Recombinant Human Platelet-derived Growth factor-BB Research Articles

Recombinant Human Platelet-Derived Growth Factor-BB and Beta-Tricalcium Phosphate (rhPDGF-BB/β-TCP): An Alternative to Autogenous Bone Graft

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 [β-TCP]) would be a safe and effective alternative to autograft. 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 β-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. Two hundred and sixty patients (394 joints) underwent arthrodesis with use of rhPDGF-BB/β-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/β-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/β-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/β-TCP group were found to have less pain and an improved safety profile. In patients requiring hindfoot or ankle arthrodesis, treatment with rhPDGF-BB/β-TCP resulted in comparable fusion rates, less pain, and fewer side effects as compared with treatment with autograft.

A Systematic Review of the Use of Growth Factors in Human Periodontal Regeneration

There is a large body of evidence using cells and animal models demonstrating the effectiveness of growth factors in periodontal regeneration. However, there appears to be minimal literature comparing the efficacy of growth factors in human periodontal regeneration compared to other techniques and procedures. Therefore, the aim of this study is to perform a systematic review of human studies using growth factors for periodontal regeneration and to compare the efficacy of these growth factors to other accepted techniques for periodontal regeneration. An electronic and manual search based on agreed search phrases between the primary investigator and a secondary investigator was performed to identify the use of growth factors in periodontics for the literature review. The articles that were identified by this systematic review were analyzed in detail, which included the study of their inclusion and exclusion criteria, outcome measures determination and analysis, risk of bias, adverse events, and conclusions or inference of the efficacy of growth factors to the general population. Five papers fulfilled the inclusion criteria. Two papers were identified that had sufficiently similar study design that a meta-analysis of their outcomes was possible. Most of the reported outcomes from the selected papers were descriptive. The articles demonstrated periodontal regeneration at least comparable to their respective positive controls, with only a couple of articles demonstrating significantly greater outcomes compared to their respective positive controls. Histologic evidence demonstrated greater periodontal regeneration when using growth factors compared to other regenerative techniques and an increased healing and bone maturation rate compared to other regenerative and bone augmentation techniques in these human studies. Within the limits of this systematic review, the use of recombinant human platelet-derived growth factor-BB (rhPDGF-BB) led to greater clinical attachment level gain of ≈1 mm compared to an osteoconductive control, β-tricalcium phosphate (β-TCP). The use of rhPDGF-BB led to greater percentage bone fill of ≈40% compared to the osseoconductive control, β-TCP. Last, the use of rhPDGF-BB led to an increased rate of bone growth of ≈2 mm compared to the osseoconductive control, β-TCP.

Block Allograft Technique versus Standard Guided Bone Regeneration: A Randomized Clinical Trial

The aim of this randomized clinical trial was to compare the potential of deproteinized bovine bone added to autologous bone or corticocancellous allograft block with or without the addition of recombinant human platelet-derived growth factor-BB (rhPDGF-BB) to regenerate mandibular atrophic ridges. parallel, allocation ratio of 1:1 using a split-mouth model. Eligibility criteria for patients: adult patients; bilateral atrophic edentulous areas in the posterior area of the mandible; a preoperatory cone beam computed tomography scan; and absence of systemic diseases affecting the bone metabolism. Bone graft intervention for control group consisted of bone chips collected with a scraper mixed with deproteinized bovine bone covered with a resorbable membrane. Bone graft intervention for test group consisted of a corticocancellous allograft block, shaped before surgery, and protected with a collagen membrane. In addition, both groups received rhPDGF-BB or a saline solution as control. As primary outcome quantity, bone variation after a 1-year healing period was considered. A p-value of.05 was considered statistically significant. Sixteen patients were enrolled in this trial. A total of 50 implants and 32 bone grafts were placed. All patients concluded the study (no dropouts). Change at 1 year in bone volume was not significantly different between the two groups (p-value = .25). Effect of treatment in terms of change in bone volume at 1 year was not significant (p-value = .89) when saline solution was used while was at limit of significance when rhPDGF-BB was used (p-value = .052). After 1 year, all the implants were successfully integrated. The block allograft and the standard regenerative procedure showed similar results in terms of regenerated bone volume after 1 year of functional loading. The rhPDGF-BB positively influenced soft-tissue healing.

