Robert E Guldberg

Università degli Studi di Trento, Trient, Trentino-Alto Adige, Italy

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Publications (172)739.65 Total impact

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    ABSTRACT: Non-healing bone defects present tremendous socioeconomic costs. Although successful in some clinical settings, bone morphogenetic protein (BMP) therapies require supraphysiological dose delivery for bone repair, raising treatment costs and risks of complications. We engineered a protease-degradable poly(ethylene glycol) (PEG) synthetic hydrogel functionalized with a triple helical, α2β1 integrin-specific peptide (GFOGER) as a BMP-2 delivery vehicle. GFOGER-functionalized hydrogels lacking BMP-2 directed human stem cell differentiation and produced significant enhancements in bone repair within a critical-sized bone defect compared to RGD hydrogels or empty defects. GFOGER functionalization was crucial to the BMP-2-dependent healing response. Importantly, these engineered hydrogels outperformed the current clinical carrier in repairing non-healing bone defects at low BMP-2 doses. GFOGER hydrogels provided sustained in vivo release of encapsulated BMP-2, increased osteoprogenitor localization in the defect site, enhanced bone formation and induced defect bridging and mechanically robust healing at low BMP-2 doses which stimulated almost no bone regeneration when delivered from collagen sponges. These findings demonstrate that GFOGER hydrogels promote bone regeneration in challenging defects with low delivered BMP-2 doses and represent an effective delivery vehicle for protein therapeutics with translational potential.
    Biomaterials 04/2014; · 7.60 Impact Factor
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    ABSTRACT: Localized intra-articular delivery of anti-inflammatory proteins can reduce inflammation in osteoarthritis but poses a challenge because of raid clearance within few hours of injection. A new class of polymer is developed that forms self-assembled nanoparticles ranging from 300 to 900 nm and demonstrates particle size dependent prolonged retention in intra-articular joint spaces compared to bolus protein over a period of 14 d.
    Journal of Interconnection Networks 03/2014;
  • F Brennan Torstrick, Robert E Guldberg
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    ABSTRACT: Despite advances in systemic osteoporosis therapeutic outcomes, management of fragility fractures and implant fixation in osteoporotic bone remain difficult clinical challenges. Low initial bone density and a prolonged healing response can lead to fracture nonunion and aseptic implant loosening. Local treatment strategies could be used to prevent fracture, accelerate healing, and increase implant fixation by locally stimulating anabolic pathways or inhibiting catabolic pathways. Local strategies under investigation include direct drug release from injectable materials or implant surface coatings. Common locally delivered drugs include bisphosphonates, parathyroid hormone, and bone morphogenetic proteins, yet additional compounds targeting novel pathways in bone biology are also being actively explored. Mechanical stimulation via low intensity pulsed ultrasound, alone or in combination with drug therapy, may also prove effective to promote local bone healing and implant fixation within osteoporotic bone.
    Current Osteoporosis Reports 02/2014;
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    ABSTRACT: Micronized dehydrated human amnion/chorion membrane (mu-dHACM) is derived from donated human placentae and has anti-inflammatory, low immunogenic and anti-fibrotic properties. The objective of this study was to quantitatively assess the efficacy of mu-dHACM as a disease modifying intervention in a rat model of osteoarthritis (OA). It was hypothesized that intra-articular injection of mu-dHACM would attenuate OA progression. Lewis rats underwent medial meniscal transection (MMT) surgery to induce OA. 24 hours post-surgery, mu-dHACM or saline was injected intra-articularly into the rat joint. Naive rats also received mu-dHACM injections. Microstructural changes in the tibial articular cartilage were assessed using equilibrium partitioning of an ionic contrast agent (EPIC-muCT) at 21 days post-surgery. The joint was also evaluated histologically and synovial fluid was analyzed for inflammatory markers at 3 and 21 days post-surgery. There was no measured baseline effect of mu-dHACM on cartilage in naive animals. Histological staining of treated joints showed presence of mu-dHACM in the synovium along with local hypercellularity at 3 and 21 days post-surgery. In MMT animals, development of cartilage lesions at 21 days was prevented and number of partial erosions was significantly reduced by treatment with mu-dHACM. EPIC-muCT analysis quantitatively showed that mu-dHACM reduced proteoglycan loss in MMT animals. mu-dHACM is rapidly sequestered in the synovial membrane following intra-articular injection and attenuates cartilage degradation in a rat OA model. These data suggest that intra-articular delivery of mu-dHACM may have a therapeutic effect on OA development.
