Growth differentiation factor 11: a "rejuvenation factor" involved in regulation of age-related diseases?

Growth differentiation factor 11 (GDF11), a member of the transforming growth factor ß superfamily of cytokines, is a critical rejuvenation factor in aging cells. GDF11 improves neurodegenerative and neurovascular disease outcomes, increases skeletal muscle volume, and enhances muscle strength. Its wide-ranging biological effects may include the reversal of senescence in clinical applications, as well as the ability to reverse age-related pathological changes and regulate organ regeneration after injury. Nevertheless, recent data have led to controversy regarding the functional roles of GDF11, because the underlying mechanisms were not clearly established in previous studies. In this review, we examine the literature regarding GDF11 in age-related diseases and discuss potential mechanisms underlying the effects of GDF11 in regulation of age-related diseases.

The correlation between sclerostin and bone mineral density in renal transplant recipients / Correlación entre la esclerostina y la densidad mineral ósea en receptores de trasplante renal

INTRODUCTION: Sclerostin is an anti-anabolic protein synthesized by osteocytes that may cause osteoporosis by inhibiting bone formation. The aim of our study was to investigate the correlation between sclerostin and bone mineral density (BMD) reduction in renal transplant recipients (RTRs) with more than 1 year after transplantation. MATERIAL AND METHODS: This cross-sectional study was conducted on 80 patients (38 (47.5%) male/42 (52.5%) female) RTRs with a mean age of 44.68±10.39 years. Patients were compared with an age and sex-matched control group of 40 healthy individuals. BMD was measured by dual-energy X-ray absorptiometry. The levels of sclerostin were determined using enzyme-linked immunosorbent assay. RESULTS: The mean sclerostin was 3.77±0.3pg/mL in patients and 3.81±0.21pg/mL in healthy individuals. The mean T score of femoral trochanter (FT) (FT-T), femoral neck (FN) (FN-T), lumbar vertebrae (L1-4) (L1-4-T) were −0.81±0.86, −1.08±1.09 and −0.8±1.2, respectively. The mean Z score of FT (FT-Z), FN (FN-Z), L1-4 (L1-4-Z) were −0.6±0.73, −0.32±0.9 and −0.54±1.13, respectively. FT-Z and L1-4-Z were lower in patients than healthy subjects (p = 0.009, p = 0.021 respectively). Serum creatinine (p < 0.001), intact parathyroid hormone (p < 0.001) were higher and phosphate (p < 0.001), was lower in patients than healthy subjects. Patients with a log10 sclerostin of >3.84pg/mL had higher FT-T (p = 0.040), FT-Z, FN-T (p = 0.018), FN-Z (p = 0.006) than those with a log10 sclerostin of ≤3.84pg/mL. There was a significant correlation between log10 sclerostin and FN-T (r=−0.296, p = 0.009) and FN-Z (r=−0.269, p = 0.019). In linear regression analysis, high sclerostin was found to be correlated with male gender, lower FN-T and lower FN-Z independently of other risk factors. CONCLUSION: The levels of sclerostin can predict reduction of proximal femur BMD and development of mineral and bone disorder in RTRs. There was no difference in sclerostin levels between RTRs and healthy individuals

