Bruce A Doll

University of Texas Health Science Center at San Antonio, San Antonio, Texas, United States

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Publications (17)49.27 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Large bone defects may be treated with autologous or allogeneic bone preparations. Each treatment has advantages and disadvantages; therefore, a clinically viable option for treating large (e.g., gap) bone defects may be a combination of the two. In the present study, bone repair was determined with combinations of autografts, allografts, and synthetic bone grafts using an established rabbit femoral defect model. Bilateral unicortical femoral defects were surgically prepared and treated with combinatorial bone grafts according to one of seven treatment groups. Recipient sites were retrieved at six weeks. Cellular/tissue responses and new bone formation were assessed by histology and histomorphometry. Histological analysis images indicated neither evidence of inflammatory, immune responses, tissue necrosis, nor osteolysis. Data suggested co-integration of implanted agents with host and newly formed bone. Finally, the histomorphometric data suggested that the tricalcium phosphate-based synthetic bone graft substitute allowed new bone formation that was similar to the allograft (i.e., demineralized bone matrix, DBM).
    Biomedical Materials 05/2014; 9(3):035010. · 2.17 Impact Factor
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    ABSTRACT: Demineralized bone matrix (DBM) is an osteoconductive and osteoinductive commercial biomaterial and approved medical device used in bone defects with a long track record of clinical use in diverse forms. True to its name and as an acid-extracted organic matrix from human bone sources, DBM retains much of the proteinaceous components native to bone, with small amounts of calcium-based solids, inorganic phosphates and some trace cell debris. Many of DBM's proteinaceous components (e.g., growth factors) are known to be potent osteogenic agents. Commercially sourced as putty, paste, sheets and flexible pieces, DBM provides a degradable matrix facilitating endogenous release of these compounds to the bone wound sites where it is surgically placed to fill bone defects, inducing new bone formation and accelerating healing. Given DBM's long clinical track record and commercial accessibility in standard forms and sources, opportunities to further develop and validate DBM as a versatile bone biomaterial in orthopedic repair and regenerative medicine contexts are attractive.
    Advanced drug delivery reviews 06/2012; 64(12):1063-77. · 11.96 Impact Factor
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    ABSTRACT: Porous three-dimensional tyrosine-derived polycarbonate (TyrPC) scaffolds with a bimodal pore distribution were fabricated to mimic bone architecture using a combination of salt-leaching and phase separation techniques. TyrPC scaffolds degraded in register with bone regeneration during the 6-week study period and compressive moduli of the scaffolds were maintained >0.5 MPa at 6 weeks of incubation in PBS at 37 °C. The TyrPC scaffolds either unsupplemented or supplemented with recombinant human bone morphogenetic protein-2 (rhBMP-2) were implanted in a rabbit calvarial critical-sized defect (CSD) model and the TyrPC scaffolds treated with rhBMP-2 or TyrPC coated with calcium phosphate scaffold alone promoted bone regeneration in a rabbit calvarial CSD at 6 weeks postimplantation. A synthetic TyrPC polymeric scaffold either without a biological supplement or with a minimal dose of rhBMP-2 induced bone regeneration comparable to a commercially available bone graft substitute in a nonrodent CSD animal model.
    Tissue Engineering Part A 02/2012; 18(11-12):1132-9. · 4.64 Impact Factor
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    ABSTRACT: The in vivo tissue response to a newly developed fiber-reinforced calcium phosphate cement (CPC) formulation was assessed using a well-established rabbit calvarial defect model. Bilateral subcritical sized (8-mm diameter) defects were surgically created in the parietal bones of each rabbit (a total of 48 rabbits), and randomized to be filled with either the new fiber-reinforced formulation, a conventional CPC (positive control), or left unfilled (negative control). The implant sites were subsequently retrieved after 12, 24, and 52 weeks postsurgery. Each specimen, including the parietal bone craniotomy and underlying brain, were recovered at necropsy and the tissue responses were assessed by histology. The resulting histological slides indicated that there was no evidence of severe inflammatory responses or osteolysis. The data showed new dural and pericranial bone formation along the implants, as well as excellent bone-to-implant interfaces in all of the CPC-filled defects. These results suggest that the biologic response to the new fiber-reinforced CPC formulations and conventional nonreinforced CPC are very similar, and both demonstrate excellent biocompatibility as well as an overall osteophylic response.
