To our knowledge, this study is the largest prospective, randomized, triple-blinded, and controlled pivotal clinical trial reported to date assessing a putative periodontal regenerative and wound healing therapy. The study demonstrated that the use of rhPDGF-BB was safe and effective in the treatment of periodontal osseous defects. Treatment with rhPDGF-BB stimulated a significant increase in the rate of CAL gain, reduced gingival recession at 3 months post-surgery, and improved bone fill as compared to a beta-TCP bone substitute at 6 months.
Use of purified rhPDGF-BB mixed with bone allograft results in robust periodontal regeneration in both Class II furcations and interproximal intrabony defects. This is the first report of periodontal regeneration demonstrated histologically in human Class II furcation defects.
The primary objective of this study was to assess the safety of recombinant human (rh) platelet-derived growth factor-BB (PDGF-BB) and (rh) insulin-like growth factor-I (IGF-I) when applied to periodontal osseous defects in humans; a secondary objective was to begin to accrue data on the therapeutic dose of these growth factors (GFs) required to stimulate periodontal regeneration. Thirty-eight human subjects possessing bilateral osseous periodontal lesions were assigned to one of two treatment groups in a split-mouth design. Following full-thickness flap reflection, test sites received local application of the therapeutic drug delivered in coded syringes by a "masked" investigator. Two dose levels were tested, 50 micrograms/ml each of rhPDGF-BB and rhIGF-I in a gel vehicle (LD-PDGF/IGF-I) and 150 micrograms/ml each of rhPDGF-BB and rhIGF-I plus vehicle (HD-PDGF/IGF-I). Control treatment consisted of either conventional periodontal flap surgery or surgery plus vehicle. Safety analyses included physical examination, hematology, serum chemistry, urinalysis, antibody titers, and radiographic evaluation of bony changes. The primary therapeutic assessment was bone fill measured at re-entry 6 to 9 months after treatment. No local or systemic safety issues were found as a result of GF administration. No patients developed antibodies to the rhGF proteins. In subjects treated with LD-PDGF/IGF-I, there were no enhancements in periodontal regeneration compared to controls. However, in patients treated with HD-PDGF/IGF-I, statistically significant increases in alveolar bone formation were noted as measured by surgical re-entry 9 months following drug delivery (P < 0.05). This corresponded to an increase of 2.08 mm of new vertical bone height and 42.3% osseous defect fill in the HD-PDGF/IGF-I subjects versus only 0.75 mm and 18.5% gains in new bone height and osseous fill, respectively, in the controls. Furcation lesions, although limited in number, responded most favorably to treatment, with 2.8 mm horizontal osseous fill. The results from this study suggest that the local application of rhPDGF-BB and rhIGF-I to periodontal lesions is safe at the dose levels studied. LD-PDGF/IGF-I did not elicit increased defect fill compared to the control; however, HD-PDGF/IGF-I resulted in a significant promotion in bone regeneration. Additional studies are warranted to more fully characterize the effects of PDGF/IGF-I on periodontal regeneration in humans.
Polypeptide growth factors are a class of potent natural biologic mediators which regulate many of the activities of wound healing including cell proliferation, migration, and metabolism. Platelet-derived growth factor (PDGF) and insulin-like growth factor-I (IGF-I) have been shown to regulate DNA and protein synthesis in bone cells in vitro and to interact synergistically to enhance soft tissue wound healing in vivo. We have hypothesized that the combination of PDGF and IGF-I may, therefore, enhance regeneration of both the soft and hard tissue components of the periodontium. To test this hypothesis we performed conventional periodontal surgery on all 4 quadrants of the mouth of 13 beagle dogs with naturally occurring periodontal disease. Following flap reflection, degranulation, and root planing, all premolar teeth in 2 quadrants of each dog received a combination of 3 micrograms of recombinant PDGF-B and IGF-I in a methylcellulose gel, while the premolar teeth in the contralateral quadrants received the gel alone. Teeth in 4 additional animals also received 125I-PDGF or 125I-IGF-I in the treated sites. The clearance rate of the 125I-labeled protein, changes in local bone metabolism, and amount of new bone and cementum with inserting collagen fibers were measured. The clearance studies revealed that the half-life of the factors at the site of application was 3.0 hours for IGF-I and to 4.2 hours for PDGF-B. Greater than 96% of the radio-labeled proteins was cleared by 96 hours and no radioactivity was detected 2 weeks after application. There was a significant (P less than 0.01) 2-fold increase in uptake of the bone-seeking radiopharmaceutical Technetium 99-MDP at 2 and 4 weeks in growth factor treated sites compared to controls, indicating that there was increased metabolic activity within the bone at these sites. Computer-aided histologic analyses of biopsies obtained at 2 and 5 weeks post-operatively revealed a significant (P less than 0.01), 5 to 10 fold increase in new bone and cementum in PDGF-B/IGF-I treated sites at both time points compared to controls receiving the placebo gel. The height and total area of new bone continued to increase from 2 to 5 weeks. The new bone underwent a normal maturation process as judged by histologic appearance. A physiologic periodontal ligament space was also formed between the new bone and new cementum. There was no increase in ankylosis in the treated sites.(ABSTRACT TRUNCATED AT 400 WORDS)