INTRODUCCIÓN: La esclerostina es una proteína con efecto antianabólico sintetizada por los osteocitos que puede causar osteoporosis al inhibir la formación de hueso. El objetivo de nuestro estudio fue investigar la correlación entre la esclerostina y la reducción de la densidad mineral ósea (DMO) en receptores de trasplante renal (RTR) más de un año después del trasplante. MATERIALES Y MÉTODOS: Este estudio transversal se realizó en 80 pacientes (38 [47,5%] varones/42 [52,5%] mujeres) RTR con una edad media de 44,68±10,39 años. Se comparó a los pacientes con un grupo de comparación emparejado por edad y sexo de 40 individuos sanos. La DMO se midió mediante absorciometría de rayos X de doble energía. Los niveles de esclerostina se determinaron utilizando un enzimoinmunoanálisis de adsorción. RESULTADOS: El nivel medio de esclerostina fue de 3,77±0,3pg/ml en pacientes y 3,81±0,21pg/ml en individuos sanos. La puntuación T media del trocánter femoral (TF) (T-TF), del cuello femoral (CF) (T-CF), las vértebras lumbares (L1-4) (T-L1-4) fue de −0,81±0,86, −1,08±1,09 y −0,8±1,2, respectivamente. La puntuación Z media del TF (Z-TF), CF (Z-CF), L1-4 (Z-L1-4) fue de -0,6±0,73, −0,32±0,9 y −0,54±1,13, respectivamente. Las puntuaciones Z-TF y Z-L1-4 fueron inferiores en los pacientes que en los sujetos sanos (p = 0,009 y p = 0,021, respectivamente). Los niveles de creatinina sérica (p < 0,001) y hormona paratiroidea intacta (p < 0,001) fueron superiores en los pacientes que en los sujetos sanos, y los niveles de fosfato (p < 0,001) fueron inferiores. Los pacientes con un log10 esclerostina >3,84pg/ml tuvieron puntuaciones T-TF (p = 0,040), Z-TF, T-CF (p = 0,018), Z-CF (p = 0,006) superiores a las de los pacientes con un log10 esclerostina ≤3,84pg/ml. Se observó una correlación significativa entre log10 esclerostina y T-CF (r=−0,296, p = 0,009) y Z-CF (r=−0,269, p = 0,019). En el análisis de regresión lineal, se observó que los niveles elevados de esclerostina estaban correlacionados con el sexo masculino, una puntuación T-CF inferior y una puntuación Z-CF inferior independientemente de otros factores de riesgo. CONCLUSIÓN: Los niveles de esclerostina pueden predecir la reducción de la DMO del fémur proximal y el desarrollo de un trastorno mineral y óseo en RTR. No se observaron diferencias en los niveles de esclerostina entre los RTR y los individuos sanos

Complications, Costs, and Quality Outcomes of Patients Undergoing Cervical Deformity Surgery With Intraoperative BMP Use.

STUDY DESIGN: An epidemiological study using national administrative data from the MarketScan database. OBJECTIVE: The aim of this study was to identify the impact of bone morphogenetic protein (BMP) on postoperative outcomes in patients undergoing adult cervical deformity (ACD) surgery. SUMMARY OF BACKGROUND DATA: BMP has been shown to stimulate bone growth and improve fusion rates in spine surgery. However, the impact of BMP on reoperation rates and postoperative complication rate is controversial. METHODS: We queried the MarketScan database to identify patients who underwent ACD surgery from 2007 to 2015. Patients were stratified by BMP use in the index operation. Patients <18 years and those with any history of tumor or trauma were excluded. Baseline demographics and comorbidities, postoperative complication rates, and reoperation rates were analyzed. RESULTS: A total of 13,549 patients underwent primary ACD surgery, of which 1155 (8.5%) had intraoperative BMP use. The overall 90-day complication rate was 27.6% in the non-BMP cohort and 31.1% in the BMP cohort (P < 0.05). Patients in the BMP cohort had longer average length of stay (4.0 days vs. 3.7 days, P < 0.05) but lower revision surgery rates at 90 days (14.5% vs. 28.3%, P < 0.05), 6 months (14.9% vs. 28.6%, P < 0.05), 1 year (15.7% vs. 29.2%, P < 0.05), and 2 years (16.5% vs. 29.9%, P < 0.05) postoperatively. BMP use was associated with higher payments throughout the 2-year follow-up period ($107,975 vs. $97,620, P < 0.05). When controlling for baseline group differences, BMP use independently increased the odds of postoperative complication (odds ratio [OR] 1.22, 95% confidence interval [CI] 1.1-1.4) and reduced the odds of reoperation throughout 2 years of follow-up (OR 0.49, 95% CI 0.4-0.6). CONCLUSION: Intraoperative BMP use has benefits for fusion integrity in ACD surgery but is associated with increased postoperative complication rate. Spine surgeons should weigh these benefits and drawbacks to identify optimal candidates for BMP use in ACD surgery. LEVEL OF EVIDENCE: 3.

Supramolecular self-assembling peptides to deliver bone morphogenetic proteins for skeletal regeneration.

Recombinant human bone morphogenetic proteins (BMPs) have shown clinical success in promoting bone healing, but they are also associated with unwanted side effects. The development of improved BMP carriers that can retain BMP at the defect site and maximize its efficacy would decrease the therapeutic BMP dose and thus improve its safety profile. In this review, we discuss the advantages of using self-assembling peptides, a class of synthetic supramolecular biomaterials, to deliver recombinant BMPs. Peptide amphiphiles (PAs) are a broad class of self-assembling peptides, and the use of PAs for BMP delivery and bone regeneration has been explored extensively over the past decade. Like many self-assembling peptide systems, PAs can be designed to form nanofibrous supramolecular biomaterials in which molecules are held together by non-covalent bonds. Chemical and biological functionality can be added to PA nanofibers, through conjugation of chemical moieties or biological epitopes to PA molecules. For example, PA nanofibers have been designed to bind heparan sulfate, a natural polysaccharide that is known to bind BMPs and potentiate their signal. Alternatively, PA nanofibers have been designed to synthetically mimic the structure and function of heparan sulfate, or to directly bind BMP specifically. In small animal models, these bio-inspired PA materials have shown the capacity to promote bone regeneration using BMP at doses 10-100 times lower than established therapeutic doses. These promising results have motivated further evaluation of PAs in large animal models, where their safety and efficacy must be established before clinical translation. We conclude with a discussion on the possiblity of combining PAs with other materials used in orthopaedic surgery to maximize their utility for clinical translation.

