Growth factors and craniofacial surgery.

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.

Simultaneous augmentation of hard and soft tissues for implant site preparation using recombinant human platelet-derived growth factor: a human case report.

This paper documents the treatment of a patient for whom a tissue engineering approach was used for both soft and hard tissue implant site development following the extraction of a failing maxillary left central incisor. The tooth had advanced pocketing and recurrent abscess formation secondary to failing endodontic treatment. Extraction revealed a lack of buccal plate as well as insufficient soft tissue for anterior esthetics. After extraction, the bony defect was filled with freeze-dried mineralized bone allograft mixed with recombinant human platelet-derived growth factor (rhPDGF), and a titanium-reinforced expanded polytetrafluoroethylene membrane was placed over it. The soft tissue deficiency was corrected with a pediculated connective tissue graft, and the graft bed was rinsed with rhPDGF. Seven months after surgery, the site was re-entered for implant placement. The grafted site was trephined for histologic analysis and an implant was placed. Subsequently, the implant osseointegrated and was restored. The radiographic and clinical results were acceptable. Histologic analysis revealed bone regeneration. Although this approach needs further investigation, this report emphasizes the potential for the use of rhPDGF for simultaneous soft and hard tissue implant site preparation.

Clinical results using recombinant human platelet-derived growth factor and mineralized freeze-dried bone allograft in periodontal defects.

Human studies have demonstrated the safety and effectiveness of highly purified recombinant human platelet-derived growth factor-BB (rhPDGF-BB) in combination with osteoconductive matrices for the treatment of moderate to severe periodontal intrabony defects. These study results, together with binding and release characteristics for rhPDGF-BB with different matrices, provide clear evidence that demineralized freeze-dried bone allograft and beta-tricalcium phosphate (beta-TCP) each can be combined with rhPDGF-BB to promote significant improvements in clinical, radiographic, and histologic parameters. The purpose of the current case series was to determine the clinical and radiographic regenerative potential of rhPDGF-BB-enhanced mineralized freeze-dried bone allograft (FDBA) for the treatment of severe periodontal intrabony defects. Clinical reentry and radiographs at up to 11 months showed complete bone fill in these challenging cases, indicating that rhPDGF combined with FDBA provides excellent clinical results.

Effect of rhPDGF-BB delivery on mediators of periodontal wound repair.

Growth factors such as platelet-derived growth factor (PDGF) exert potent effects on wound healing including the regeneration of tooth-supporting structures. This investigation examined the effect of the local delivery of PDGF-BB when combined with reconstructive periodontal surgery on local wound fluid (WF) levels of PDGF-AB, vascular endothelial growth factor (VEGF), and bone collagen telopeptide (ICTP) in humans with advanced periodontitis. Sixteen patients exhibiting localized periodontal osseous defects were randomized to one of three groups (beta-TCP carrier alone, beta-TCP + 0.3 mg/mL of recombinant human PDGF-BB [rhPDGF-BB], or beta-TCP + 1.0 mg/mL of rhPDGF-BB) and monitored for 6 months. WF was harvested and analyzed for PDGF-AB, VEGF, and ICTP WF levels. Teeth contralateral to the target lesions served as controls. Increased levels of VEGF in the WF was observed for all surgical treatment groups with the 1.0 mg/mL rhPDGF-BB group showing the most pronounced difference at 3 weeks in the AUC analysis versus control (p < 0.0001). PDGF-AB WF levels were increased for the carrier alone group compared to both rhPDGFBB groups. Low-dose rhPDGF-BB application elicited increases in ICTP at days 3-5 in the wound healing process, suggesting a promotion of bone turnover at early stages of the repair process (p < 0.02). These results demonstrate contrasting inducible expression patterns of PDGF-AB, VEGF, and ICTP during periodontal wound healing in humans.

New composite endpoints to assess efficacy in periodontal therapy clinical trials.

