Publications (13)30.37 Total impact
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Article: Dose-response effect of an intra-tendon application of recombinant human platelet-derived growth factor-BB (rhPDGF-BB) in a rat Achilles tendinopathy model.
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ABSTRACT: The purpose of this study was to assess whether intra-tendon delivery of recombinant human platelet-derived growth factor-BB (rhPDGF-BB) would improve Achilles tendon repair in a rat collagenase-induced tendinopathy model. Seven days following collagenase induction of tendinopathy, one of four intra-tendinous treatments was administered: (i) Vehicle control (sodium acetate buffer), (ii) 1.02 µg rhPDGF-BB, (iii) 10.2 µg rhPDGF-BB, or (iv) 102 µg rhPDGF-BB. Treated tendons were assessed for histopathological (e.g., proliferation, tendon thickness, collagen fiber density/orientation) and biomechanical (e.g., maximum load-to-failure and stiffness) outcomes. By 7 days post-treatment, there was a significant increase in cell proliferation with the 10.2 and 102 µg rhPDGF-BB-treated groups (p = 0.049 and 0.015, respectively) and in thickness at the tendon midsubstance in the 10.2 µg of rhPDGF-BB group (p = 0.005), compared to controls. All groups had equivalent outcomes by Day 21. There was a dose-dependent effect on the maximum load-to-failure, with no significant difference in the 1.02 and 102 µg rhPDGF-BB doses but the 10.2 µg rhPDGF-BB group had a significant increase in load-to-failure at 7 (p = 0.003) and 21 days (p = 0.019) compared to controls. The rhPDGF-BB treatment resulted in a dose-dependent, transient increase in cell proliferation and sustained improvement in biomechanical properties in a rat Achilles tendinopathy model, demonstrating the potential of rhPDGF-BB treatment in a tendinopathy application. Consequently, in this model, data suggest that rhPDGF-BB treatment is an effective therapy and thus, may be an option for clinical applications to treat tendinopathy. © 2012 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res.Journal of Orthopaedic Research 08/2012; · 2.81 Impact Factor -
Article: Effect of recombinant human platelet-derived growth factor-BB-coated sutures on Achilles tendon healing in a rat model: A histological and biomechanical study.
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ABSTRACT: 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. Vicryl sutures were coated with 0, 0.3, 1.0, and 10.0 mg/mL concentrations of recombinant human platelet-derived growth factor-BB using a dip-coating process. In vitro release was quantified by an enzyme-linked immunosorbent assay. Acutely transected rat Achilles tendons were repaired using one of the four suture groups (n = 12 per group). Four weeks following repair, the tensile biomechanical and histological (i.e. collagen organization and angiogenesis) properties were determined. A dose-dependent bolus release of recombinant human platelet-derived growth factor-BB occurred within the first hour in vitro, followed by a gradual release over 48 h. There was a significant increase in ultimate tensile strength (p < 0.01) in the two highest recombinant human platelet-derived growth factor-BB dose groups (1.9 ± 0.5 and 2.1 ± 0.5 MPa) relative to controls (1.0 ± 0.2 MPa). The modulus significantly increased (p = 0.031) with the highest recombinant human platelet-derived growth factor-BB dose group (7.2 ± 3.8 MPa) relative to all other groups (control: 3.5 ± 0.9 MPa). No significant differences were identified for the maximum load or stiffness. The histological collagen and angiogenesis scores were comparable in all groups, although there was a trend for improved collagen organization in the recombinant human platelet-derived growth factor-BB-treated groups (p = 0.054). The results of this study suggest that recombinant human platelet-derived growth factor-BB can be used to reproducibly coat Vicryl sutures and improve remodeling in a rat Achilles tendon transection model by significantly decreasing the resulting cross-sectional area, thus improving the material properties of the repaired tendon.Journal of tissue engineering. 01/2012; 3(1):2041731412453577. -
Article: Growth factors and craniofacial surgery.