Comparison of bone morphogenetic protein and autologous grafting in the treatment of limb long bone nonunion: a systematic review and meta-analysis.

BACKGROUND: Bone morphogenetic proteins (BMPs) have strong bone induction properties and can promote healing of fractures and other defects. However, BMP treatment efficacy for long bone nonunion remains controversial. The aim of this meta-analysis was to synthetically evaluate the advantages and disadvantages of BMP plus bone grafting (observation group) versus autologous bone grafting (control group) for limb long bone nonunion. METHODS: PubMed, Embase, Web of Science, Cochrane Library, OVID, CNKI, Weipu Journal, Chinese Biomedical Literature, and WanFang were searched for randomized and non-randomized controlled trials published before November 2019. A meta-analysis of outcome indicators was performed using RevMan 5.3 and Stata 12.0. RESULTS: Five randomized and four non-randomized controlled trials involving 30-124 cases were included, with a total of 655 nonunion cases. There were no significant group differences in postoperative healing rate, infection, and secondary operation rates (P > 0.05), but the study group demonstrated significantly shorter mean healing time (WMD = - 1.27, 95%CI - 1.67 to - 0.88, P < 0.00001), a greater frequency of excellent/good post-treatment limb function (RR = 1.18, 95%CI 1.01-1.39, P = 0.04), and lower intraoperative blood loss (P < 0.05). Alternatively, the hospitalization cost was significantly higher in the study group (P < 0.01). CONCLUSIONS: Bone morphogenetic protein is a viable alternative to autologous bone grafting, with potential advantages of accelerated fracture healing and improved postoperative function.

Topical GDF11 accelerates skin wound healing in both type 1 and 2 diabetic mouse models.

This study aimed to investigate the role of truncated growth differentiation factor 11 (GDF11), in which the recognition site of Furin from wild-type GDF11 was deleted to enhance the cellular stability, in skin wound healing in the setting of diabetes mellitus (DM) and the underlying mechanisms. Our study found that both truncated and natural GDF11s effectively accelerated wound healing processes in both T1DM and T2DM mice with a potency compatible to PDGF, bFGF, and EGF, but being much higher than GDF8. At the cellular level, GDF11 stimulated the proliferation and suppressed HG-induced apoptosis of HSFs. Further study revealed that GDF11 activated the YAP-Smad2/3-CTGF fibrotic signaling pathway by reversing HG-induced upregulation of phosphorylated form of YAP (p-YAP), increases p-Smad2/3 levels, and restoring HG-induced repression of CTGF expression by GDF11. Overall, the study shows that both natural and truncated GDF11s promote the healing process of skin wound in mice of both T1DM and T2DM partly via stimulating dermal fibrosis via the YAP-Smad2/3-CTGF pathway, suggesting it a potential agent for treating skin wound in diabetic population.

Elastin-derived scaffolding associated or not with bone morphogenetic protein (BMP) or hydroxyapatite (HA) in the repair process of metaphyseal bone defects.

Tissue engineering represents a promising alternative for reconstructive surgical procedures especially for the repair of bone defects that do not regenerate spontaneously. The present study aimed to evaluate the effects of the elastin matrix (E24/50 and E96/37) incorporated with hydroxyapatite (HA) or morphogenetic protein (BMP) on the bone repair process in the distal metaphysis of rat femur. The groups were: control group (CG), hydrolyzed elastin matrix at 50°C/24h (E24/50), E24/50 + HA (E24/50/HA), E24/50 + BMP (E24/50/BMP), hydrolyzed elastin matrix at 37°C/96h (E96/37), E96/37 + HA (E96/37/HA), E96/37 + BMP (E96/37/BMP). Macroscopic and radiographic analyses showed longitudinal integrity of the femur in all groups without fractures or bone deformities. Microtomographically, all groups demonstrated partial closure by mineralized tissue except for the E96/37/HA group with hyperdense thin bridge formation interconnecting the edges of the ruptured cortical. Histologically, there was no complete cortical recovery in any group, but partial closure with trabecular bone. In defects filled with biomaterials, no chronic inflammatory response or foreign body type was observed. The mean volume of new bone formed was statistically significant higher in the E96/37/HA and E24/50 groups (71.28 ± 4.26 and 66.40 ± 3.69, respectively) than all the others. In the confocal analysis, it was observed that all groups presented new bone markings formed during the experimental period, being less evident in the CG group. Von Kossa staining revealed intense calcium deposits distributed in all groups. Qualitative analysis of collagen fibers under polarized light showed a predominance of red-orange birefringence in the newly regenerated bone with no difference between groups. It was concluded that the E24/50 and E96/37/HA groups promoted, with greater speed, the bone repair process in the distal metaphysis of rat femur.