Growth factors may enhance current cartilage repair techniques via multiple mechanisms including recruitment of chondrogenic cells (chemotaxis), stimulation of chondrogenic cell proliferation (mitogenesis) and enhancement of cartilage matrix synthesis. Two growth factors that have been studied in cartilage repair are insulin-like growth factor (IGF) and platelet derived growth factor (PDGF). IGF plays a key role in cartilage homeostasis, balancing proteoglycan synthesis and breakdown. Incorporating IGF into a fibrin clot placed in an equine cartilage defect improved the quality and quantity of repair tissue and reduced synovial inflammation. PDGF is a potent mitogenic and chemotactic factor for all cells of mesenchymal origin, including chondrocytes and mesenchymal stem cells. Resting zone chondrocytes cultured with PDGF demonstrated increased cell proliferation and proteoglycan production, while maturation of these cells along the endochondral pathway was inhibited. Pretreating chondrocytes with PDGF promotes heterotopic cartilage formation in the absence of any mechanical stimulus. PDGF has also been shown to be a potent stimulator of meniscal cell proliferation and migration. These studies and others suggest a potential role for these potent biological regulators of chondrocytes in cartilage repair. More work needs to be performed to define their appropriate dosing and the optimum delivery method. Combining tissue growth factors with a biological matrix can provide a physical scaffold for cell adhesion and growth as well as a means to control the release of these potent molecules. This could result in biological devices that enhance the predictability and quality of current cartilage repair techniques.
The combination of platelet-derived growth factor (PDGF) and insulin-like growth factor one (IGF-1) has previously been shown to enhance repair of soft tissue wounds. Here we report initial observations following application of PDGF and IGF-1 to periodontitis-affected teeth in beagle dogs. 1 micrograms of PDGF and IGF-1 in an aqueous gel was applied to the root surfaces of test teeth following open flap debridement. Control sites received the gel alone. Block biopsies of the teeth and surrounding bone were taken 2 weeks after treatment. Histologic analyses of control specimens revealed a long junctional epithelial attachment, and no new bone or cementum formation. In contrast, growth factor treated sites exhibited significant amounts of new bone and cementum formation. A nearly continuous layer of osteoblasts lined the newly formed bone, and there was a dense cellular "front" at the coronal extent of the new bone. These preliminary results suggest that in vivo application of the combination of PDGF and IGF-1 may enhance regeneration of the periodontal structures.
The abilities of bone to remodel, fractures to repair, and bone grafts to incorporate are all fundamental reflections of the bone remodeling cycle. This process is characterized by the recruitment and differentiation of osteoblastic and osteoclastic cell populations, whose cellular activities are coordinated and regulated by an elaborate system of growth factors and cytokines. One of the crucial biological factors responsible for reparative osseous activity is platelet-derived growth factor (PDGF). The potent stimulatory effects of PDGF as a chemoattractant and mitogen for mesenchymal cells (including osteogenic cells), along with its ability to promote angiogenesis, have been demonstrated in a variety of preclinical models predicting maxillofacial, spine and appendicular skeletal, and soft-tissue applications. The biological profile of PDGF, including its ability to recruit osteoprogenitor cells, makes it particularly suited to address the skeletal defects that are seen with comorbid conditions such as osteoporosis, diabetes, and the effects of smoking. The clinical success and safety that have been demonstrated with use of recombinant human PDGF (rhPDGF) in the repair of periodontal defects have led to U.S. Food and Drug Administration (FDA) approval of rhPDGF for this indication. Ongoing pilot and pivotal trials in the United States and internationally will continue to clarify the promising role of PDGF in the treatment of challenging skeletal disorders.
Platelet-derived growth factor (PDGF) in vitro stimulates DNA synthesis and chemotaxis of fibroblasts and smooth muscle cells and stimulates collagen, glycosaminoglycan, and collagenase production by fibroblasts. These in vitro properties suggest that PDGF, delivered by platelets to the site of injury in vivo, may play an important role in the initiation of the wound repair process. Studies presented here show that the addition of pure PDGF to a wound site involving the epidermis and dermis has little effect on the morphology or biochemistry of the healing wound. In contrast, the addition of partially purified PDGF resulted in significant dose-dependent increases in the width of the newly synthesized connective tissue and epidermal layers. Autoradiography using [3H]thymidine revealed increased numbers of labeled cells in the new connective tissue and epithelial layers. Furthermore, addition of partially purified PDGF resulted in significant increases in the rate of protein and DNA synthesis and the total content of these components in biopsies taken from the wound site. Similar effects were obtained when insulin-like growth factor I was added in combination with pure PDGF. This combination of factors caused a 2.4-fold increase in the width of the newly formed connective tissue layer and a 95% increase in epidermal thickness compared with controls. Insulin-like growth factor I alone caused no significant morphologic changes. Epidermal growth factor alone or in combination with PDGF resulted in a thickening only of the epidermis. These results indicate that the synergistic actions of other factors with PDGF are important in the modulation of the wound healing process.
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