Bone Regeneration of Tibial Defects in Rats with Enzymatic Hydrogelation of Gelatin Derivative and Recombinant Human Platelet-Derived Growth Factor-BB Complex

To evaluate the capabilities of gelatin derivatives that incorporate phenolic hydroxyl groups (gelatin-Ph) as a delivery carrier with recombinant human platelet-derived growth factor-BB (rhPDGF-BB) for bone regeneration. The growth factor release profile from gelatin-Ph gel or atelocollagen was analyzed to evaluate the capability of gelatin-Ph as a carrier. The biocompatibility of gelatin-Ph (ie, the survival rates of the cells during gelation, and the morphology and proliferation of the cells) were investigated with rat bone marrow cells (RBMCs) in vitro. To evaluate the effect of the gelatin-Ph-rhPDGF-BB complex on bone formation, the complex was applied to bone defects in rat tibiae and undecalcified specimens were fabricated for histologic analysis. Scarce amounts of rhPDGF-BB from gelatin-Ph gel were detected during 30 days, but the addition of protease induced the release of rhPDGF-BB on day 31. No differences were observed in the survival rates of RBMCs during gelation and in the morphology and proliferation of RBMCs on the gel sheet between groups. Histological analyses demonstrated that the complex enhanced bone formation and mineralization at 2 and 4 weeks. These results suggest that gelatin-Ph gel can be an ideal delivery carrier, and the localized delivery of rhPDGF-BB in gelatin-Ph can contribute to bone formation.

PSU9 Budget Impact of Autograft Harvest, Bone Graft Supplements and Orthobiologic Bone Graft Substitute in Foot and Ankle Fusion Procedures

No multicenter studies currently assess the incremental costs of autogenous bone graft harvest (autograft) in foot and ankle procedures. This study applied conservatively estimated incremental costs of autograft (with and without bone graft supplements/enhancers) using an interactive budgetary impact model comparing costs and cost offsets of an orthobiologic bone graft substitute (β-TCP with recombinant human platelet-derived growth factor-BB [rhPDGF-BB]) in foot and ankle fusion procedures. A Canadian hospital-based budget impact model was developed utilizing International Society of Pharmacoeconomics and Outcomes Research (ISPOR) guidelines. Clinical and health economic literature, data from a 434-patient randomized control trial and data from a panel of ten experienced orthopaedic surgeons provided estimates of medical resource utilization and associated hospital costs. Model parameters were confirmed by six individuals representing 15 Canadian hospitals. Autograft carries incremental costs related to operating suite time (37.9 ± 17.0 minutes for an iliac crest donor site and 22.1 ± 21.6 minutes for local donor sites), recovery room time (25.0 ± 12.3 minutes for iliac and 3.5 ± 9.4 minutes for local), and donor site complications. Conservative base case incremental costs were $1,601(CAD) for iliac crest and $755 (CAD) for local sites. Complications at the harvest site contributed an additional base case cost of $414 for iliac crest and $182 for local sites. Use of an orthobiologic bone graft substitute had higher acquisition costs, but yielded per-case and annualized cost savings ($34 and $2,454, respectively, base case) by eliminating incremental costs, graft harvest complications, and patient pain reported for autograft harvest during clinical trial. The gold standard of harvesting autogenous bone graft as an adjunct to foot and ankle fusion surgery is associated with significant health care costs. The use of β-TCP with rhPDGF-BB eliminated variable, incremental hospital costs associated with bone graft harvesting and treating related complications.