    Arthritis research & therapy 02/2014; 16(1):R47. · 4.27 Impact Factor
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    ABSTRACT: The functional regeneration of thick vascularized tissues such as bone and muscle is complicated by the large volume of lost tissue, challenging biomechanical environment, and the need to reproduce the highly organized structure of both the native tissue extracellular matrix and its vascular support system. Stem cell or progenitor cell delivery approaches, for example, continue to be plagued by low viability and engraftment in part due to the initial absence of a vascular supply. Recognition of diffusion limitations in thick tissues has prompted regenerative strategies that seek to accelerate establishment of a functional vasculature. The successful design of robust regeneration strategies for these challenging clinical scenarios will rely on a thorough understanding of interactions between construct design parameters and host biological and biomechanical factors. Here, we discuss the critical role of vascularization in normal bone tissue homeostasis and repair, vascular network adaptation to the local biomechanical environment, and the future directions of revascularization approaches being developed and integrated with bone regeneration strategies.
    Annals of Biomedical Engineering 01/2014; · 2.58 Impact Factor
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    ABSTRACT: The temporomandibular joint (TMJ) is susceptive to the development of osteoarthritis (OA). More detailed knowledge of its development is essential to improve our insight into TMJ-OA. It is imperative to have a standardized, reliable 3-D imaging method that allows for detailed assessment of both bone and cartilage in healthy and diseased joints. We aimed to determine the applicability of a contrast-enhanced µCT technique for ex vivo research of mouse and human TMJ. Equilibrium Partitioning of an Ionic Contrast agent via µCT (EPIC-µCT) was previous applied for cartilage assessment in the knee joint. The method was ex vivo applied to the mouse TMJ and adapted for the human TMJ. EPIC-µCT (30' immersion time) was applied to mouse mandibular condyles and 3-D imaging revealed an average cartilage thickness of 110 ± 16 µm. These measurements via EPIC-µCT were comparable to the histomorphometric measures (113 ± 19 µm). For human healthy and OA-affected TMJ samples the protocol was adjusted to an immersion time of one hour. 3-D imaging revealed a significant thicker cartilage layer in joints with early signs of OA compared to healthy joints (414.2 ± 122.6 µm and 239.7 ± 50.5 µm, respectively). A subsequent significant thinner layer was found in human joints with late signs of OA (197.4 ± 159.7 µm). The EPIC-µCT technique is effective for the ex vivo assessment of 3-D cartilage morphology in the mouse as well as human TMJ and allows bone-cartilage interaction research in TMJ-OA.
    Dentomaxillofacial Radiology 12/2013; · 1.15 Impact Factor
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    ABSTRACT: Severe injuries to the extremities often result in muscle trauma and, in some cases, significant volumetric muscle loss (VML). These injuries continue to be challenging to treat, with few available clinical options, a high rate of complications, and often persistent loss of limb function. To facilitate the testing of regenerative strategies for skeletal muscle, we developed a novel quadriceps VML model in the rat, specifically addressing functional recovery of the limb. Our outcome measures included muscle contractility measurements to assess muscle function and gait analysis for evaluation of overall limb function. We also investigated treatment with muscle autografts, whole or minced, to promote regeneration of the defect area. Our defect model resulted in a loss of muscle function, with injured legs generating less than 55% of muscle strength from the contralateral uninjured control legs, even at 4 weeks post-injury. The autograft treatments did not result in significant recovery of muscle function. Measures of static and dynamic gait were significantly decreased in the untreated, empty defect group, indicating a decrease in limb function. Histological sections of the affected muscles showed extensive fibrosis, suggesting that this scarring of the muscle may be in part the cause of the loss of muscle function in this VML model. Taken together, these data are consistent with clinical findings of reduced muscle function in large VML injuries. This new model with quantitative functional outcome measures offers a platform on which to evaluate treatment strategies designed to regenerate muscle tissue volume and restore limb function.