BACKGROUND: Clinical attachment level (CAL) and bone height (radiographic or clinical) are two well-accepted endpoint measures for periodontal clinical trials; however, neither one has been shown to be more predictive of long-term success than the other. We propose using a composite endpoint analysis combining clinical and radiological parameters to assess the beneficial effects on both hard and soft tissues following periodontal therapy using a single statistical test. To address this need, two composite endpoint alternatives are offered as a yardstick for clinical success; each includes the improvement in CAL and either improvement in linear bone growth or percent bone fill. METHODS: The data for composite endpoint analyses were derived from a clinical trial evaluating two concentrations of recombinant human platelet-derived growth factor-BB (rhPDGF-BB) with beta-tricalcium phosphate (beta-TCP) compared to beta-TCP plus buffer as follows: group I, beta-TCP + 0.3 mg/ml rhPDGF-BB; group II, beta-TCP + 1.0 mg/ml rhPDGF-BB; and group III, beta-TCP + buffer. The construction of composite endpoints was based on the greatest values for change, accepted by the U.S. Food and Drug Administration (FDA), for clinical attachment level (DeltaCAL), mean change in radiographic linear bone gain (LBG), and mean radiographic percent bone fill (%BF), with the following dual standards defining a successful clinical result: CAL gain > or =2.67 mm and radiographic LBG > or =1.1 mm at 6 months and CAL gain > or =2.67 mm and radiographic %BF > or =14.1% at 6 months. RESULTS: Group I (beta-TCP + 0.3 mg/ml rhPDGF-BB) demonstrated statistically significant differences from group III (active control) for both composite endpoints. For the CAL/LBG composite endpoint, 61.7% of sites in group I versus 30.4% of sites in group III met the composite endpoint benchmarks (P <0.001). For the CAL/%BF composite endpoint, 70% of sites in group I versus 44.6% of sites in group III met the composite endpoint benchmarks (P = 0.003). A non-significant trend was observed for group II versus group III with 37.9% (P = 0.20) and 55.2% (P = 0.13) of sites meeting the CAL/LBG and CAL/%BF composite endpoints, respectively. These results are further emphasized by findings demonstrating a low correlation between the individual efficacy endpoints (DeltaCAL and %BF; DeltaCAL and LBG) for each of the three treatment groups. CONCLUSIONS: Composite endpoints are advantageous in periodontal clinical trials where no single efficacy endpoint has been established as the most important. A composite endpoint, combining outcome measures of both hard and soft tissue components of the periodontium, may be preferable for assessing efficacy of periodontal regenerative therapies. Two composite endpoints are offered to meet this need.

rhPDGF-BB promotes healing of periodontal defects: 24-month clinical and radiographic observations.

A new therapeutic system using purified recombinant human platelet-derived growth factor-BB (rhPDGF-BB) in combination with a biocompatible, osteoconductive, synthetic scaffold beta-tricalcium phosphate (beta-TCP) has recently been shown in a large-scale, prospective, blinded, randomized clinical trial to safely and effectively treat advanced periodontal osseous defects. A significant gain in clinical attachment level was observed 3 months postsurgery for sites treated with 0.3 mg/mL rhPDGF-BB + beta-TCP versus beta-TCP + buffer (active control), with this trend continuing at 6 months postsurgery. Additionally, sites treated with 0.3 mg/mL rhPDGF-BB + beta-TCP also had significantly greater radiographic linear bone gain and percent defect fill at 6 months postsurgery than sites that received bone substitute with buffer. Representative cases from the clinical trial were followed to assess their ability to maintain the initial effect of treatment observed at 6 months. At 18 or 24 months postsurgery, with the same clinical and radiographic measurement techniques used as were performed at the 6-month time point for the clinical trial, these cases demonstrated maintenance of the clinical attachment level for all but one case, with all cases demonstrating substantial increases in linear bone gain and percent bone fill versus measurements obtained at 6 months postsurgery. Substantial radiographic changes in the appearance of the defect fill were observed for both rhPDGF-BB treatment groups, consisting of increased radiopacity and bone trabeculation, indicative of increased mineralization and maturation of the bone observed 6 months postsurgery.