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ABSTRACT: The specialty of craniofacial surgery is broad and includes trauma, aesthetics, reconstruction of congenital deformities, and regeneration of tissues. Moreover, craniofacial surgery deals with a diverse range of tissues including both "soft" and "hard" tissues. Technological advances in materials and biological sciences and improved surgical techniques have remarkably improved clinical outcomes. The quest to raise the bar for patient care continues to inspire advances for predictable biological regeneration of soft and hard tissues. As a consequence of this quest for advancement, a wide spectrum of biologicals is becoming available to surgeons. Is the use of recombinant DNA engineered biologicals daring? Sensible? Logical? Timely? Safe? It is crucial for the practicing craniofacial surgeon to take a step back periodically and carefully review the biological factors that have the potential for dramatically altering the discipline of craniofacial surgery. With this emphasis, the coauthors of this article will focus on growth factor technology underscoring bone tissue regeneration. As the 21st-century matures, recombinant human biologicals will have an overwhelming impact on the practice of craniofacial surgery.The Journal of craniofacial surgery 01/2012; 23(1):20-9. · 0.81 Impact Factor -
Article: Safety of recombinant human platelet-derived growth factor-BB in Augment(®) Bone Graft.
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ABSTRACT: 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.Journal of tissue engineering. 01/2012; 3(1):2041731412442668. -
Article: Regenerative tendon and ligament healing: opportunities with recombinant human platelet-derived growth factor BB-homodimer.
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ABSTRACT: Intrinsic tendon healing in response to injury is a reparative process that often results in formation of scar tissue with functional and mechanical properties inferior to those of the native tendon. Development of therapies that can promote regenerative, rather than reparative, healing hold the promise of improving patient recovery from tendon and ligament injuries by producing tissue that is morphologically and functionally equivalent to the native tissue. One therapeutic approach that has been a frequent topic of investigation in the preclinical literature is the use of recombinant human platelet-derived growth factor-BB (rhPDGF-BB) to augment tendon and ligament repair. The chemotactic, mitogenic, and pro-angiogenic properties of rhPDGF-BB have been shown to result in recruitment and proliferation of tenogenic cells and a commensurate boost in extracellular matrix deposition and organization, improving the morphological and biomechanical properties of healing tendons and ligaments. The outcomes of the preclinical studies reviewed here strongly suggest that rhPDGF-BB will provide a new therapeutic opportunity to improve the treatment of injured tendons and ligaments.Tissue Engineering Part B Reviews 12/2011; 18(3):225-34. · 4.64 Impact Factor -
Article: Augment bone graft products compare favorably with autologous bone graft in an ovine model of lumbar interbody spine fusion.
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ABSTRACT: This study was designed to determine whether Augment Bone Graft (Augment, Biomimetic Therapeutics, Inc., Franklin, TN) and Augment Injectable Bone Graft (Augment Injectable, Biomimetic Therapeutics, Inc., Franklin, TN), 2 combination devices comprising recombinant human platelet-derived growth factor-BB and β-tricalcium phosphate-containing matrices, promote bone bridging in an ovine model of lumbar spine fusion. Autologous bone graft (autograft) was used as a positive control. The purpose of this study was to determine the ability of Augment products to promote fusion of the L2-L3 and L4-L5 vertebral bodies in an ovine model. In interbody spine fusion, the intervertebral disc is removed and a spacer is inserted for support and to facilitate bone growth. The fusion is commonly enhanced with grafts. Autograft is the "gold standard" but it has limitations including availability and donor-site morbidity. Synthetic graft substitutes eliminate these complications. Augment products are combination devices including recombinant human platelet-derived growth factor-BB, a well-characterized chemotactic, mitogenic, and proangiogenic protein essential in wound and bone healing. Twenty-two sheep received an uninstrumented, double-level, interbody lumbar spinal fusion procedure using a polyetheretherketone spacer, which was either empty or packed with iliac crest autograft, Augment or Augment Injectable. The same treatment was used at both levels. Animals were 24 weeks after surgery, and fusion was assessed by micro-computed tomography (micro-CT) and histology. Micro-CT and histologic assessment of fusion revealed that empty controls had significantly lower fusion rates. No differences were detected among autografts, Augment, and Augment Injectable-treated specimens. Residual β-tricalcium phosphate particles embedded in the newly formed bone were visible in Augment- and Augment Injectable-treated specimens. Augment-treated specimens had the highest fusion scores. Treatment with either of the Augment products significantly promoted interbody spine fusion compared with empty spacers and was equivalent to autograft-induced fusion. No adverse events were noted.Spine 10/2011; 37(8):E461-7. · 2.08 Impact Factor -
Article: Augmentation of a rotator cuff suture repair using rhPDGF-BB and a type I bovine collagen matrix in an ovine model.