Exogenous GDF11, but not GDF8, reduces body weight and improves glucose homeostasis in mice.

Insulin resistance is associated with aging in mice and humans. We have previously shown that administration of recombinant GDF11 (rGDF11) to aged mice alters aging phenotypes in the brain, skeletal muscle, and heart. While the closely related protein GDF8 has a role in metabolism, limited data are available on the potential metabolic effects of GDF11 or GDF8 in aging. To determine the metabolic effects of these two ligands, we administered rGDF11 or rGDF8 protein to young or aged mice fed a standard chow diet, short-term high-fat diet (HFD), or long-term HFD. Under nearly all of these diet conditions, administration of exogenous rGDF11 reduced body weight by 3-17% and significantly improved glucose tolerance in aged mice fed a chow (~30% vs. saline) or HF (~50% vs. saline) diet and young mice fed a HFD (~30%). On the other hand, exogenous rGDF8 showed signifcantly lesser effect or no effect at all on glucose tolerance compared to rGDF11, consistent with data demonstrating that GFD11 is a more potent signaling ligand than GDF8. Collectively, our results show that administration of exogenous rGDF11, but not rGDF8, can reduce diet-induced weight gain and improve metabolic homeostasis.

rhBMP in lumber fusion for lumbar spondylolisthesis: A systematic review and meta-analysis.

PURPOSE: To compare the efficacy and safety of recombinant human bone morphogenetic protein (rhBMP) and iliac crest autograft in the fusion treatment of lumbar spondylolisthesis. METHODS: The studies using randomized controlled trials to compare the rhBMP with iliac crest autograft in the treatment of lumbar spondylolisthesis were retrieved from Embase, Pubmed, ProQuest dissertations & theses (PQDT), China national knowledge infrastructure (CNKI), Chinese Biomedical Database, Wanfang Data, Cochrane Library (from March 1998 to March 2018). Postoperative fusion rate, clinical success rate, postoperative intervertebral height, complications, operation time, blood loss and duration of hospitalization were chosen as the outcome indicators. Methodological quality of the trials was critically assessed, and relevant data were extracted. Statistical software Revman 5.3 was used for data-analysis. RESULTS: Eleven articles were included in the meta-analysis. The results showed that, comparing the efficacy of rhBMP with iliac crest autograft, statistical significance was found in the 24-month fusion rate post operation [95% CI (1.38, 24.70), p = 0.02] and operation time [95% CI (-14.22, -2.08), p = 0.008]. There is not sufficient evidence for statistical differences in the remaining indicators. CONCLUSION: The current literature shows rhBMP is a safe and effective grafting material in the treatment of lumbar spondylolisthesis. Further evidence is dependent on the emergence of more randomized controlled trials with higher quality and larger sample sizes in the future.

Sclerostin injection enhances orthodontic tooth movement in rats.

OBJECTIVE: It was aimed to investigate the in vivo effects of local injection of sclerostin protein on orthodontic tooth movement. DESIGN: A total of 48 rats underwent orthodontic mesialization of the maxillary first molars on both sides. Local injection was given at the compression side in the alveolar bone on both maxillary sides, with sclerostin protein carried by hydrogel on one side, and the same volume of normal saline carried by hydrogel on the other side serving as the control. After two weeks, the tooth movement amount and effects on the periodontium were assessed through micro-computed tomography (µCT) analysis, tartrate-resistant acid phosphatase (TRAP) staining and immunohistochemistry (IHC) analysis. RESULTS: After two weeks of intervention, tooth movement was significantly greater in the 4 µg/kg and 20 µg/kg sclerostin injection groups, compared to the control. Analysis of the furcation area of the maxillary first molar showed that the 20 µg/kg group had significantly decreased BV/TV. At the compression side, the number of TRAP-positive osteoclasts was significantly increased in 20 µg/kg group compared to the control. The expression of RANKL was statistically higher in all the sclerostin groups, while the expression of OPG was statistically lower in the 4 µg/kg and 20 µg/kg groups, compared to the control. At the tension side, the expression of RUNX2 and COL-1 was statistically higher in the 20 µg/kg group compared to the control. CONCLUSIONS: Local injection of sclerostin protein in the alveolar bone at the compression side accelerates OTM in rats by promoting osteoclastogenesis.