Dose–response effect of an intra‐tendon application of recombinant human platelet‐derived growth factor‐BB (rhPDGF‐BB) in a rat Achilles tendinopathy model

The purpose of this study was to assess whether intra-tendon delivery of recombinant human platelet-derived growth factor-BB (rhPDGF-BB) would improve Achilles tendon repair in a rat collagenase-induced tendinopathy model. Seven days following collagenase induction of tendinopathy, one of four intra-tendinous treatments was administered: (i) Vehicle control (sodium acetate buffer), (ii) 1.02 µg rhPDGF-BB, (iii) 10.2 µg rhPDGF-BB, or (iv) 102 µg rhPDGF-BB. Treated tendons were assessed for histopathological (e.g., proliferation, tendon thickness, collagen fiber density/orientation) and biomechanical (e.g., maximum load-to-failure and stiffness) outcomes. By 7 days post-treatment, there was a significant increase in cell proliferation with the 10.2 and 102 µg rhPDGF-BB-treated groups (p=0.049 and 0.015, respectively) and in thickness at the tendon midsubstance in the 10.2 µg of rhPDGF-BB group (p=0.005), compared to controls. All groups had equivalent outcomes by Day 21. There was a dose-dependent effect on the maximum load-to-failure, with no significant difference in the 1.02 and 102 µg rhPDGF-BB doses but the 10.2 µg rhPDGF-BB group had a significant increase in load-to-failure at 7 (p=0.003) and 21 days (p=0.019) compared to controls. The rhPDGF-BB treatment resulted in a dose-dependent, transient increase in cell proliferation and sustained improvement in biomechanical properties in a rat Achilles tendinopathy model, demonstrating the potential of rhPDGF-BB treatment in a tendinopathy application. Consequently, in this model, data suggest that rhPDGF-BB treatment is an effective therapy and thus, may be an option for clinical applications to treat tendinopathy.

Effect of recombinant human platelet-derived growth factor-BB-coated sutures on Achilles tendon healing in a rat model: A histological and biomechanical study

Purpose: Repairing tendon injuries with recombinant human platelet-derived growth factor-BB has potential for improving surgical outcomes. Augmentation of sutures, a critical component of surgical tendon repair, by coating with growth factors may provide a clinically useful therapeutic device for improving tendon repair. Therefore, the purpose of this study was to (a) coat Vicryl sutures with a defined dose of recombinant human platelet-derived growth factor-BB without additional coating excipients (e.g. gelatin), (b) quantify the recombinant human platelet-derived growth factor-BB released from the suture, and (c) use the recombinant human platelet-derived growth factor-BB-coated sutures to enhance tendon repair in a rat Achilles tendon transection model. Methods: Vicryl sutures were coated with 0, 0.3, 1.0, and 10.0 mg/mL concentrations of recombinant human platelet-derived growth factor-BB using a dip-coating process. In vitro release was quantified by an enzyme-linked immunosorbent assay. Acutely transected rat Achilles tendons were repaired using one of the four suture groups (n = 12 per group). Four weeks following repair, the tensile biomechanical and histological (i.e. collagen organization and angiogenesis) properties were determined. Results: A dose-dependent bolus release of recombinant human platelet-derived growth factor-BB occurred within the first hour in vitro, followed by a gradual release over 48 h. There was a significant increase in ultimate tensile strength (p < 0.01) in the two highest recombinant human platelet-derived growth factor-BB dose groups (1.9 ± 0.5 and 2.1 ± 0.5 MPa) relative to controls (1.0 ± 0.2 MPa). The modulus significantly increased (p = 0.031) with the highest recombinant human platelet-derived growth factor-BB dose group (7.2 ± 3.8 MPa) relative to all other groups (control: 3.5 ± 0.9 MPa). No significant differences were identified for the maximum load or stiffness. The histological collagen and angiogenesis scores were comparable in all groups, although there was a trend for improved collagen organization in the recombinant human platelet-derived growth factor-BB-treated groups (p = 0.054). Conclusions: The results of this study suggest that recombinant human platelet-derived growth factor-BB can be used to reproducibly coat Vicryl sutures and improve remodeling in a rat Achilles tendon transection model by significantly decreasing the resulting cross-sectional area, thus improving the material properties of the repaired tendon.