A new era in periodontal and periimplant regeneration: use of growth-factor enhanced matrices incorporating rhPDGF.

A new, powerful off-the-shelf wound healing and bone regeneration technology termed growth-factor enhanced matrix (GEM) has recently become available for clinical use. This graft material consists of a concentrated solution of pure recombinant human platelet-derived growth factor (rhPDGF-BB), the synthetic form of the body's key natural wound healing stimulator PDGF-BB, and an osteoconductive (bone scaffold) matrix. This is the first available purified, recombinant (synthetic) growth factor product and is the result of over a decade of extensive research. Clinical and animal study results with this graft material demonstrate that it is capable of simultaneously promoting wound healing, regeneration of bone, and acceleration of gingival attach-plent gain in challenging periodontal and periimplant defects.

Platelet-derived growth factor enhancement of two alloplastic bone matrices.

BACKGROUND: The use of alloplastic matrices that mimic the mineral phase of bone has become a viable alternative to current mainstream therapies in dentistry such as allografts and autogenous grafts. Because alloplastic bone substitutes generally have relatively poor osteogenic properties, analyzing their potential as vehicles to deliver growth factors is an important step in assessing methods to enhance their clinical efficacy. The aim of these studies was to treat beta-tricalcium phosphate (beta-TCP) and calcium sulfate (CaSO(4)) with platelet-derived growth factor (PDGF)-BB to enhance the osteogenic capabilities of these materials. METHODS: In the beta-TCP studies, PDGF-BB adsorption and release were accomplished using (125)I radiolabeled growth factor and non-radioactive human recombinant PDGF at a ratio of 1:300 M. For the adsorption studies, the radiolabeled PDGF-BB/ non-radioactive PDGF solutions with resultant PDGF concentrations of 10(7) and 10(8) M were incubated with beta-TCP from 1 to 120 minutes, and the amount of adsorbed (125)I-PDGF-BB was measured using a gamma counter. Similar adsorption studies were conducted with a 30-minute incubation of beta-TCP with various PDGF concentrations. In vitro release studies were conducted with beta-TCP to which radiolabeled PDGF had been adsorbed as above. Release studies were also conducted with CaSO(4) that was hydrated with the radioactive PDGF solution described above for the TCP studies. In vivo PDGF-BB release from beta-TCP and CaSO(4) was evaluated in a mouse model, where the radioactive PDGF/non-radioactive PDGF-BB treated beta-TCP or CaSO(4) sample was inserted subcutaneously and later removed for radioactive measurement. Proliferation of human osteoblastic cells in the presence of PDGF- treated beta-TCP or CaSO(4) was assessed by (3)H thymidine incorporation. RESULTS: The absorption studies revealed that PDGF-BB was absorbed in a concentration and time-dependent manner to beta-TCP. In the in vitro release studies, approximately 45% of the adsorbed PDGF-BB was released after 10 days. In vivo release from both materials occurred faster than in vitro release. Osteoblastic cells incubated with PDGF-BB-treated matrices showed significantly (P <0.05, ANOVA) greater proliferation than with control matrices alone. CONCLUSION: These experiments demonstrate the feasibility of using PDGF-BB in combination with alloplastic materials such as beta-TCP or CaSO(4) to serve as more effective bone graft materials with enhanced osteogenic properties.

Platelet-derived growth factor stimulates bone fill and rate of attachment level gain: results of a large multicenter randomized controlled trial.