    Journal of biomechanics 11/2013; · 2.66 Impact Factor
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    Dataset: JrOrthoRes
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    Dataset: JrOrthoRes
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    ABSTRACT: Electrospun nanofiber meshes have emerged as a new generation of scaffold membranes possessing a number of features suitable for tissue regeneration. One of these features is the flexibility to modify their structure and composition in order to orchestrate specific cellular responses. In this study, we investigated the effects of nanofiber orientation and surface functionalization on human mesenchymal stem cell (hMSC) migration and osteogenic differentiation. We used an in vitro model to examine hMSC migration into a cell-free zone on nanofiber meshes and mitomycin C treatment to assess the contribution of proliferation to the observed migration. Poly (ε-caprolactone) meshes with oriented topography were created by electrospinning aligned nanofibers on a rotating mandrel, while randomly-oriented controls were collected on a stationary collector. Both aligned and random meshes were coated with a triple-helical, type I collagen-mimetic peptide, containing the glycine-phenylalanine-hydroxyproline-glycine-glutamate-arginine (GFOGER) motif. Our results indicate nanofiber GFOGER peptide-functionalization and orientation modulate cellular behavior, individually, and in combination. GFOGER significantly enhanced the migration, proliferation and osteogenic differentiation of hMSCs on nanofiber meshes. Aligned nanofiber meshes displayed increased cell migration along the direction of fiber orientation compared to random meshes; however, fiber alignment did not influence osteogenic differentiation. Compared to each other, GFOGER coating resulted in a higher proliferation-driven cell migration, whereas fiber orientation appeared to generate a larger direct migratory effect. This study demonstrates that peptide surface modification and topographical cues associated with fiber alignment can be used to direct cellular behavior on nanofiber mesh scaffolds, which may be exploited for tissue regeneration.
    Tissue Engineering Part A 09/2013; · 4.64 Impact Factor
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    ABSTRACT: This article demonstrates a method to engineer, in vitro, a nascent microvasculature within a collagen-GAG scaffold with a view to overcoming the major issue of graft failure due to avascular necrosis of tissue engineered constructs. Human umbilical vein endothelial cells (ECs) were cultured alone and in various co-culture combinations with human mesenchymal stem cells (MSCs) to determine their vasculogenic abilities in vitro. Results demonstrated that the delayed addition of MSCs to pre-formed EC networks, whereby MSCs act as pericytes to the nascent vessels, resulted in the best developed vasculature. The results also demonstrate that the crosstalk between ECs and MSCs during microvessel formation occurs in a highly regulated, spatio-temporal fashion, whereby the initial seeding of ECs results in platelet derived growth factor (PDGF) release; the subsequent addition of MSCs 3 days later leads to a cessation in PDGF production, coinciding with increased vascular endothelial cell growth factor expression and enhanced vessel formation. Functional assessment of these pre-engineered constructs in a subcutaneous rat implant model demonstrated anastomosis between the in vitro engineered vessels and the host vasculature, with significantly increased vascularisation occurring in the co-culture group. This study has thus provided new information on the process of in vitro vasculogenesis within a 3D porous scaffold for tissue engineering and demonstrates the potential for using these vascularised scaffolds in the repair of critical sized bone defects.
    Acta biomaterialia 08/2013; · 5.09 Impact Factor
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    ABSTRACT: 1α,25-Dihydroxyvitamin D3 [1α,25(OH)2D3] and bone morphogenetic protein-2 (BMP2) are both used to stimulate osteoblastic differentiation. 1α,25(OH)2D3 regulates osteoblasts through classical steroid hormone receptor mechanisms and through rapid responses that are mediated by two receptors, the traditional vitamin D receptor (VDR) and protein disulphide isomerase family A member 3 (Pdia3). The interaction between 1α,25(OH)2D3 and BMP2, especially in three-dimensional (3D) culture, and the roles of the two vitamin D receptors in this interaction are not well understood. We treated wild-type (WT), Pdia3-silenced (Sh-Pdia3) and VDR-silenced (Sh-VDR) pre-osteoblastic MC3T3-E1 cells with either 1α,25(OH)2D3, or BMP2, or with 1α,25(OH)2D3 and BMP2 together, and measured osteoblast marker expression in 2D culture and mineralization in a 3D poly(ε-caprolactone)-collagen scaffold model. Quantitative PCR showed that silencing Pdia3 or VDR had a differential effect on baseline expression of osteoblast markers. 1α,25(OH)2D3 + BMP2 caused a synergistic increase in osteoblast marker expression in WT cells, while silencing either Pdia3 or VDR attenuated this effect. 1α,25(OH)2D3 + BMP2 also caused a synergistic increase in Dlx5 in both silenced cell lines. Micro-computed tomography (μCT) showed that the mineralized volume of untreated Sh-Pdia3 and Sh-VDR 3D cultures was greater than that of WT. 1α,25(OH)2D3 reduced mineral in WT and Sh-VDR cultures; BMP2 increased mineralization; and 1α,25(OH)2D3 + BMP2 caused a synergistic increase, but only in WT cultures. SEM showed that mineralized matrix morphology in 3D cultures differed for silenced cells compared to WT cells. These data indicate a synergistic crosstalk between 1α,25(OH)2D3 and BMP2 toward osteogenesis and mineral deposition, involving both VDR and Pdia3. Copyright © 2013 John Wiley & Sons, Ltd.