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ABSTRACT: Rotator cuff tears are a common source of shoulder pain. High rates (20%-94%) of structural failure of the repair have been attributed to multiple factors, including poor repair tissue quality and tendon-to-bone integration. Biologic augmentation using growth factors has potential to promote tendon-to-bone integration, improving the function and long-term success of the repair. One such growth factor is platelet-derived growth factor-BB (PDGF-BB), which has been shown to improve healing in tendon and bone repair models. Recombinant human PDGF-BB (rhPDGF-BB) combined with a highly porous type I bovine collagen matrix will improve the biomechanical function and morphologic appearance of the repair in a dose-dependent manner, relative to a suture-only control, after 12 weeks in an acute ovine model of rotator cuff repair. Controlled laboratory study. An interpositional graft consisting of rhPDGF-BB and a type I collagen matrix was implanted in an ovine model of rotator cuff repair. Biomechanical and histologic analyses were performed to determine the functional and anatomic characteristics of the repair after 12 weeks. A significant increase in the ultimate load to failure was observed in repairs treated with 75 µg (1490.5 ± 224.5 N, P = .029) or 150 µg (1486.6 ± 229.0 N, P = .029) of rhPDGF-BB, relative to suture-only controls (910.4 ± 156.1 N) and the 500-µg rhPDGF-BB group (677.8 ± 105.9 N). The 75-µg and 150-µg rhPDGF-BB groups also exhibited increased tendon-to-bone interdigitation histologically. No differences in inflammation or cellularity were observed among treatments. This study demonstrated that an interpositional graft consisting of rhPDGF-BB (75 or 150 µg) and a type I collagen matrix was able to improve the biomechanical strength and anatomic appearance in an ovine model of rotator cuff repair compared to a suture-only control and the 500-µg rhPDGF-BB group. Recombinant human PDGF-BB combined with a type I collagen matrix has potential to be used to augment surgical repair of rotator cuff tears, thereby improving clinical success.The American journal of sports medicine 05/2011; 39(8):1630-9. · 3.61 Impact Factor -
Article: Differential surface antigen expression and 1α,25-dihydroxyvitamin D3 responsiveness distinguish human dermal fibroblasts with age-dependent osteogenic differentiation potential from marrow-derived stromal cells in vitro.
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ABSTRACT: Recent studies have demonstrated that cells committed to a fibroblastic lineage, including dermal fibroblasts, may undergo osteoblastic differentiation when treated with steroid hormones. However, stem cells have also been isolated from the dermis, making it unclear whether osteoinduction of dermal fibroblasts is the result of transdifferentiation of committed fibroblasts or differentiation of resident multipotent stromal cells, which are morphologically indistinguishable. Flow cytometry was used to characterize the expression of CD26, CD90 and CD105 on neonatal and adult human dermal fibroblasts and adult human bone marrow-derived stromal cells. These cells were then cultured with the steroid hormones 1α,25-dihydroxyvitamin D(3) and dexamethasone, and evaluated for protein expression and mineral deposition typical of an osteoblastic phenotype. The surface peptidase, dipeptidyl peptidase IV (CD26), was differentially expressed between human neonatal (98.22 ± 1.47%) and adult (90.73 ± 7.97%) dermal fibroblasts and adult bone marrow-derived stromal cells (6.84 ± 5.07%). In addition, neonatal dermal fibroblasts treated with vitamin D(3) expressed alkaline phosphatase, osteocalcin and bone sialoprotein, and deposited mineral, which is consistent with an osteoblastic phenotype. Such differentiation was not observed in adult dermal fibroblasts. In contrast, marrow-derived stromal cells required dexamethasone in order to undergo osteoblastic differentiation. Taken together, the differential surface antigen expression and disparate response to steroid hormones suggest that committed neonatal dermal fibroblasts are distinct from mesenchymal stromal cells and possess osteogenic differentiation potential.Cytotherapy 05/2011; 13(5):528-38. · 3.63 Impact Factor -
Article: A rat model of temporomandibular joint pain with histopathologic modifications.