BACKGROUND: Growth factors are generally accepted to be essential mediators of tissue repair via well-established mechanisms of action that include stimulatory effects on angiogenesis and cellular proliferation, ingrowth, differentiation, and matrix biosynthesis. The aim of this study was to evaluate in a large-scale, prospective, blinded, and randomized controlled clinical trial the safety and effectiveness of purified recombinant human platelet-derived growth factor (rhPDGF-BB) mixed with a synthetic beta-tricalcium phosphate (beta-TCP) matrix for the treatment of advanced periodontal osseous defects at 6 months of healing. METHODS: Eleven clinical centers enrolled 180 subjects, each requiring surgical treatment of a 4 mm or greater intrabony periodontal defect and meeting all inclusion and exclusion criteria. Subjects were randomized into one of three treatment groups: 1) beta-TCP + 0.3 mg/ml rhPDGF-BB in buffer; 2) beta-TCP + 1.0 mg/ml rhPDGF-BB in buffer; and 3) beta-TCP + buffer (active control). Safety data were assessed by the frequency and severity of adverse events. Effectiveness measurements included clinical attachment levels (CAL) and gingival recession (GR) measured clinically and linear bone growth (LBG) and percent bone fill (% BF) as assessed radiographically by an independent centralized radiology review center. The area under the curve (AUC), an assessment of the rate of healing, was also calculated for CAL measurements. The surgeons, clinical and radiographic evaluators, patients, and study sponsor were all masked with respect to treatment groups. RESULTS: CAL gain was significantly greater at 3 months for group 1 (rhPDGF 0.3 mg/ml) compared to group 3 (beta-TCP + buffer) (3.8 versus 3.3 mm; P = 0.032), although by 6 months, this finding was not statistically significant (P = 0.11). This early acceleration of CAL gain led to group 1 exhibiting a significantly greater rate of CAL gain between baseline and 6 months than group 3 as assessed by the AUC (68.4- versus 60.1-mm weeks; P = 0.033). rhPDGF (0.3 mg/ml)-treated sites also had significantly greater linear bone gain (2.6 versus 0.9 mm, respectively; P < 0.001) and percent defect fill (57% versus 18%, respectively; P < 0.001) than the sites receiving the bone substitute with buffer at 6 months. There was less GR at 3 months in group 1 compared to group 3 (P = 0.04); at 6 months, GR for group 1 remained unchanged, whereas there was a slight gain in gingival height for group 3 resulting in comparable GR. There were no serious adverse events attributable to any of the treatments. CONCLUSIONS: 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.

Three-dimensional micro-computed tomographic evaluation of periodontal regeneration: a human report of intrabony defects treated with Bio-Oss collagen.

This study utilized three-dimensional micro-computed tomography (micro-CT) to evaluate the regenerative response to Bio-Oss Collagen when used alone or in combination with a Bio-Gide bilayer collagen membrane for the treatment of four intrabony defects (5 to 7 mm) around single-rooted teeth. The micro-CT observations are compared to the clinical, radiographic, and histologic results, which have been previously reported. After reflecting a full-thickness flap, thorough degranulation and root planing were accomplished. Bio-Oss Collagen was then used to fill the defects, and in two cases a Bio-Gide membrane was placed over the filled defect. Radiographs, clinical probing depths, and attachment levels were obtained before treatment and immediately preceding en bloc resection of teeth and surrounding tissues 9 months later. A mean pocket depth reduction of 5.75 mm and mean clinical attachment level gain of 5.25 mm were recorded. The histologic evaluation demonstrated the formation of a complete new attachment apparatus with new cementum, periodontal ligament, and alveolar bone at the level of and coronal to the calculus reference notch. Micro-CT evaluation confirmed the histologic results and demonstrated the absence of ankylosis or root resorption for all specimens. This human histologic study demonstrated that Bio-Oss Collagen has the capacity to facilitate regeneration of the periodontal attachment apparatus when placed in intrabony defects. Micro-CT observations confirmed the histologic results and enhanced the three-dimensional understanding of periodontal wound healing. The results indicate that micro-CT may be useful for three-dimensional evaluation of periodontal regenerative procedures.