Current Updates on Bone Grafting Biomaterials and Recombinant Human Growth Factors Implanted Biotherapy for Spinal Fusion: A Review of Human Clinical Studies.

BACKGROUND: Owing to their great promise in the spinal surgeries, bone graft substitutes have been widely investigated for their safety and clinical potential. By the current advances in the spinal surgery, an understanding of the precise biological mechanism of each bone graft substitute is mandatory for upholding the induction of solid spinal fusion. OBJECTIVE: The aim of the present review is to critically discuss various surgical implications and level of evidence of most commonly employed bone graft substitutes for spinal fusion. METHOD: Data was collected via electronic search using "PubMed", "SciFinder", "ScienceDirect", "Google Scholar", "Web of Science" and a library search for articles published in peer-reviewed journals, conferences, and e-books. RESULTS: Despite having exceptional inherent osteogenic, osteoinductive, and osteoconductive features, clinical acceptability of autografts (patient's own bone) is limited due to several perioperative and postoperative complications i.e., donor-site morbidities and limited graft supply. Alternatively, allografts (bone harvested from cadaver) have shown great promise in achieving acceptable bone fusion rate while alleviating the donor-site morbidities associated with implantation of autografts. As an adjuvant to allograft, demineralized bone matrix (DBM) has shown remarkable efficacy of bone fusion, when employed as graft extender or graft enhancer. Recent advances in recombinant technologies have made it possible to implant growth and differentiation factors (bone morphogenetic proteins) for spinal fusion. CONCLUSION: Selection of a particular bone grafting biotherapy can be rationalized based on the level of spine fusion, clinical experience and preference of orthopaedic surgeon, and prevalence of donor-site morbidities.

Spatiotemporal Control Strategies for Bone Formation through Tissue Engineering and Regenerative Medicine Approaches.

Global increases in life expectancy drive increasing demands for bone regeneration. The gold standard for surgical bone repair is autografting, which enjoys excellent clinical outcomes; however, it possesses significant drawbacks including donor site morbidity and limited availability. Although collagen sponges delivered with bone morphogenetic protein, type 2 (BMP2) are a common alternative or supplement, they do not efficiently retain BMP2, necessitating extremely high doses to elicit bone formation. Hence, reports of BMP2 complications are rising, including cancer promotion and ectopic bone formation, the latter inducing complications such as breathing difficulties and neurologic impairments. Thus, efforts to exert spatial control over bone formation are increasing. Several tissue engineering approaches have demonstrated the potential for targeted and controlled bone formation. These approaches include biomaterial scaffolds derived from synthetic sources, e.g., calcium phosphates or polymers; natural sources, e.g., bone or seashell; and immobilized biofactors, e.g., BMP2. Although BMP2 is the only protein clinically approved for use in a surgical device, there are several proteins, small molecules, and growth factors that show promise in tissue engineering applications. This review profiles the tissue engineering advances in achieving control over the location and onset of bone formation (spatiotemporal control) toward avoiding the complications associated with BMP2.

Growth Differentiation Factor 11 treatment leads to neuronal and vascular improvements in the hippocampus of aged mice.

Aging is the biggest risk factor for several neurodegenerative diseases. Parabiosis experiments have established that old mouse brains are improved by exposure to young mouse blood. Previously, our lab showed that delivery of Growth Differentiation Factor 11 (GDF11) to the bloodstream increases the number of neural stem cells and positively affects vasculature in the subventricular zone of old mice. Our new study demonstrates that GDF11 enhances hippocampal neurogenesis, improves vasculature and increases markers of neuronal activity and plasticity in the hippocampus and cortex of old mice. Our experiments also demonstrate that systemically delivered GDF11, rather than crossing the blood brain barrier, exerts at least some of its effects by acting on brain endothelial cells. Thus, by targeting the cerebral vasculature, GDF11 has a very different mechanism from that of previously studied circulating factors acting to improve central nervous system (CNS) function without entering the CNS.

Bone morphogenetic proteins for articular cartilage regeneration.