Vertical Ridge Augmentation Using an Equine Bone and Collagen Block Infused With Recombinant Human Platelet‐Derived Growth Factor‐BB: A Randomized Single‐Masked Histologic Study in Non‐Human Primates

This study tests the effectiveness of hydroxyapatite and collagen bone blocks of equine origin (eHAC), infused with recombinant human platelet-derived growth factor-BB (rhPDGF-BB), to augment localized posterior mandibular defects in non-human primates (Papio hamadryas). Bilateral critical-sized defects simulating severe atrophy were created at the time of the posterior teeth extraction. Test and control blocks (without growth factor) were randomly grafted into the respective sites in each non-human primate. All sites exhibited vertical ridge augmentation, with physiologic hard- and soft-tissue integration of the blocks when clinical and histologic examinations were done at 4 months after the vertical ridge augmentation procedure. There was a clear, although non-significant, tendency to increased regeneration in the test sites. As in the first two preclinical studies in this series using canines, experimental eHAC blocks infused with rhPDGF-BB proved to be a predictable and technically viable method to predictably regenerate bone and soft tissue in critical-sized defects. This investigation supplies additional evidence that eHAC blocks infused with rhPDGF-BB growth factor is a predictable and technically feasible option for vertical augmentation of severely resorbed ridges.

Safety of recombinant human platelet-derived growth factor-BB in Augment® Bone Graft

This article discusses nonclinical and clinical data regarding the safety of recombinant human platelet-derived growth factor-BB as a component of the Augment® Bone Graft (Augment). Augment is a bone graft substitute intended to be used as an alternative to autologous bone graft in the fusion of hindfoot and ankle joints. Nonclinical studies included assessment of the pharmacokinetic profile of intravenously administered recombinant human platelet-derived growth factor-BB in rat and dog, effects of intravenous administration of recombinant human platelet-derived growth factor-BB in a reproductive and development toxicity study in rats, and chronic toxicity and carcinogenicity of Augment in a 12-month implantation model. These studies showed that systemic exposure was brief and clearance was rapid. No signs of toxicity, carcinogenicity, or tumor promotion were observed even with doses far exceeding the maximum clinical dose. Results of clinical trials (605 participants) and commercial use of recombinant human platelet-derived growth factor-BB containing products indicate that these products are not associated with increased incidence of adverse events or cancer. The safety data presented provide evidence that recombinant human platelet-derived growth factor-BB is a safe therapeutic when used in combination products as a single administration during surgical procedures for bone repair and fusion. There is no evidence associating use of recombinant human platelet-derived growth factor-BB in Augment with chronic toxicity, carcinogenicity, or tumor promotion.

Augment Bone Graft Products Compare Favorably With Autologous Bone Graft in an Ovine Model of Lumbar Interbody Spine Fusion