Periodontal regeneration in humans using recombinant human platelet-derived growth factor-BB (rhPDGF-BB) and allogenic bone.

BACKGROUND: Purified recombinant human platelet-derived growth factor BB (rhPDGF-BB) is a potent wound healing growth factor and stimulator of the proliferation and recruitment of both periodontal ligament (PDL) and bone cells. The hypothesis tested in this study was that application of rhPDGF-BB incorporated in bone allograft would induce regeneration of a complete new attachment apparatus, including bone, periodontal ligament, and cementum in human interproximal intrabony defects and molar Class II furcation lesions. METHODS: Nine adult patients (15 sites) with advanced periodontitis exhibiting at least one tooth requiring extraction due to an extensive interproximal intrabony and/or molar Class II furcation defect were entered into the study. Eleven defects were randomly selected to receive rhPDGF-BB. Following full-thickness flap reflection and initial debridement, the tooth roots were notched at the apical extent of the calculus, the osseous defects were thoroughly debrided, and the tooth root(s) were planed/prepared. The osseous defects were then filled with demineralized freeze-dried bone allograft (DFDBA) saturated with one of three concentrations of rhPDGF-BB (0.5 mg/ml, 1.0 mg/ml, or 5.0 mg/ml). Concurrently, four interproximal defects were treated with a well accepted commercially available graft (anorganic bovine bone in collagen, ABB-C) and a bilayer collagen membrane. Radiographs, clinical probing depths, and attachment levels were obtained preoperatively (at baseline) and 9 months later. At 9 months postoperatively, the study tooth and surrounding tissues were removed en bloc. Clinical and radiographic data were analyzed for change from baseline by defect type and PDGF concentration. The histologic specimens were analyzed for the presence of regeneration of a complete new attachment apparatus coronal to the reference notch. RESULTS: The post-surgical wound rapidly healed and was characterized by firm, pink gingivae within 7 to 10 days of surgery. There were no unfavorable tissue reactions or other safety concerns associated with the treatments throughout the course of the study. In rhPDGF/allograft sites, the vertical probing depth (vPD) reduction for interproximal defects was 6.42 +/- 1.69 mm (mean +/- SD) and clinical attachment level (CAL) gain was 6.17 +/- 1.94 mm (both P < 0.01). Radiographic fill was 2.14 +/- 0.85 mm. Sites filled with ABB-C had a PD reduction and CAL gain of 5.75 +/- 0.5 and 5.25 +/- 1.71, respectively. Furcation defects treated with rhPDGF/allograft exhibited a mean horizontal and vertical PD reduction of 3.40 +/- 0.55 mm (P < 0.001) and 4.00 +/- 1.58 mm (P < 0.005), respectively. The CAL gain for furcation defects was 3.2 +/- 2.17 mm (P < 0.030). Histologic evaluation revealed regeneration of a complete periodontal attachment apparatus, including new cementum, PDL, and bone coronal to the root notch in four of the six interproximal defects and all evaluable (four of four) furcation defects treated with PDGF. Two of the four interproximal intrabony defects treated with ABB-C and membrane exhibited regeneration. CONCLUSIONS: 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.

Evaluation of periodontal regeneration following grafting intrabony defects with bio-oss collagen: a human histologic report.

This study evaluated the clinical, radiographic, and histologic response to Bio-Oss Collagen when used alone or in combination with Bio-Gide bilayer collagen membrane for the treatment of four intrabony defects (5 to 7 mm) around single-rooted teeth. After reflecting a full-thickness flap, thorough degranulation and root planing were accomplished. In all cases, Bio-Oss Collagen was then used to fill the defects, and in two cases, a Bio-Gide membrane was placed over the filled defect. Radiographs, clinical probing depths, and attachment levels were obtained before treatment and immediately preceding en bloc resection of teeth and surrounding tissues 9 months later. Reduction in pocket depth and gain in clinical attachment level were observed for both treatment protocols. The histologic evaluation demonstrated the formation of a complete new attachment apparatus, evidencing periodontal regeneration that varied with defect morphology. This human histologic study demonstrated that Bio-Oss Collagen has the capacity to induce regeneration of the periodontal attachment apparatus when placed in intrabony defects.