Degeneration of articular cartilage (AC) tissue is the most common cause of osteoarthritis (OA) and rheumatoid arthritis. Bone morphogenetic proteins (BMPs) play important roles in bone and cartilage formation. This article reviews the experimental and clinical applications of BMPs in cartilage regeneration. Experimental evidence indicates that BMPs play an important role in protection against cartilage damage caused by inflammation or trauma, by binding to different receptor combinations and, consequently, activating different intracellular signaling pathways. Loss of function of BMP-related receptors contributes to the decreased intrinsic repair capacity of damaged cartilage and, thus, the multifunctional effects of BMPs make them attractive tools for the treatment of cartilage damage in patients with degenerative diseases. However, the development of BMP therapy as a treatment modality for cartilage regeneration has been hampered by certain factors, such as the eligibility of participants in clinical trials, financial support, drug delivery carrier safety, availabilities of effective scaffolds, appropriate selection of optimal dose and timing of administration, and side effects. Further research is needed to overcome these issues for future routine clinical applications. Research and development leading to the successful application of BMPs can initiate a new era in the treatment of cartilage degenerative diseases like OA.

Effects of Local Drug and Chemical Compound Delivery on Bone Regeneration Around Dental Implants in Animal Models: A Systematic Review and Meta-Analysis.

PURPOSE: One of the suggested methods for enhancing osseointegration is the local application of drug agents around implant surfaces. The aim of this review was to evaluate the methods most commonly used for local drug and chemical compound delivery to implant sites and assess their influence on osseointegration. MATERIALS AND METHODS: An electronic search was undertaken in three databases (PubMed, Scopus, Embase). The search was limited to animal experiments using endosseous implants combined with local drug delivery systems. Meta-analyses were performed for the outcome bone-to-implant contact (BIC). RESULTS: Sixty-one studies met the inclusion criteria. Calcium phosphate (CaP), bisphosphonates (BPs), and bone morphogenetic proteins (BMPs) were the most commonly used chemical compounds. There were two main methods for local drug delivery at the bone-implant interface: (1) directly from an implant surface by coating or immobilizing techniques, and (2) the local application of drugs to the implant site, using carriers. There was a statistically significant increase in BIC for both local drug delivery methods (P = .02 and P < .0001, respectively) compared with the control methods. There was a statistically significant increase in BIC when CaP (P = .0001) and BMPs (P = .02) were either coating implants or were delivered to the implant site, in comparison to when drugs were not used. The difference was not significant for the use of BPs (P = .15). CONCLUSION: It is suggested that the use of local chemical compound delivery systems around implants could significantly improve implant osseointegration in animal models. It is a matter of debate whether these in vivo results might have some significant effect in the human clinical setting in the long term.

[Bone substitute materials as local drug carriers : Current status of substitutes of various origins]. / Knochenersatzwerkstoffe als lokale Wirkstoffträger : Aktueller Stand bei Ersatzstoffen verschiedenen Ursprungs.

BACKGROUND: Autologous bone grafts (autografts) are used in surgery for defect filling and impaction grafting during hip socket and femur reconstruction. Because of their superior osteoinductive capacity, autografts are considered the "gold standard" for these treatments. However, because of a better cost-benefit ratio, allografts are also often used. In the case of limited donor availability for autologous or allogenic bone grafts, bone substitute materials (BSMs) are a reasonable alternative or supplement. BSM are based on or combine different substances. Growth factors of the bone morphogenetic protein family BMP are recombinant proteins that specifically induce the growth of bone and cartilage tissue. CHARACTERISTICS: One advantage of BSM is the option to combine them with several anti-infective agents. The choice of the anti-infective substance should not only be based on the antimicrobial efficacy, but should also take into account possible dose-dependent cellular and pharmacological side effects at the implantation site. Thus, microbiologists, pharmacists and surgeons should decide together which combination is the most appropriate. COMBINATION PRODUCTS: BSM with active agent additives are considered combination products that are characterized by a main effect (bone replacement function) and a secondary effect (prophylaxis of bacterial recolonization of BSM). Both functions must be thoroughly (clinically) evidenced in the course of the registration process as a class III medical device. Drug authorities evaluate the active agents, their function and corresponding indication. Currently, only a few combination products are available on the market. As a consequence of the only limited availability of such commercial combination products, surgeons in clinical practice often manually add the active agent to BSM in the theatre prior to implantation. However, such a customized addition of antibiotics places the surgeon in a situation of a manufacturer where he assumes liability for the product.