This study was designed to determine whether Augment Bone Graft (Augment, Biomimetic Therapeutics, Inc., Franklin, TN) and Augment Injectable Bone Graft (Augment Injectable, Biomimetic Therapeutics, Inc., Franklin, TN), 2 combination devices comprising recombinant human platelet-derived growth factor-BB and β-tricalcium phosphate-containing matrices, promote bone bridging in an ovine model of lumbar spine fusion. Autologous bone graft (autograft) was used as a positive control. The purpose of this study was to determine the ability of Augment products to promote fusion of the L2-L3 and L4-L5 vertebral bodies in an ovine model. In interbody spine fusion, the intervertebral disc is removed and a spacer is inserted for support and to facilitate bone growth. The fusion is commonly enhanced with grafts. Autograft is the "gold standard" but it has limitations including availability and donor-site morbidity. Synthetic graft substitutes eliminate these complications. Augment products are combination devices including recombinant human platelet-derived growth factor-BB, a well-characterized chemotactic, mitogenic, and proangiogenic protein essential in wound and bone healing. Twenty-two sheep received an uninstrumented, double-level, interbody lumbar spinal fusion procedure using a polyetheretherketone spacer, which was either empty or packed with iliac crest autograft, Augment or Augment Injectable. The same treatment was used at both levels. Animals were 24 weeks after surgery, and fusion was assessed by micro-computed tomography (micro-CT) and histology. Micro-CT and histologic assessment of fusion revealed that empty controls had significantly lower fusion rates. No differences were detected among autografts, Augment, and Augment Injectable-treated specimens. Residual β-tricalcium phosphate particles embedded in the newly formed bone were visible in Augment- and Augment Injectable-treated specimens. Augment-treated specimens had the highest fusion scores. Treatment with either of the Augment products significantly promoted interbody spine fusion compared with empty spacers and was equivalent to autograft-induced fusion. No adverse events were noted.

The healing of critical-size calvarial bone defects in rat with rhPDGF-BB, BMSCs, and β-TCP scaffolds

Platelet-derived growth factor-BB (PDGF-BB) plays important roles in regenerating damaged tissue. In this study we investigated the effects of a tissue-engineered bone combined with recombinant human PDGF-BB (rhPDGF-BB), bone marrow stem cells (BMSCs) and β-tricalcium phosphate (β-TCP) to repair critical-size calvarial bone defects in rat. Proliferation and osteogenic differentiation of BMSCs treated with different concentration rhPDGF-BB (0, 10, and 50 ng/ml) was evaluated by MTT, alkaline phosphatase (ALP) activity, alizarin red staining and real-time quantitative PCR (RT-qPCR) analysis of osteogenic gene. BMSCs were then combined with rhPDGF-BB-loaded β-TCP and transplanted into 5 mm calvarial bone defects. The new bone formation and mineralization was evaluated by micro-computerized tomography (Micro-CT) and histological analysis at week 8 after operation. It was observed that the proliferation of BMSCs treated with rhPDGF-BB was enhanced with a time- and dose- dependent manner. There were increased ALP activity, mineralized deposition and elevated mRNA levels of osteogenic gene for BMSCs treated with rhPDGF-BB, particularly in the 50 ng/ml group. Histological analysis showed new bone formation and mineralization in the rhPDGF-BB/BMSCs/β-TCP group was significantly higher than BMSCs/β-TCP, rhPDGF-BB/β-TCP, and β-TCP alone group (P < 0.05). In conclusion, rhPDGF-BB/BMSCs/β-TCP is a promising tissue-engineered bone for craniofacial bone regeneration.

Regenerative Tendon and Ligament Healing: Opportunities with Recombinant Human Platelet-Derived Growth Factor BB-Homodimer

Intrinsic tendon healing in response to injury is a reparative process that often results in formation of scar tissue with functional and mechanical properties inferior to those of the native tendon. Development of therapies that can promote regenerative, rather than reparative, healing hold the promise of improving patient recovery from tendon and ligament injuries by producing tissue that is morphologically and functionally equivalent to the native tissue. One therapeutic approach that has been a frequent topic of investigation in the preclinical literature is the use of recombinant human platelet-derived growth factor-BB (rhPDGF-BB) to augment tendon and ligament repair. The chemotactic, mitogenic, and pro-angiogenic properties of rhPDGF-BB have been shown to result in recruitment and proliferation of tenogenic cells and a commensurate boost in extracellular matrix deposition and organization, improving the morphological and biomechanical properties of healing tendons and ligaments. The outcomes of the preclinical studies reviewed here strongly suggest that rhPDGF-BB will provide a new therapeutic opportunity to improve the treatment of injured tendons and ligaments.