Periodontal regeneration in human Class II furcations using purified recombinant human platelet-derived growth factor-BB (rhPDGF-BB) with bone allograft.

This human clinical trial evaluated the clinical and histologic response to recombinant human platelet-derived growth factor-BB (rhPDGF-BB) delivered in bone allograft for the treatment of advanced Class II furcation defects. Three mandibular and one maxillary molar furcation defects were treated: Two received 0.5 mg/mL and two received 1.0 mg/mL rhPDGF-BB, in all cases mixed with DFDBA. Clinical probing depths and attachment levels were obtained presurgically and 9 months postsurgical, after which the teeth and surrounding tissues were removed en bloc. Both concentrations of rhPDGF-BB resulted in substantially improved horizontal (mean 3.5 mm) and vertical (mean 4.25 mm) probing depths and attachment levels (mean 3.75 mm). Histologic evaluation revealed periodontal regeneration, including new bone, cementum, and periodontal ligament coronal to the reference notch. Regeneration was also present coronal to the original osseous crest In one case where an enamel projection extended into the fornix of the furcation, new calcified tissue with new inserting connective tissue fibers was observed over the enamel. This study documented the favorable tissue response to rhPDGF-BB treatment at both the clinical and microscopic levels, provided the first human histologic evidence that new calcified tissue with inserting collagen fibers can occur over enamel projections within furcations, and demonstrated for the first time that complete periodontal regeneration can be achieved in advanced Class II furcation defects using a combination of purified recombinant growth factor and bone allograft.

The role of recombinant human platelet-derived growth factor-BB (rhPDGF-BB) in orthopaedic bone repair and regeneration.

Recombinant human PDGF BB homodimer (rhPDGF-BB) is a potent recruiter of, and strong mitogenic factor for, cells crucial to musculoskeletal tissue repair, including mesenchymal stem cells (MSCs), osteogenic cells and tenocytes. rhPDGF-BB also upregulates angiogenesis. These properties allow rhPDGF-BB to trigger the cascade of bone and adjoining soft tissue repair and regeneration. This mechanism of action has been established in numerous preclinical and clinical studies. Demonstration of the safety and efficacy of rhPDGF-BB in the healing of chronic foot ulcers in diabetic patients and regeneration of alveolar (jaw) bone lost due to chronic infection from periodontal disease has resulted in two FDA-approved products based on this molecule. A third product is in late stages of clinical development, with pilot and pivotal clinical studies of rhPDGF-BB mixed with an osteoconductive bone matrix (Augment(®) Bone Graft) in foot and ankle fusions demonstrating that this product is at least as effective as bone autograft, and has an improved safety profile. Additional combinations of rhPDGF-BB with tissue-specific matrices are also being studied clinically in additional musculoskeletal indications.

Percutaneous injection of augment injectable bone graft (rhPDGF-BB and ß-tricalcium phosphate [ß-TCP]/bovine type I collagen matrix) increases vertebral bone mineral density in geriatric female baboons.