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ABSTRACT: To develop a rat model of temporomandibular joint (TMJ) pain and to characterize in it the development and temporal response of behavioral hypersensitivity as well as to evaluate if and to what extent a loading protocol is associated with histological changes in the TMJ consistent with osteoarthritic pathology. A novel rat model of TMJ pain was developed using a noninvasive, mechanical loading protocol. Rats were exposed to steady mouth-opening for 7 days (2 N force, 1 hour/day), and mechanical hyperalgesia (increased pain response) was measured during the loading period and for 14 days thereafter. Histological modifications in the joint cartilage were also evaluated. Outcomes for the mouth-opening exposure were compared to age-matched controls. Thresholds for evoking responses were compared using a ranked ANOVA with repeated measures. Increased mechanical hypersensitivity in the temporomandibular region developed during daily loading and persisted even after the termination of the loading protocol. Histologic characterization revealed thinning of the cartilaginous structures of the joint and irregular zonal cellular arrangements in the condylar cartilage of rats subjected to the daily loading protocol. The injury model presented here is the first to demonstrate mechanically-induced behavioral hypersensitivity accompanied by osteoarthritic pathology in the TMJ.Journal of orofacial pain 01/2010; 24(3):298-304. · 2.59 Impact Factor -
Article: Endogenous bone morphogenetic proteins mediate 1alpha, 25-dihydroxyvitamin D(3)-induced expression of osteoblast differentiation markers in human dermal fibroblasts.
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ABSTRACT: Human dermal fibroblasts are generally considered to be restricted to a fibroblastic lineage. Although dermal fibroblasts do not typically express markers of osteoblastic differentiation, they have previously been shown to undergo osteoinduction when stimulated with bone morphogenetic proteins (BMPs) or vitamin D(3). However, involvement of BMP signaling in vitamin D(3)-mediated osteoinduction has not been reported. In this study, human dermal fibroblasts were cultured in chemically defined medium containing vitamin D(3), in the presence of the BMP antagonist noggin or neutralizing antibodies specific for BMP-4 or BMP-6, and characterized for markers of osteoblastic differentiation. Treatment of dermal fibroblasts with vitamin D(3) induced expression of BMP-4 (1.2 +/- 0.2, 1.7 +/- 0.2, and 1.8 +/- 0.2 relative fold increase) and BMP-6 (9.1 +/- 0.3, 23.3 +/- 2.1, and 30.4 +/- 3.0 relative fold increase) at 3, 14, and 21 days, respectively. Vitamin D(3) was also shown to induce the expression of the osteoblast-specific markers, alkaline phosphatase and osteocalcin, in a dose-dependent manner in human dermal fibroblasts. Addition of noggin, BMP-4 antibodies, and BMP-6 antibodies resulted in a downregulation of alkaline phosphatase activity (by 42%, 22%, and 20%, respectively) and secreted osteocalcin (by 20%, 31%, and 49%, respectively) after 21 days in culture. However, blocking BMP signaling did not result in complete recovery of a fibroblastic phenotype. Taken together, these results suggest that BMP signaling plays a role in the induction of an osteoblastic phenotype in human dermal fibroblasts in response to vitamin D(3) stimulation.Journal of Orthopaedic Research 09/2008; 27(2):162-8. · 2.81 Impact Factor -
Article: Influence of three-dimensional scaffold on the expression of osteogenic differentiation markers by human dermal fibroblasts.