The effect of Emdogain® and platelet-derived growth factor on the osteoinductive potential of hydroxyapatite tricalcium phosphate

The aim of this study was to determine whether hydroxyapatite β-tricalcium phosphate (HA-TCP) either alone or coated with Emdogain (EMD) or recombinant human platelet-derived growth factor-BB (rhPDGF-BB) becomes osteoinductive in the murine thigh muscle model for osteoinduction. Twenty CD1 adult male mice had gelatin capsules implanted into the thigh muscle of both hind limbs. The capsules were either empty or contained one of the following: uncoated particulate HA-TCP, EMD-coated HA-TCP or rhPDGF-BB-coated HA-TCP. The implant sites were assessed histologically at 4 and 8 weeks. A semi-quantitative histological examination was performed to assess the inflammatory changes, reparative processes and osteoinduction within the graft site. At both 4 and 8 weeks, histological analysis failed to demonstrate any osteoinductive activity in any of the specimens from the experimental groups. A minimal chronic inflammatory response and foreign body reaction around the implanted materials was seen which reduced over time. The HA-TCP particles were embedded within fibrous connective tissue and were encapsulated by a dense cellular layer consisting of active fibroblasts and occasional macrophages with the thickness of this layer decreasing over time. The results of this study suggest that the use of commercially available HA-TCP alone or in combination with EMD or rhPDGF-BB is biocompatible but not osteoinductive in the murine thigh muscle model of osteoinduction. Coating HA-TCP with EMD or rhPDGF-BB does not enhance its osteoinductive potential.

Expression and Production of Therapeutic Recombinant Human Platelet-Derived Growth Factor-BB in Pleurotus eryngii

Recombinant human platelet-derived growth factor-BB (rhPDGF-BB) is widely used in many therapeutic applications. Until now, there has been no report on rhPDGF-BB expressed in fungi. In this study, we tested whether Pleurotus eryngii could support the expression of human therapeutic rhPDGF-BB protein. A binary vector pCAMBIA1304 containing the hPDGF-BB gene was constructed and introduced into P. eryngii via Agrobacterium tumefaciens-mediated transformation. The transformation of hPDGF-BB gene was confirmed by Southern blot and PCR, whereas the expression was confirmed by Western blot analysis. The recombinant hPDGF-BB reached a maximum expression level of 1.98% of total soluble protein in transgenic mycelia and was in dimeric form. A bioassay revealed that hPDGF-BB expressed in P. eryngii increased proliferation of NIH-3T3 cells similarly to standard material. These results suggest that P. eryngii can be a robust system for the production of human therapeutic proteins including the hPDGF-BB.

Augmentation of a Rotator Cuff Suture Repair Using rhPDGF-BB and a Type I Bovine Collagen Matrix in an Ovine Model

Background Rotator cuff tears are a common source of shoulder pain. High rates (20%-94%) of structural failure of the repair have been attributed to multiple factors, including poor repair tissue quality and tendon-to-bone integration. Biologic augmentation using growth factors has potential to promote tendon-to-bone integration, improving the function and long-term success of the repair. One such growth factor is platelet-derived growth factor–BB (PDGF-BB), which has been shown to improve healing in tendon and bone repair models. Hypothesis Recombinant human PDGF-BB (rhPDGF-BB) combined with a highly porous type I bovine collagen matrix will improve the biomechanical function and morphologic appearance of the repair in a dose-dependent manner, relative to a suture-only control, after 12 weeks in an acute ovine model of rotator cuff repair. Study Design Controlled laboratory study. Methods An interpositional graft consisting of rhPDGF-BB and a type I collagen matrix was implanted in an ovine model of rotator cuff repair. Biomechanical and histologic analyses were performed to determine the functional and anatomic characteristics of the repair after 12 weeks. Results A significant increase in the ultimate load to failure was observed in repairs treated with 75 μg (1490.5 ± 224.5 N, P = .029) or 150 μg (1486.6 ± 229.0 N, P = .029) of rhPDGF-BB, relative to suture-only controls (910.4 ± 156.1 N) and the 500-μg rhPDGF-BB group (677.8 ± 105.9 N). The 75-μg and 150-μg rhPDGF-BB groups also exhibited increased tendon-to-bone inter-digitation histologically. No differences in inflammation or cellularity were observed among treatments. Conclusion This study demonstrated that an interpositional graft consisting of rhPDGF-BB (75 or 150 μg) and a type I collagen matrix was able to improve the biomechanical strength and anatomic appearance in an ovine model of rotator cuff repair compared to a suture-only control and the 500-μg rhPDGF-BB group. Clinical Relevance Recombinant human PDGF-BB combined with a type I collagen matrix has potential to be used to augment surgical repair of rotator cuff tears, thereby improving clinical success.