    Journal of Tissue Engineering and Regenerative Medicine 06/2013; · 2.83 Impact Factor
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    ABSTRACT: OBJECTIVE: Current histological scoring methods to evaluate efficacy of potential therapeutics for slowing or preventing joint degeneration are time-consuming and semi-quantitative in nature. Hence, there is a need to develop and standardize quantitative outcome measures to define sensitive metrics for studying potential therapeutics. The objectives of this study were to use equilibrium partitioning of an ionic contrast agent via Microcomputed tomography (EPIC-μCT) to quantitatively characterize morphological and compositional changes in the tibial articular cartilage in two distinct models of joint degeneration and define localized regions of interest to detect degenerative cartilage changes. MATERIALS AND METHODS: The monosodium iodoacetate (MIA) and medial meniscal transection (MMT) rat models were used in this study. Three weeks post-surgery, tibiae were analyzed using EPIC-μCT and histology. EPIC-μCT allowed measurement of 3D morphological changes in cartilage thickness, volume and composition. RESULTS: Extensive cartilage degeneration was observed throughout the joint in the MIA model after 3 weeks. In contrast, the MMT model showed more localized degeneration with regional thickening of the medial tibial plateau and a decrease in attenuation consistent with proteoglycan depletion. Focal lesions were also observed and 3D volume calculated as an additional outcome metric. CONCLUSIONS: EPIC-μCT was used to quantitatively assess joint degeneration in two distinct preclinical models. The MMT model showed similar features to human OA, including localized lesion formation and proteoglycan loss, while the MIA model displayed extensive cartilage degeneration throughout the joint. EPIC-μCT imaging provides a rapid and quantitative screening tool for preclinical evaluation of OA therapeutics.
    Osteoarthritis and Cartilage 06/2013; · 4.26 Impact Factor
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    ABSTRACT: Despite the appreciated interdependence of skeletal and hematopoietic development, the cell and matrix components of the hematopoietic niche remain to be fully defined. Utilizing mice with disrupted function of collagen X, a major hypertrophic cartilage matrix protein associated with endochondral ossification, our data identified a cytokine defect in trabecular bone cells at the chondro-osseous hematopoietic niche as a cause for aberrant B lymphopoiesis in these mice. Specifically, analysis of collagen X transgenic and null mouse chondro-osseous regions via micro-computed tomography revealed an altered trabecular bone environment. Additionally, co-cultures with hematopoietic and chondro-osseous cell types highlighted impaired hematopoietic support by collagen X transgenic and null mouse derived trabecular bone cells. Further, cytokine arrays with conditioned media from the trabecular osteoblast co-cultures suggested an aberrant hematopoietic cytokine milieu within the chondro-osseous niche of the collagen X deficient mice. Accordingly, B lymphopoiesis was rescued in the collagen X mouse derived trabecular osteoblast co-cultures with interlukin-7, stem cell factor and stromal derived factor-1 supplementation. Moreover, B cell development was restored in vivo after injections of interlukin-7. These data support our hypothesis that endrochondrally-derived trabecular bone cells and matrix constituents provide cytokine-rich niches for hematopoiesis. Furthermore, this study contributes to the emerging concept that niche defects may underlie certain immuno-osseous and hematopoietic disorders.