BACKGROUND CONTEXT: Recombinant human platelet-derived growth factor-BB (rhPDGF-BB) homodimer is a chemotactic, mitogenic, and angiogenic factor expressed by platelets. This biological triad is profoundly important in the bone regenerative cascade. Therefore, the expectation was that rhPDGF-BB locally administered to designated lumbar vertebrae in a soluble Type I bovine collagen/ß-tricalcium phosphate (ß-TCP) injectable paste would have an osteoanabolic effect. PURPOSE: The study objective focused on safety and efficacy of the rhPDGF-BB and soluble Type I bovine collagen/ß-TCP to increase bone density when injected directly into specific lumbar vertebral bodies in elderly (17- to 18-year-old) female baboons. STUDY DESIGN/SETTING: The study was designed to determine whether vertebral bone mineral density (BMD) in aged female baboons could be increased by locally administering recombinant rhPDGF-BB combined in a soluble Type I bovine collagen/ß-TCP paste formulation. METHODS: A total of six baboons were divided equally into two groups. Group 1 received 1.0 mg/mL rhPDGF-BB in 20 mM sodium acetate plus soluble Type I bovine collagen/ß-TCP. Group 2 was treated with 20 mM sodium acetate plus soluble Type I bovine collagen/ß-TCP. Baboons in each group also received a sham surgery. Surgery was conducted using a percutaneous, fluoroscopically guided approach, and quantitative computed tomography (qCT) and radiographs were done at dedicated time periods. The qCT was used to determine volumetric BMD (vBMD). At euthanasia (36-week posttreatment), lumbar vertebrae were recovered and analyzed by qCT scans and histology. Funds were received to support this work from BioMimetic Therapeutics, Inc. The device that is the subject of this manuscript is not Food Drug Administration approved for this indication and is not commercially available in the United States. RESULTS: The qCT and histopathological data suggested that vBMD and bone morphology increased significantly in the lumbar vertebrae treated with the rhPDGF-BB-containing composition. CONCLUSIONS: Bone mineral density and bone morphology quality of lumbar vertebrae in aged female baboons were improved by direct injection of rhPDGF-BB in a soluble Type I bovine collagen/ß-TCP paste. Throughout the course of the study, there were neither local nor systemic adverse effects.

Recombinant human platelet-derived growth factor-BB and beta-tricalcium phosphate (rhPDGF-BB/ß-TCP): an alternative to autogenous bone graft.

BACKGROUND: Joint arthrodesis employing autogenous bone graft (autograft) remains a mainstay in the treatment of many foot and ankle problems. However, graft harvest can lead to perioperative morbidity and increased cost. We tested the hypothesis that purified recombinant human platelet-derived growth factor-BB (rhPDGF-BB) homodimer combined with an osteoconductive matrix (beta-tricalcium phosphate [ß-TCP]) would be a safe and effective alternative to autograft. METHODS: A total of 434 patients were enrolled in thirty-seven clinical sites across North America in a prospective, randomized (2:1), controlled, non-inferiority clinical trial to compare the safety and efficacy of the combination rhPDGF-BB and ß-TCP with those of autograft in patients requiring hindfoot or ankle arthrodesis. Radiographic, clinical, functional, and quality-of-life end points were assessed through fifty-two weeks postoperatively. RESULTS: Two hundred and sixty patients (394 joints) underwent arthrodesis with use of rhPDGF-BB/ß-TCP. One hundred and thirty-seven patients (203 joints) underwent arthrodesis with use of autograft. With regard to the primary end point, 159 patients (61.2% [262 joints (66.5%)]) in the rhPDGF-BB/ß-TCP group and eighty-five patients (62.0% [127 joints (62.6%)]) in the autograft group were fused as determined by computed tomography at six months (p < 0.05). Clinically, 224 patients (86.2%) [348 joints (88.3%)]) in the rhPDGF-BB/ß-TCP group were considered healed at fifty-two weeks, compared with 120 patients (87.6% [177 joints (87.2%)] in the autograft group (p = 0.008). Overall, fourteen of sixteen secondary end points at twenty-four weeks and fifteen of sixteen secondary end points at fifty-two weeks demonstrated statistical non-inferiority between the groups, and patients in the rhPDGF-BB/ß-TCP group were found to have less pain and an improved safety profile. CONCLUSIONS: In patients requiring hindfoot or ankle arthrodesis, treatment with rhPDGF-BB/ß-TCP resulted in comparable fusion rates, less pain, and fewer side effects as compared with treatment with autograft.