Platelet-derived growth factor applications in periodontal and peri-implant bone regeneration

Introduction: Achieving successful tissue regeneration following traditional therapeutic protocols, combining bone grafts and barrier membranes, may be challenging in certain clinical scenarios. A deeper understanding of periodontal and peri-implant wound healing and recent advances in the field of tissue engineering have provided clinicians with novel means to obtain predictable clinical outcomes. The use of growth factors such as recombinant human platelet-derived growth factor-BB (rhPDGF) with biocompatible matrices to promote tissue regeneration represents a promising approach in the disciplines of periodontology and implantology.Areas covered: This review covers the basic principles of bone and periodontal regeneration, and provides an overview of the biology of PDGF and its potential to predictably and reproducibly promote bone regeneration in regular clinical practice. The results of preclinical and clinical human studies evaluating the effectiveness of growth-factor-enhanced matrices are analyzed and discussed.Expert opinion: Current available evidence supports the use of rhPDGF-enhanced matrices to promote periodontal and peri-implant bone regeneration.

Growth/differentiation factor‐5 significantly enhances periodontal wound healing/regeneration compared with platelet‐derived growth factor‐BB in dogs

Recombinant human growth/differentiation factor-5 (rhGDF-5) in a particulate beta-tricalcium phosphate (beta-TCP) carrier is being evaluated to support periodontal regeneration. The objective of this study was to evaluate periodontal wound healing/regeneration following an established clinical (benchmark) protocol including surgical implantation of rhGDF-5/beta-TCP in comparison with that following implantation of recombinant human platelet-derived growth factor-BB (rhPDGF) combined with a particulate beta-TCP biomaterial using an established canine defect model. Bilateral, 4 x 5 mm (width x depth), one-wall, critical-size, intrabony periodontal defects were surgically created at the mandibular second and fourth pre-molar teeth in five adult Beagle dogs. Defect sites were randomized to receive rhGDF-5/beta-TCP or the rhPDGF construct followed by wound closure for primary intention healing. The animals were sacrificed following an 8-week healing interval for histological and histometric examination. Clinical healing was generally uneventful. Sites receiving rhGDF-5/beta-TCP exhibited a significantly enhanced cementum formation compared with sites receiving the rhPDGF construct, averaging (+/-SD) 4.49+/-0.48 versus 2.72+/-0.91 mm (p<0.001). Similarly, bone regeneration height and area were significantly enhanced at sites receiving rhGDF-5/beta-TCP versus that of the rhPDGF construct averaging, 3.08+/-0.74 versus 1.29+/-0.78 mm (p<0.001) and 6.03+/-1.28 versus 2.98+/-2.61 mm(2) (p<0.01), respectively. Cementum regeneration included cellular/acellular mixed (extrinsic/intrinsic) fibre cementum at sites receiving rhGDF-5/beta-TCP; sites receiving the rhPDGF/beta-TCP showed a pre-dominantly acellular cementum. Newly formed cementum generally extended above the adjoining alveolar bone. Both protocols displayed beta-TCP residues apparently undergoing resorption. Application of both materials appears safe, as they were associated with limited, if any, adverse events. rhGDF-5/beta-TCP shows a significant potential to support/accelerate periodontal wound healing/regeneration. Application of rhGDF-5/beta-TCP appears safe and should be further evaluated in human clinical trials.