[Potential of allogeneic bone grafts as antibiotic carriers : Effect of different preparation processes on efficacy]. / Allogene spongiöse Knochenpräparate als Antibiotikaträger : Einfluss verschiedener Aufbereitungsverfahren auf die Wirksamkeit.

BACKGROUND: The rising number of primary joint replacements worldwide is causing an increase of endoprosthetic revision surgery due bacterial infection. Revision surgery using non-cemented implants seems beneficial for the long-term outcome, and the use of antibiotic-impregnated bone grafts might control the infection and provide a good support for the implant. In this study, we evaluated the release of antibiotics from fresh-frozen and lyophilized allogeneic bone grafts. METHODS: Heat-treated, lyophilized and fresh frozen cryopreserved bone chips were impregnated with gentamicin sulphate, gentamicin palmitate and vancomycin, and calcium carbonate/calcium sulphate treated with antibiotics. The efficacy of each preparation was measured by drug release tests and bacterial susceptibility using B. subtilis, S. aureus and methicillin-resistant Staphylococcus aureus. RESULTS: The release of gentamicin from lyophilized bone was similar to the release rate from fresh frozen bone during the entire experiment. This might be related to the similar porosity and microstructure of the bone chips. The release of gentamicin from lyophilized and fresh frozen bone was high on the first and second days, then decreased and stayed at a low rate until the end of the second week. CONCLUSION: Depending on the surgical strategy, either polymethylmethacrylate or allogeneic bone are able to deliver sufficient concentrations of gentamicin to achieve bacterial inhibition within 2 weeks after surgery. In the case of uncemented revision of joint replacements, allogeneic bone can deliver therapeutic doses of gentamicin and peak levels immediately and a fortnight after implantation.

Osteoinductive Effects of Cyplexinol in the Management of Osteoporosis: A Case Series.

Aims • A case study was conducted on a subject with a history of documented bone loss and the observed outcome of bone mineral density (BMD) changes when utilizing supplementation with Cyplexinol, a natural bone morphogenetic protein complex. Method and Results • A case of osteoporosis was reviewed with pertinent medical history and dual energy X-ray absorptiometry history described both pre- and postsupplementation. Results demonstrated a significant change in bone density parameter for the individual when the bone support supplement, Cyplexinol, was used. Given this promising initial result, 3 additional cases were reviewed for potential replication and generalizability. Results showed a range of positive bone density changes of 18.5% to 63.63% during a supplementation period of 2 to 5 y. Conclusions • Cyplexinol may effectively manage BMD loss experienced during osteoporosis, though more studies are warranted with larger samples to replicate these findings. Given that administration of Cyplexinol was found to improve density scores in both mild and severe cases, despite the extent of the patient's history of documented bone loss, Cyplexinol has a more diverse range of applicability than prescription medications, suggesting the first, natural alternative to bisphosphonates, hormone replacement therapies and antireceptor activator of nuclear factor kappa-B ligand (anti-RANKL) agents. Furthermore, due to Cyplexinol's safety profile of no known side effects, it may be the ideal long-term strategy for individuals with bone loss and a possible preventative agent for individuals with known risk factors (eg, cigarette use, alcohol and carbonated drink usage, calcium deficiency, and family history) for osteoporosis. Although a larger pool of subjects is necessary to further support Cyplexinol's role in managing osteoporosis, these data are consistent with other studies examining the benefits of Cyplexinol's protein complex on BMD loss as a potential new, orally bioavailable therapeutic for the effective treatment of osteoporosis.

An intramedullary nail coated with antibiotic and growth factor nanoparticles: An individualized state-of-the-art treatment for chronic osteomyelitis with bone defects.

Among various infections, chronic osteomyelitis is one of the most challenging in terms of treatment. This infection is more common among patients with open fractures and those who have undergone elective orthopedic procedures. The treatment of osteomyelitis requires high antibiotic doses and an aggressive and multifaceted surgical approach. The use of parenteral antibiotics alone, without debridement, is not sufficiently effective, due to the formation of sequestra and the low vascularity of the affected area. The surgical options available for patients with chronic osteomyelitis include sequestrectomy, curettage, and intramedullary reaming, although these procedures usually result in bone defects that require further surgical intervention. Polymethyl methacrylate or calcium phosphate beads, impregnated with antibiotics, are commonly placed in such cases; however, this option has several disadvantages, including the need for future removal of cement, uncontrollable local release of antibiotics, and the need for broad-spectrum agents. The resulting bone defects also require additional treatments involving vascularized fibula grafting, intramedullary nails, use of techniques like Masquelet and Ilizarov, and even soft tissue transfers. All of these methods have certain limitations, such as the eventual requirement of more than one surgical event. Certain growth factors aid in the development and vascularization of new bone, such as bone morphogenetic proteins (BMPs) and insulin-like growth factor I (IGF-1). We propose that nanoparticles of BMPs, IGL-1, and microorganism-specific antibiotics can be placed on the surface of intramedullary nails. These nanoparticles can be attached to various different polymeric materials such as poly(d,l-lactide), which is a biocompatible and biodegradable polymer, and can be positioned in several layers, to ensure controlled and systematic release. The placement of nanoparticles at the infection site alone will also ensure local delivery of the drugs only to the required areas. Moreover, these intramedullary nails will be useful for both infected non-unions and mal-unions. Over time, the nanoparticles will eradicate the infection and stimulate new healthy bone formation, whereas the intramedullary nail itself will provide constant stability and immobilization. This model provides new and revolutionary ideas for the development of individualized technologies in medicine.