Platelet-derived growth factor promotes periodontal regeneration in localized osseous defects: 36-month extension results from a randomized, controlled, double-masked clinical trial.

BACKGROUND: Recombinant human platelet-derived growth factor (rhPDGF) is safe and effective for the treatment of periodontal defects in short-term studies up to 6 months in duration. We now provide results from a 36-month extension study of a multicenter, randomized, controlled clinical trial evaluating the effect and long-term stability of PDGF-BB treatment in patients with localized severe periodontal osseous defects. METHODS: A total of 135 participants were enrolled from six clinical centers for an extension trial. Eighty-three individuals completed the study at 36 months and were included in the analysis. The study investigated the local application of ß-tricalcium phosphate scaffold matrix with or without two different dose levels of PDGF (0.3 or 1.0 mg/mL PDGF-BB) in patients possessing one localized periodontal osseous defect. Composite analysis for clinical and radiographic evidence of treatment success was defined as percentage of cases with clinical attachment level (CAL) ≥2.7 mm and linear bone growth (LBG) ≥1.1 mm. RESULTS: The participants exceeding this composite outcome benchmark in the 0.3 mg/mL rhPDGF-BB group went from 62.2% at 12 months, 75.9% at 24 months, to 87.0% at 36 months compared with 39.5%, 48.3%, and 53.8%, respectively, in the scaffold control group at these same time points (P <0.05). Although there were no significant increases in CAL and LBG at 36 months among all groups, there were continued increases in CAL gain, LBG, and percentage bone fill over time, suggesting overall stability of the regenerative response. CONCLUSION: PDGF-BB in a synthetic scaffold matrix promotes long-term stable clinical and radiographic improvements as measured by composite outcomes for CAL gain and LBG for patients possessing localized periodontal defects ( ClinicalTrials.gov no. CT01530126).

Augment bone graft products compare favorably with autologous bone graft in an ovine model of lumbar interbody spine fusion.

STUDY DESIGN: 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 ß-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. OBJECTIVE: 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. SUMMARY OF BACKGROUND DATA: 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. METHODS: 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. RESULTS: 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 ß-tricalcium phosphate particles embedded in the newly formed bone were visible in Augment- and Augment Injectable-treated specimens. CONCLUSION: 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.

Stability of Recombinant Human Platelet-Derived Growth Factor-BB- Regenerated Periodontal Defects: Sixty-Month Clinical and Radiographic Observations.

INTRODUCTION: The availability of recombinant human platelet-derived growth factor-BB (rhPDGF-BB) plus ß-tricalcium phosphate (ß-TCP) for periodontal therapeutic use resulted from a large-scale, prospective, masked, randomized clinical trial. This pivotal trial indicated that this combination can safely and effectively be used to treat advanced periodontal osseous defects. Previous reports demonstrated significant gain in clinical attachment level, linear bone gain, and percentage bone fill after 6 months. Subsequent evaluation of selected cases 24 months after treatment indicated the clinical gains were maintainable. Furthermore, there appeared to be substantial increase in linear bone gain and percentage bone fill. Radiographically, there was increased radiopacity and bone trabeculation, suggesting bone maturation. CASE SERIES: This report presents representative cases from the rhPDGF-BB plus ß-TCP pivotal clinical trial after 60 months. Maximal regenerative results were achieved after 12 months and maintained ≥5 years. Sites treated with rhPDGF-BB plus ß-TCP were generally healthy, with no evidence of ankylosis, root resorption, or abnormal tissue reaction. However, a limited number of cases deteriorated, suggesting that smoking and poor self/supportive care compliance can adversely affect periodontal regenerative results. CONCLUSIONS: The use of rhPDGF-BB plus ß-TCP was safe and effective in the treatment of periodontal osseous defects. The regenerated results are maintainable ≥5 years, with adverse events attributable to the treatment.