A novel serum-free medium for the expansion of human mesenchymal stem cells

IntroductionHuman multipotent mesenchymal stem cell (MSC) therapies are being tested clinically for a variety of disorders, including Crohn's disease, multiple sclerosis, graft-versus-host disease, type 1 diabetes, bone fractures, and cartilage defects. However, despite the remarkable clinical advancements in this field, most applications still use traditional culture media containing fetal bovine serum. The ill-defined and highly variable nature of traditional culture media remains a challenge, hampering both the basic and clinical human MSC research fields. To date, no reliable serum-free medium for human MSCs has been available.MethodsIn this study, we developed and tested a serum-free growth medium on human bone marrow-derived MSCs through the investigation of multiple parameters including primary cell isolation, multipassage expansion, mesoderm differentiation, cellular phenotype, and gene-expression analysis.ResultsSimilar to that achieved with traditional culture medium, human MSCs expanded in serum-free medium supplemented with recombinant human platelet-derived growth factor-BB (PDGF-BB), basic fibroblast growth factor (bFGF), and transforming growth factor (TGF)-β1 showed extensive propagation with retained phenotypic, differentiation, and colony-forming unit potential. To monitor global gene expression, the transcriptomes of bone marrow-derived MSCs expanded under serum-free and serum-containing conditions were compared, revealing similar expression profiles. In addition, the described serum-free culture medium supported the isolation of human MSCs from primary human marrow aspirate with continual propagation.ConclusionsAlthough the described serum-free MSC culture medium is not free of xenogeneic components, this medium provides a substitute for serum-containing medium for research applications, setting the stage for future clinical applications.

Effect of β tricalcium phosphate particle size on recombinant human platelet-derived growth factor-BB-induced regeneration of periodontal tissue in dog

The aim of this study was to investigate the effect of β tricalcium phosphate (β-TCP) particle size on recombinant human platelet-derived growth factor-BB (rhPDGF-BB)-induced regeneration of periodontal tissue in dog. The control group (rhPDGF-BB alone) was characterized by incomplete, newly formed bone. The large-particle β-TCP (L-TCP(O))/rhPDGF-BB group showed a statistically significant increase in both new bone and cementum formation compared to the small-particle β-TCP (S-TCP(G))/rhPDGF-BB group. These findings suggest that L-TCP(O)-particle promotes rhPDGF-BB-induced formation of bone and cementum.

Preclinical Toxicology Studies of Recombinant Human Platelet-Derived Growth Factor-BB Either Alone or in Combination with Beta-Tricalcium Phosphate and Type I Collagen

Human platelet-derived growth factor-BB (hPDGF-BB) is a basic polypeptide growth factor released from platelets at the injury site. It is a multifunctional molecule that regulates DNA synthesis and cell division and induces biological effects that are implicated in tissue repair, atherosclerosis, inflammatory responses, and neoplastic diseases. This paper is an overview of the toxicology data generated from a broad testing platform to determine bone, soft tissue, and systemic responses following administration of rhPDGF-BB. Moreover, the systemic and local toxicity of recombinant human PDGF-BB (rhPDGF-BB) in combination with either beta-tricalcium phosphate (β-TCP) or collagen combined with β-TCP was studied to determine dermal sensitization, irritation, intramuscular tissue responses, pyrogenicity, genotoxicity, and hemolytic properties. All data strongly suggest that rhPDGF-BB either alone or in combination with β-TCP or collagen with β-TCP is biocompatible and has neither systemic nor local toxicity, supporting its safe use in enhancing wound healing in patients.