    Journal of Biomedical Materials Research Part B Applied Biomaterials 11/2011; 100(4):1170-8. · 2.31 Impact Factor
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    ABSTRACT: Poly(ε-caprolactone fumarate) (PCLF) scaffold formulations were assessed as a delivery system for recombinant human bone morphogenetic protein (rhBMP-2) for bone tissue engineering. The formulations included PCLF with combinations of poly(vinyl alcohol) (PVA) and hydroxyapatite (HA). The assessments included in vitro and in vivo assays. In vitro assays validated cell attachment using a pre-osteoblast cell line (MC3T3-E1). Additionally, in vitro release profiles of rhBMP-2 from PCLF scaffolds were determined up to 21 days. The data suggested that PCLF incorporated with PVA and HA accelerated rhBMP-2 release and that the released protein was bioactive. For the in vivo study, a critical-sized defect (CSD) model in rabbit calvaria was used to test PCLF scaffolds. At 6 weeks post-implantation, significantly more bone formation was measured in PCLF scaffolds containing rhBMP-2 than in scaffolds without rhBMP-2. In conclusion, we demonstrated that PCLF delivered biologically active rhBMP-2, promoted bone healing in a CSD and has potential as a bone tissue engineering scaffold.
    Journal of Tissue Engineering and Regenerative Medicine 07/2011; 6(5):404-13. · 4.43 Impact Factor
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    ABSTRACT: Migration, adhesion, proliferation and differentiation of mesenchymal stem cells into osteoblasts, osteoclasts, chondroblasts, fi broblasts and endothelial cells characterize the cellular activities suspended within a collagenous matrix during fracture repair. Throughout life fracture repair is a dynamic process – orchestrated events directing the inflammatory response, chondrogenesis, osteogenesis and remodeling. These steps may involve many differently expressed genes. Fracture healing is also closely aligned with neo-angiogenesis. Matrix degradation and angiogenesis are concurrent processes supportive of endochondral bone formation. This chapter will focus on the biological hierarchy of bone and its capacity for repair. The cell and molecular biology of fracture repair will be considered as a context for proposed therapies for bone regeneration. Keywordsfracture–bone–repair–skeletal injury–osteoblast–osteogenesis–healing
    12/2007: pages 39-61;
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    ABSTRACT: C3H10T1/2/Osx, a stably transfected cell line with Osterix (Osx), was produced and chondrocytic and osteoblastic differentiation were studied in vitro. Osx promoted osteoblastic lineage that was dexamethasone dependent. Furthermore, in vivo, Osx induced ectopic mineralization in a heterotopic mouse muscle model. Skeletogenesis involves a cascade of molecular activities sequentially performed by osteoblasts and chondroblasts. A transcriptional factor gene Osx appears to influence cell disposition toward the chondrocytic or osteoblastic phenotype and therefore may be an important signaling cue for bone formation. Understanding the molecular conditions involved with Osx promoted osteoblast differentiation will facilitate therapeutic applications of Osx. Consequently, the objective of this study was to investigate chondrocytic and osteoblastic phenotype differentiation using an Osx plasmid DNA exploiting both in vitro and in vivo methodologies. In vitro, a stably transfected C3H10T1/2/Osx cell line was established and promotion of either an osteoblast or chondroblast phenotype was performed by selectively introducing dexamethasone (dex) and assaying mRNA content and phenotype markers. In vivo, a mouse muscle model was used to determine heterotopic ossification using designated Osx plasmid DNA doses incorporated in a (50:50 Poly (D,L-lactide-co-glycolide) (i.e., PLGA) 3D scaffold. Histological assessment was used to determine implant responses. Quantitative real-time polymerase chain reaction (q-RT-PCR) showed a significant increase in mRNA expression of osteocalcin (Ocn), Runx2, osteonectin (On) and osteopontin (Op) (p < 0.05) in the C3H10T1/2/Osx cells compared to the empty vector transfected cell control. At day 21, mineralization was demonstrated in the cultures of C3H10T1/2/Osx exposed to dex, but neither in cultures lacking dex nor controls. In the absence of dex, C3H10T1/2/Osx cells revealed a significantly higher expression of Sox9 and Aggrecan (Agc). In vivo, 80 microg of Osx plasmid DNA induced heterotopic mineralization 4 weeks following implantation in a mouse muscle model and the effect was dependent on the Osx plasmid DNA dose delivered in the PLGA scaffold. Using a non-committed cell line (C3H10T1/2), cell differentiation to an osteoblast phenotype appears to be dependent upon an interaction between intracellular events initiated by the transcriptional factor Osx and the presence of dex. The in vivo findings suggest Osx may promote osteoblast differentiationand mineralization at a heterotopic site.
    Journal of Biomedical Materials Research Part A 12/2007; 83(3):770-8. · 2.83 Impact Factor
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    ABSTRACT: The economic impact of musculoskeletal conditions in the United States represents $126 billion. Bone fracture repairs are among the most commonly performed orthopedic procedures; about 6.8 million come to medical attention each year in the United States (1). Advances through research and enhanced understanding of fracture repair have enabled orthopedic surgeons to provide patients with many treatment options and improved outcome. In this chapter we will review the current knowledge of fracture from both chronological and molecular biology aspects; we will then address bone healing in elderly patients and the different technologies used to enhance fracture repair.
