Safety of recombinant human platelet-derived growth factor-BB in                         Augment<sup>®</sup> Bone Graft

Solchaga, Luis A.; Hee, Christopher K.; Roach, Stephen; Snel, Leo

doi:10.1177/2041731412442668

Cited by 49 publications

(25 citation statements)

References 33 publications

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“…As it is FDA approved and used in clinical settings for other applications, no safety problems are expected to arise with its use for tendon repair (Paul et al, 2015;Solchaga et al, 2012;Ziyadeh et al, 2011). Many in vitro studies with tenocytes clearly demonstrate its biological properties (Raghavan et al, 2012;Zhao and Hadjiargyrou, 2011), while studies of its effects on the tendon progenitor stem cell population are still missing.…”

Section: Current Limitations and Future Workmentioning

confidence: 99%

In vitro and in vivo effects of PDGF-BB delivery strategies on tendon healing: a review

Evrova

Buschmann

2017

eCM

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To promote and support tendon healing, one viable strategy is the use or administration of growth factors at the wound/rupture site. Platelet derived growth factor-BB (PDGF-BB), together with other growth factors, is secreted by platelets after injury. PDGF-BB promotes mitogenesis and angiogenesis, which could accelerate tendon healing. Therefore, in vitro studies with PDGF-BB have been performed to determine its effect on tenocytes and tenoblasts. Moreover, accurate and sophisticated drug delivery devices, aiming for a sustained release of PDGF-BB, have been developed, either by using heparin-binding and fibrin-based matrices or different electrospinning techniques.In this review, the structure and composition, as well as the healing process of tendons, are described. Part A deals with in vitro studies. They focus on the multiple effects evoked by PDGF-BB on the cellular level. Moreover, they address strategies for the sustained delivery of PDGF-BB. Part B focuses on animal models used to test different delivery strategies for PDGF-BB, in the context of tendon reconstruction. These studies showed that dosage and timing of PDGF-BB application are the most important factors for deciding which delivery device should be applied for a specific tendon laceration.

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Section: Current Limitations and Future Workmentioning

confidence: 99%

In vitro and in vivo effects of PDGF-BB delivery strategies on tendon healing: a review

Evrova

Buschmann

2017

eCM

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“…In addition, there have been considerable successful applications of PDGF-BB-based therapies on various types of maladies, including tendon, periodontal ligament, and bone fracture repairs (12,13). The safety of PDGF-BB has been demonstrated in several clinical trials (14,15), and it has been approved by the Food and Drug Administration for treatment of patients with oral and maxillofacial bony defects (15). Second, we used various promoters of different strengths to express PDGFB to identify the optimal PDGF-BB dosage.…”

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confidence: 99%

PDGFB-based stem cell gene therapy increases bone strength in the mouse

Chen

Baylink

Brier-Jones

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Substantial advances have been made in the past two decades in the management of osteoporosis. However, none of the current medications can eliminate the risk of fracture and rejuvenate the skeleton. To this end, we recently reported that transplantation of hematopoietic stem/progenitor cells (HSCs) or Sca1 + cells engineered to overexpress FGF2 results in a significant increase in lamellar bone matrix formation at the endosteum; but this increase was attended by the development of secondary hyperparathyroidism and severe osteomalacia. Here we switch the therapeutic gene to PDGFB, another potent mitogen for mesenchymal stem cells (MSCs) but potentially safer than FGF2. We found that modest overexpression of PDGFB using a relatively weak phosphoglycerate kinase (PGK) promoter completely avoided osteomalacia and secondary hyperparathyroidism, and simultaneously increased trabecular bone formation and trabecular connectivity, and decreased cortical porosity. These effects led to a 45% increase in the bone strength. Transplantation of PGK-PDGFB-transduced Sca1 + cells increased MSC proliferation, raising the possibility that PDGF-BB enhances expansion of MSC in the vicinity of the hematopoietic niche where the osteogenic milieu propels the differentiation of MSCs toward an osteogenic destination. Our therapy should have potential clinical applications for patients undergoing HSC transplantation, who are at high risk for osteoporosis and bone fractures after total body irradiation preconditioning. It could eventually have wider application once the therapy can be applied without the preconditioning.PDGFB | hematopoietic stem cells | bone formation | gene therapy