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ABSTRACT: Current research in the field of tissue engineering utilizes biomaterial scaffolds, cells, and growth factors for the creation of a functional, biologically active tissue. This study examined the effect of two commercially available, three-dimensional scaffolds, ultraporous beta-tricalcium phosphate ceramics (beta-TCP, Vitoss) and open-celled poly(lactic acid) foams (OPLA, Drilac), on the osteogenic differentiation potential of human dermal fibroblasts. Serum-free, chemically-defined medium containing the metabolic factor 1alpha,25-dihydroxyvitamin D3 was used to promote an osteogenic phenotype in these cells. Osteoblast differentiation was assessed using PCR and immunohistochemical methods to detect gene and protein expression for the osteoblast markers alkaline phosphatase, osteopontin, and osteocalcin. Dermal fibroblasts cultured on beta-TCP scaffolds in chemically-defined medium with vitamin D3 exhibited up-regulated gene and protein expression compared to cells cultured on OPLA scaffolds. These results suggest that Vitoss (beta-TCP) scaffolds seeded with dermal fibroblasts and maintained in chemically-defined medium with vitamin D3 are better suited for bone tissue engineering applications than Drilac (OPLA) foams.Biomaterials 03/2006; 27(6):875-84. · 7.40 Impact Factor -
Article: Induction of osteoblast differentiation markers in human dermal fibroblasts: potential application to bone tissue engineering.
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ABSTRACT: Tissue engineered constructs have the potential to be used as replacements for current bone graft technologies. One component necessary for bone tissue engineering is a readily available, osteogenic cell source. Human dermal fibroblasts may have the potential to differentiate along an osteoblastic lineage, making them a candidate for use in bone tissue engineering applications. The objective of this study was to validate the ability of dermal fibroblasts to express gene and protein markers of osteoblastic differentiation and to explore their potential, in combination with biomaterial scaffolds and signaling factors, for use in bone tissue engineering.Conference proceedings: ... Annual International Conference of the IEEE Engineering in Medicine and Biology Society. IEEE Engineering in Medicine and Biology Society. Conference 02/2006; 1:521-4. -
Article: Osteogenic differentiation of human dermal fibroblasts
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ABSTRACT: Approximately 1.5 million bone graft procedures are performed annually in the United States. Given limitations in current bone graft technology, tissue engineering represents an alternate strategy to repair damaged or diseased tissues. A major component of any engineered construct is a viable source of cells that can perform the function of the native cells. Dermal fibroblasts, which are committed to a fibroblastic lineage, represent a potential substitute for osteoblasts in the repair of osseous defects, as they are readily available from a small skin biopsy and may be easily expanded. Furthermore, dermis-derived fibroblastic cells have recently been shown to undergo osteoblastic differentiation when cultured in the presence of various biochemical mediators. However, the origin of these bone-forming cells is unknown. Therefore, the objectives of this thesis were to identify a selective marker to distinguish between dermis-derived fibroblasts and stem cells and to investigate the influence of specific environmental stimuli (i.e., steroid hormones, material substrates) on the osteogenic differentiation potential of human dermal fibroblasts. We hypothesized that human dermal fibroblasts are a committed cell type, which exhibit a surface marker profile that is distinct from bone marrow-derived stem cells, and are able to undergo age-dependent osteogenic differentiation when supplemented with 1α,25-dihydroxyvitamin D3 in two- and three-dimensional culture, with cells from adult donors exhibiting a reduced differentiation capacity. We also hypothesized that the biochemical induction of osteoblastic differentiation in human dermal fibroblasts by vitamin D3 is mediated by bone morphogenetic protein signaling. We found that dermal fibroblasts could be distinguished from marrow-derived stem cells based on the selective expression of the surface peptidase, dipeptidyl peptidase IV (CD26). Further, neonatal human dermal fibroblasts were able to undergo osteogenic differentiation when cultured in the presence of 100 nM vitamin D3 in two-dimensional monolayer culture and when seeded on β-tricalcium phosphate scaffolds. Adult fibroblasts exhibited reduced differentiation capacity under similar culture conditions. In addition, the initial seeding density and serum-free culture influenced the osteoinductive process for both neonatal and adult cells. We also demonstrated that the osteoblastic differentiation of human dermal fibroblasts induced by vitamin D3 is regulated, in part, through bone morphogenetic protein signaling. Taken together, the results of this work suggest that neonatal human dermal fibroblasts are able to differentiate along an osteoblastic lineage pathway, and therefore, have the potential to serve as an alternate cell source for bone tissue repair strategies.Dissertations available from ProQuest.
Top co-authors
Top Journals
- Journal of Orthopaedic Research (2)
- Biomaterials (1)
- Journal of orofacial pain (1)
- Cytotherapy (1)
- Spine (1)
Institutions
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2006–2011
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University of Pennsylvania
- Department of Bioengineering
Philadelphia, PA, USA
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