    10/2007: pages 21-44;
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    ABSTRACT: Clinical experience gives rise to the impression that there are differences in fracture healing in different age groups. It is evident that fractures heal more efficiently in children than in adults. However, minimal objective knowledge exists to evaluate this assumption. Temporal, spatial, and cellular quantitative and qualitative interrelationships, as well as signaling molecules and extracellular matrix have not been comprehensively and adequately elucidated for fracture healing in the geriatric skeleton. The biological basis of fracture healing will provide a context for revealing the pathophysiology of delayed or even impaired bone regeneration in the elderly. We will summarize experimental studies on age-related changes at the cellular and molecular level that will add to the pathophysiological understanding of the compromised bone regeneration capacity believed to exist in the elderly patient. We will suggest why this understanding would be useful for therapeutics focused on bone regeneration, in particular fracture healing at an advanced age.
    Experimental Gerontology 12/2006; 41(11):1080-93. · 3.91 Impact Factor
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    ABSTRACT: A biodegradable, biocompatible, ascorbic acid-containing three-dimensional polyurethane matrix was developed for bone tissue-engineering scaffolds. This matrix was synthesized with lysine-di-isocyanate (LDI), ascorbic acid (AA), glycerol, and polyethylene glycol (PEG). LDI-glycerol-PEG-AA prepolymer when reacted with water foamed with the liberation of CO(2) to provide a pliable, spongy urethane polymer with pore diameters of 100 to 500 microm. The LDI-glycerol-PEG-AA matrix degraded in aqueous solution and yielded lysine, glycerol, PEG, and ascorbic acid as breakdown products. The degradation products did not significantly affect the solution pH. The LDI-glycerol-PEG-AA matrix can be fabricated into diverse scaffold dimensions and the physicochemical properties of the polymer network supported in vitro cell growth. Green fluorescent protein-transgenic mouse bone marrow cells (GFP-MBMCs) attached to the polymer matrix and remained viable, and the cells became confluent cultures. Furthermore, ascorbic acid released from LDI-glycerol-PEG-AA matrix stimulated cell proliferation, type I collagen, and alkaline phosphatase synthesis in vitro. Cells grown on LDI-glycerol-PEG-AA matrix did not differ phenotypically from cells grown on tissue culture polystyrene plates as assessed by cell growth, expression of mRNA for collagen type I, and transforming growth factor beta(1). These observations suggest that AA-containing polyurethane may be useful in bone tissue-engineering applications.
    Tissue Engineering 01/2004; 9(6):1143-57. · 4.25 Impact Factor
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    ABSTRACT: A novel, nontoxic, biodegradable, sponge-like polyurethane scaffold was synthesized from lysine-di-isocyanate (LDI) and glycerol. Ascorbic acid (AA) was copolymerized with LDI-glycerol. Our hypothesis was that the AA-containing polymer foam would enhance the biological activity of the osteoblastic precursor cell (OPCs). The LDI-glycerol-AA matrix degraded in aqueous solution to the nontoxic products of lysine, glycerol, and AA. The degradation products did not significantly affect the solution pH. The physical properties of the polymer network supported the cell growth in vitro. Mouse OPCs attached to the polymer matrix and remained viable. OPCs produced multilayered confluent cultures, a characteristic typical of bone cells. Furthermore, AA release stimulated cell proliferation, type I collagen, and alkaline phosphatase synthesis. Cells grown on the LDI-glycerol-AA matrix also showed an enhancement of mRNA expression for pro-alpha1 (I) collagen and transforming growth factor-alpha1 after 1 week. Data were tested for significance with an analysis of variance model and multiple comparison test (Fisher's Protected Least Significant Difference) at p < or = 0.05. The observations suggest that AA-containing polyurethane may be useful in bone tissue engineering applications.
    Journal of Biomedical Materials Research Part A 11/2003; 67(2):389-400. · 2.83 Impact Factor
  • Oral and Maxillofacial Surgery Clinics of North America 03/2002; 14(1):1-14. · 0.73 Impact Factor
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    ABSTRACT: Aging is a process of cumulative effects. Aging effects sometimes appear random in sequence and consequence. We propose that considerable complexity underlies changes associated with aging. Apparent simplicity masks the interrelated events at a molecular, cellular, systemic, and organism level. Clinical observation suggests the majority of age-related events are initially constructive, optimal, and conducive to maximized survivability. Then, in subtle, poorly understood mechanisms, the fate of the organism progresses toward degeneration. Clinical experiences give rise to the impression that there might be differences in fracture healing in different age groups. Minimal knowledge exists in the literature objectively evaluating this impression. In this review, we focus on cellular and molecular evidence that suggests that changes occur in the aging skeletons capacity to heal. The medical community is faced with an aging population, steadily increasing fracture numbers in the elderly population, increasing treatment costs, and the most important, quality-of-life issues. An understanding of age-related changes in bone healing is necessary as a basis for the development of future research strategies. Understanding bone healing in an aging individual devoid of pathological complications is a challenging first step toward rationalizing therapies to restore the aged skeleton to health.