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“…Bone repair is strongly regulated by various cytokines, and cytokines are critical for host cell recruitment and tissue regeneration . Some cytokines have been explored therapeutically, but their translation to clinical use in tissue engineering has been limited, likely in part because of their use at supraphysiological levels as well as issues related to persistent delivery and cost effectiveness . Physiological levels of cytokines are necessary and are generated by cell secretion.…”

Section: Discussionmentioning

confidence: 99%

Sustained release of bioactive protein from a lyophilized tissue‐engineered construct promotes the osteogenic potential of mesenchymal stem cells

Deng

Chang

Hou

et al. 2015

Journal Orthopaedic Research

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Tissue-engineered constructs (TECs) seeded with mesenchymal stem cells (MSCs) represent a therapy for large bone defects. However, massive cell death in TECs in the early postimplantation period prompted us to investigate the osteoinductive mechanism of TECs. Previous studies demonstrated that stem cell extracts retained equivalent levels of bioactive proteins and exhibited an osteoinductive nature similar to that of intact cells. These data led us to hypothesize that despite the massive cell death in TECs, devitalized MSC-derived proteins remain on the scaffolds and are released to improve cell function. Here, TECs were prepared using demineralized bone matrix seeded with human umbilical cord Wharton's jelly-derived MSCs (hWJMSCs), and the cells seeded in TECs were devitalized by lyophilizing the TECs. Scanning electron microscopy, BCA protein assays, quantitative cytokine array analysis and immunofluorescent staining indicated that approximately 3 mg/cm 3 of total protein and 49 types of cytokines derived from hWJMSCs were preserved in the lyophilized TECs (LTECs). The sustainable release of total protein and cytokines from LTECs lasted for more than 2 weeks. The released protein improved the osteogenic behavior of and gene expression in MSCs. Furthermore, the lyophilized hWJMSC-derived proteins had immunoregulatory properties similar to those of live MSCs in mixed lymphocyte reactions. Collectively, we present a novel perspective on the osteoinductive mechanism of TECs and introduce LTECs as new systems for delivering multiple cytokines to enhance MSC behavior. Keywords: lyophilized tissue-engineered construct; bioactive protein; sustained release; osteogenesis Large bone defects caused by traumatic bone injury, tumor resection, and osteitis are a challenge confronted in orthopedic surgery. Tissue-engineered constructs (TECs) seeded with mesenchymal stem cells (MSCs) could promote osteogenesis in vivo, and these TECs are a promising therapy for large bone defects. 1 However, several obstacles still impede the widespread clinical application of TECs, including the fact that the osteoinductive mechanism is unclear. It is possible that the osteoinductive mechanism involves the differentiation of MSCs followed by the synthesis and deposition of bone matrix on the scaffold substrate. 2 Alternatively, MSCs may recruit endogenous cells to produce bone matrix by secreting cytokines. 3 However, most studies showed that massive MSC death (from 70% to 100%) in TECs occurred in the first week of the postimplantation period because of local tissue ischemia. 4,5 This observation is inconsistent with the aforementioned mechanisms. Moreover, recent studies showed that stem cell-derived extracts contained a large amount of protein and retained some properties similar to those of intact cells, such as immunoregulatory activity and osteoinductive capacity, among other characteristics. 6,7 It is logical to assume that proteins derived from the devitalized MSCs in TECs should possess these modulatory properties. Therefo...

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Safety of recombinant human platelet-derived growth factor-BB in Augment^® Bone Graft

Cited by 49 publications

References 33 publications

In vitro and in vivo effects of PDGF-BB delivery strategies on tendon healing: a review

In vitro and in vivo effects of PDGF-BB delivery strategies on tendon healing: a review

PDGFB-based stem cell gene therapy increases bone strength in the mouse

Sustained release of bioactive protein from a lyophilized tissue‐engineered construct promotes the osteogenic potential of mesenchymal stem cells

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Safety of recombinant human platelet-derived growth factor-BB in Augment® Bone Graft

Cited by 49 publications

References 33 publications

In vitro and in vivo effects of PDGF-BB delivery strategies on tendon healing: a review

In vitro and in vivo effects of PDGF-BB delivery strategies on tendon healing: a review

PDGFB-based stem cell gene therapy increases bone strength in the mouse

Sustained release of bioactive protein from a lyophilized tissue‐engineered construct promotes the osteogenic potential of mesenchymal stem cells

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Safety of recombinant human platelet-derived growth factor-BB in Augment^® Bone Graft