    Stem cells and development 05/2013; · 4.15 Impact Factor
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    ABSTRACT: Although severe extremity trauma is often inclusive of skeletal and vascular damage in combination, segmental bone defect repair with concomitant vascular injury has yet to be experimentally investigated. To this end, we developed a novel rat composite limb injury model by combining a critically-sized segmental bone defect with surgically-induced hind limb ischemia (HLI). Unilateral 8 mm femoral defects were created alone (BD) or in combination with HLI (BD+HLI), and all defects were treated with rhBMP-2 via a hybrid biomaterial delivery system. Based on reported clinical and experimental observations on the importance of vascular networks in bone repair, we hypothesized that HLI would impair bone regeneration. Interestingly, the BD+HLI group displayed improved radiographic bridging, and quantitative micro-CT analysis revealed enhanced bone regeneration as early as week 4 (p<0.01) that was sustained through week 12 (p<0.001) and confirmed histologically. This effect was observed in two independent studies and at two different doses of rhBMP-2. Micro-CT angiography was used to quantitatively evaluate vascular networks at week 12 in both the thigh and the regenerated bone defect. No differences were found between groups in total blood vessel volume in the thigh, but clear differences in morphology were present as the BD+HLI group possessed a more interconnected network of smaller diameter vessels (p<0.001). Accordingly, while the overall thigh vessel volume was comparable between groups, the contributions to vessel volume based on vessel diameter differed significantly. Despite this evidence of a robust neovascular response in the thigh of the BD+HLI group, differences were not observed between groups for bone defect blood vessel volume or morphology. In total, our results demonstrate that a transient ischemic insult and the subsequent recovery response to HLI significantly enhanced BMP-2-mediated segmental bone defect repair, providing additional complexity to the relationship between vascular tissue networks and bone healing. Ultimately, a better understanding of the coupling mechanisms may reveal important new strategies for promoting bone healing in challenging clinical scenarios.
    Bone 05/2013; · 3.82 Impact Factor
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    ABSTRACT: : Craniosynostosis is the premature fusion of cranial sutures early in development. Mice are commonly used to study the mechanisms driving both normal and pathologic cranial suture development. Despite their frequency of use as a model, the time course of bone formation and mineralization during fusion of mouse posterior frontal suture is not well defined. : To address this, C57Bl/6J mice were euthanized at ages ranging from 6 to 107 days, and the posterior frontal sutures were imaged using micro-computed tomography. Scans were analyzed with an image-processing algorithm that was previously validated with serial histology to quantify both suture fusion and mineral content. The expression profile of genes associated with key developmental time points was examined using real-time polymerase chain reaction in both the bone and the dura. : Results demonstrate that the bones of the posterior frontal suture come together during days 10 to 20 and then increase in mineral content and volume between days 21 and 45. The onset of posterior frontal suture fusion was associated with an increase in cartilage-associated genes on day 12. Later mineralization of the suture was associated with an increase in mRNAs for osteoblast differentiation markers, bone morphogenetic proteins, and bone morphogenetic protein inhibitors. : Complete analysis fusion posterior frontal suture shows that it occurs in a discontinuous biphasic manner. The first phase is from days 10 to 20 and involves production of cartilage. A second mineralization phase from days 21 to 45 was seen with both the imaging algorithm and changes in gene expression.
    Plastic and reconstructive surgery 04/2013; 131(4):727-40. · 2.74 Impact Factor

Publication Stats

4k Citations
739.65 Total Impact Points


  • 2013
    • Università degli Studi di Trento
      • Departmental Area of Materials Engineering and Industrial Technologies
      Trient, Trentino-Alto Adige, Italy
  • 1998–2013
    • Georgia Institute of Technology
      • • Institute for Bioengineering and Bioscience
      • • Department of Biomedical Engineering
      • • School of Mechanical Engineering
      Atlanta, Georgia, United States
  • 2010–2012
    • Emory University
      • • Division of Cardiology
      • • Division of Plastic and Reconstructive Surgery
      Atlanta, GA, United States
  • 2011
    • Queensland University of Technology
      • Institute of Health and Biomedical Innovation
      Brisbane, Queensland, Australia
  • 2008–2011
    • Morehouse College
      Atlanta, Georgia, United States
  • 2006–2009
    • University Center Rochester
      • • Center for Musculoskeletal Research
      • • Department of Orthopaedics
      Rochester, Minnesota, United States
  • 2007–2008
    • University of Rochester
      • Center for Musculoskeletal Research
      Rochester, NY, United States
    • Université Paris-Est Créteil Val de Marne - Université Paris 12
      • Faculty of Sciences and technologies
      Créteil, Ile-de-France, France
  • 1996–1997
    • University of Michigan
      Ann Arbor, Michigan, United States