    Operative Techniques in Orthopaedics 01/2002; 12(2):72-77.
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    ABSTRACT: Recently, there has been substantial progress in the area of bone morphogenetic protein (BMP) research. This review serves as an up-to-date summary of the history of BMPs, the mechanisms of BMP signalling and the role of BMPs in adipose, kidney, liver, bone and nervous system. The potential of BMPs as therapeutic agents will also be discussed.
    Expert Opinion on Investigational Drugs 10/2001; 10(9):1677-86. · 4.74 Impact Factor
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    ABSTRACT: Recent advances in bone tissue engineering are established on the understanding of an engineered scaffold, the molecular milieu within the osteogenic site, and the cell(s) predisposed to an osteogenic lineage. Advances in the incorporation of a generative vehicle into a skeletal defect require temporal and spatial distribution of the scaffold, growth factor, and cell compatible with enhanced bone healing. Monitoring events culminating in osteogenesis has focused on phenotypic and intracellular indicators. Phenotypic and intracellular indicators include the presence of receptors and intracellular signals that enable cell proliferation and differentiation. Progress in the areas of scaffold design, growth factor utilization, bone cell lineage, and intracellular signaling are reviewed.
    Critical Reviews in Eukaryotic Gene Expression 02/2001; 11(1-3):173-98. · 2.07 Impact Factor
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    ABSTRACT: The purpose of this study was to determine the quantity of new bone formation in critical sized calvaria defects in rats treated with two composite graft systems. The systems consisted of either a combination of the bone inductive protein (osteogenin) plus type I collagen (Os + C) or the combination of osteogenin with coralline hydroxyapatite (Os + HA). Additional treatments consisted of coralline hydroxyapatite (HA) or untreated control defects. After 28 days the calvaria were recovered and processed for quantitative radiography (radiomorphometry) and histomorphometry. Histomorphometric results were based on quantitation of regenerated trabecular bone. Results indicated that the Os + C combination produced substantially more bone than the Os + HA, HA, or control groups (P less than 0.05). Radiomorphometric assessment was based on the detection of radiopacity in the calvarial wounds. Due to the radiopaque property of HA, it was not possible to accurately quantitate the radiopacity of the regenerating bone from HA and host bone. Therefore, conclusions about the efficacy of the treatments must be derived from histomorphometric data. Results from histometric measurements of healing indicate that the Os + C combination has the greatest potential for regenerating calvarial bone defects. The potential for osteogenin in regenerating alveolar bone lost due to periodontal disease is suggested by these studies.
    Journal of Periodontology 01/1991; 61(12):745-50. · 2.40 Impact Factor
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    ABSTRACT: Annually, skeletal injury and specifically craniofacial injury total approx 12.2 million people in the United States (1). Advances in craniofacial therapy, founded on developing knowledge of the molecular signals and intercellular communication, has greatly improved the restoration of form and function. Fracture healing is a complex physiological process. Cellular and biochemical processes that occur during fracture healing parallel those that take place in the growth plate during development, except in fracture healing these processes occur on a temporal scale (2–4). Similarities in the processes occurring at the growth plate and at the fracture site permit some knowledge from growthplate analysis to comprehend events in fracture healing. Fracture healing involves a series of distinct cellular responses. Specific paracrine and autocrine intercellular signaling pathways control cellular and osseous tissue mineralization (Fig. 1). However, extrapolation of knowledge of growth-plate molecular dynamics is insufficient to achieve consistently optimal bone regeneration during primary and secondary fracture healing.
    01/1970: pages 337-358;

Publication Stats

193 Citations
49.27 Total Impact Points

Institutions

  • 2014
    • University of Texas Health Science Center at San Antonio
      • Department of Orthopaedics
      San Antonio, Texas, United States
  • 2012
    • Synthes Holding AG
      Soleure, Solothurn, Switzerland
  • 2002–2012
    • Carnegie Mellon University
      • • Department of Biomedical Engineering
      • • Bone Tissue Engineering Center (BTEC)
      Pittsburgh, PA, United States
  • 2011
    • Rutgers, The State University of New Jersey
      New Brunswick, New Jersey, United States
  • 1970–2007
    • University of Pittsburgh
      • • Periodontics
      • • Chemical and Petroleum Engineering
      Pittsburgh, PA, United States
  • 2006
    • Medical University of Vienna
      Wien, Vienna, Austria
  • 1991
    • United States Naval Academy
      Annapolis, Maryland, United States