Combined Administration of ASCs and BMP-12 Promotes an M2 Macrophage Phenotype and Enhances Tendon Healing.

BACKGROUND: Outcomes after intrasynovial tendon repair are highly variable. An intense inflammatory cascade followed by a delayed healing response can cause adhesion formation and repair-site failure that severely impair the function of repaired digits. No effective remedies exist to fully address these issues. Cell- and growth factor-based therapies have been shown to modulate inflammation and improve cell proliferation and matrix synthesis and therefore are promising treatment approaches for intrasynovial tendon repair. QUESTIONS/PURPOSES: (1) Can autologous adipose-derived mesenchymal stromal cells (ASCs) and recombinant bone morphogenetic protein-12 (rBMP-12) be effectively delivered to an intrasynovial flexor tendon repair without adverse effects? (2) Do autologous ASCs modulate the inflammatory response after intrasynovial tendon injury and repair? (3) Does the combined application of autologous ASCs and rBMP-12 modulate the proliferative and remodeling responses after intrasynovial tendon injury and repair? METHODS: Sixteen 1- to 2-year-old female canines were used in this study. Autologous ASC sheets, with and without rBMP-12, were applied to the surface of sutured flexor tendons. Fourteen days after repair, the effects of treatment were determined using quantitative PCR (six per group) for the expression of genes related to macrophage phenotype or inflammation (IL-4, CD163, VEGF, NOS2, IL-1B, and IFNG), cell proliferation (CCND1), and tendon formation (SCX, TNMD, COL1A1 and COL3A1). Proteomics analysis (four per group) was performed to examine changes in tendon protein abundances. CD146 immunostaining and hematoxylin and eosin staining (four per group) were used to detect tendon stem or progenitor cells and to semiquantitatively evaluate cellularity at the tendon repair; analyses were done blinded to group. RESULTS: Gross inspection and cell tracing showed that autologous ASCs and rBMP-12 were delivered to the flexor tendon repair site without the deleterious effects of adhesion and repair-site gap formation. Quantitative assessment of gene and protein expression showed effects of treatment: ASC-sheet treatment modulated the postrepair inflammatory response and facilitated healing by increasing regenerative M2 macrophages (M2 marker CD204, twofold of normal, p = 0.030), inflammatory inhibitor (prostaglandin reductase 1 [PTRG1], 1.6-fold of normal, p = 0.026), and proteins involved in tendon formation (periostin [POSTN], 1.9-fold of normal, p = 0.035). Consistently, semiquantitative and qualitative evaluations of repaired tissue showed that ASC-sheet treatment reduced mononuclear cell infiltration (12% less than nontreated tendons, p = 0.021) and introduced CD146+ stem or progenitor cells to the repair site. The combined administration of ASCs and rBMP-12 further stimulated M2 macrophages by increasing IL-4 (116-fold of normal, p = 0.002) and led to the increase of M2 effector matrix metalloproteinase-12 involved in matrix remodeling (twofold of normal, p = 0.016) and reduction of a negative regulator of angiogenesis and cell migration (StAR-related lipid transfer domain protein13 [STARD13]; 84% of normal, p = 0.000), thus facilitating the proliferative stage of tendon repair. CONCLUSIONS: ASCs and BMP-12 accelerated the progression of healing in the proliferative stage of tendon repair. The effects of ASCs and BMP-12 on tendon functional recovery should be evaluated in future studies. CLINICAL RELEVANCE: The cell sheet approach is an effective, biocompatible, and surgeon-friendly approach for cell and growth factor delivery during tendon repair. Combined application of ASCs and BMP-12 may accelerate intrasynovial tendon healing while suppressing the adverse inflammatory response.