deviate from their baseline values (medians of the combined cohorts were 2.87, 14.95 and 20.19 ng/mL for PDGF-AA, PDGF-AB and total PDGF, respectively) except for the last time point in which they were increased (medians for the combined cohorts were 4.71, 20.42 and 30.29 ng/mL for PDGF-AA, PDGF-AB and total PDGF, respectively). There were no differences between the two treatment groups with regard to changes in the serum concentrations of PDGF. None of the samples tested contained anti-PDGF-BB antibodies. Conclusion Analysis of the data demonstrated that the serum concentrations of all three PDGF isoforms analysed were unaffected by implantation of Augment® Bone Graft.
    No preview · Article · Jan 2013 · Clinical Drug Investigation
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