P-15 small peptide bone graft substitute in the treatment of non-unions and delayed union. A pilot clinical trial.
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ABSTRACT:
SUBMITTER: Gomar F
PROVIDER: S-EPMC2267538 | biostudies-other | 2007 Feb
REPOSITORIES: biostudies-other
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Project description:The normal bone regeneration process is a complex and coordinated series of events involving different cell types and molecules. However, this process is impaired in critical-size/large bone defects, with non-unions or delayed unions remaining a major clinical problem. Novel strategies are needed to aid the current therapeutic approaches. Mesenchymal stem/stromal cells (MSCs) are able to promote bone regeneration. Their beneficial effects can be improved by modulating the expression levels of specific genes with the purpose of stimulating MSC proliferation, osteogenic differentiation or their immunomodulatory capacity. In this context, the genetic engineering of MSCs is expected to further enhance their pro-regenerative properties and accelerate bone healing. Herein, we review the most promising molecular candidates (protein-coding and non-coding transcripts) and discuss the different methodologies to engineer and deliver MSCs, mainly focusing on in vivo animal studies. Considering the potential of the MSC secretome for bone repair, this topic has also been addressed. Furthermore, the promising results of clinical studies using MSC for bone regeneration are discussed. Finally, we debate the advantages and limitations of using MSCs, or genetically-engineered MSCs, and their potential as promoters of bone fracture regeneration/repair.
| S-EPMC6678255 | biostudies-literature
Project description:BackgroundOverall, 5-10% of fractures result in delayed unions or non-unions, causing major disabilities and a huge socioeconomic burden. Since rescue surgery with autologous bone grafts can cause additional challenges, alternative treatment options have been developed to stimulate a deficient healing process. This study assessed the technical feasibility, safety and preliminary efficacy of local percutaneous implantation of allogeneic bone-forming cells in delayed unions of long bone fractures.MethodsIn this phase I/IIA open-label pilot trial, 22 adult patients with non-infected delayed unions of long bone fractures, which failed to consolidate after 3 to 7 months, received a percutaneous implantation of allogeneic bone-forming cells derived from bone marrow mesenchymal stem cells (ALLOB; Bone Therapeutics) into the fracture site (50 × 106 to 100 × 106 cells). Patients were monitored for adverse events and need for rescue surgery for 30 months. Fracture healing was monitored by Tomographic Union Score (TUS) and modified Radiographic Union Score. The health status was evaluated using the Global Disease Evaluation (GDE) score and pain at palpation using a visual analogue scale. The presence of reactive anti-human leukocyte antigen (HLA) antibodies was evaluated.ResultsDuring the 6-month follow-up, three serious treatment-emergent adverse events were reported in two patients, of which two were considered as possibly treatment-related. None of the 21 patients in the per-protocol efficacy population needed rescue surgery within 6 months, but 2/21 (9.5%) patients had rescue surgery within 30 months post-treatment. At 6 months post-treatment, an improvement of at least 2 points in TUS was reached in 76.2% of patients, the GDE score improved by a mean of 48%, and pain at palpation at the fracture site was reduced by an average of 61% compared to baseline. The proportion of blood samples containing donor-specific anti-HLA antibodies increased from 8/22 (36.4%) before treatment to 13/22 (59.1%) at 6 months post-treatment, but no treatment-mediated allogeneic immune reactions were observed.ConclusionThis pilot study showed that the percutaneous implantation of allogeneic bone-forming cells was technically feasible and well tolerated in patients with delayed unions of long bone fractures. Preliminary efficacy evidence is supporting the further development of this treatment.Trial registrationNCT02020590 . Registered on 25 December 2013. ALLOB-DU1, A pilot Phase I/IIa, multicentre, open proof-of-concept study on the efficacy and safetyof allogeneic osteoblastic cells (ALLOB®) implantation in non-infected delayed-union fractures.
| S-EPMC8235864 | biostudies-literature
Project description:Bone graft substitute such as calcium sulfate are frequently used as carrier material for local antimicrobial therapy in orthopedic surgery. This study aimed to assess the systemic absorption and disposition of tobramycin in patients treated with a tobramycin-laden bone graft substitute (Osteoset® T).Nine blood samples were taken from 12 patients over 10 days after Osteoset® T surgical implantation. Tobramycin concentration was measured by fluorescence polarization. Population pharmacokinetic analysis was performed using NONMEM to assess the average value and variability (CV) of pharmacokinetic parameters. Bioavailability (F) was assessed by equating clearance (CL) with creatinine clearance (Cockcroft CLCr). Based on the final model, simulations with various doses and renal function levels were performed. (ClinicalTrials.gov number, NCT01938417).The patients were 52 +/- 20 years old, their mean body weight was 73 +/- 17 kg and their mean CLCr was 119 +/- 55 mL/min. Either 10 g or 20 g Osteoset® T with 4% tobramycin sulfate was implanted in various sites. Concentration profiles remained low and consistent with absorption rate-limited first-order release, while showing important variability. With CL equated to CLCr, mean absorption rate constant (ka) was 0.06 h-1, F was 63% or 32% (CV 74%) for 10 and 20 g Osteoset® T respectively, and volume of distribution (V) was 16.6 L (CV 89%). Simulations predicted sustained high, potentially toxic concentrations with 10 g, 30 g and 50 g Osteoset® T for CLCr values below 10, 20 and 30 mL/min, respectively.Osteoset® T does not raise toxicity concerns in subjects without significant renal failure. The risk/benefit ratio might turn unfavorable in case of severe renal failure, even after standard dose implantation.
| S-EPMC3944781 | biostudies-literature
Project description:Fracture healing complications are common and result in significant healthcare burden. The aim of this study was to determine the rate, costs and predictors of two-year readmission for surgical management of healing complications (delayed, mal, non-union) following fracture of the humerus, tibia or femur. Humeral, tibial and femoral (excluding proximal) fractures registered by the Victorian Orthopaedic Trauma Outcomes Registry over five years (n = 3962) were linked with population-level hospital admissions data to identify two-year readmissions for delayed, mal or non-union. Study outcomes included hospital length-of-stay (LOS) and inpatient costs. Multivariable logistic regression was used to determine demographic and injury-related factors associated with admission for fracture healing complications. Of the 3886 patients linked, 8.1% were readmitted for healing complications within two years post-fracture, with non-union the most common complication and higher rates for femoral and tibial shaft fractures. Admissions for fracture healing complications incurred total costs of $4.9 million AUD, with a median LOS of two days. After adjusting for confounders, patients had higher odds of developing complications if they were older, receiving compensation or had tibial or femoral shaft fractures. Patients who are older, with tibial and femoral shaft fractures should be targeted for future research aimed at preventing complications.
| S-EPMC6313538 | biostudies-literature
Project description:Revision anterior cruciate ligament (ACL) reconstruction is a technically demanding procedure, and the surgeon should be prepared to address bone tunnel osteolysis, concurrent meniscal, ligamentous, or cartilage lesions, and limb malalignment. ACL revision can typically be done in one procedure, but it may need to be staged if there is poor previous tunnel positioning or excessive tunnel osteolysis. Bone grafting of the tunnels can be accomplished in several ways, including autograft, allograft, or bone substitutes. Currently, no consensus is available regarding the optimal choice of bone graft material for bone tunnel augmentation in revision ACL reconstruction. Bone graft substitute for tunnel augmentation has been showed to have good histologic, radiographic, and intraoperative integration, comparable to that of autologous bone. In this Technical Note, the technical details of arthroscopic treatment of attenuated anterior cruciate ligament graft with enlarged bone tunnels are described. The tunnels are debrided arthroscopically and filled up with PRO-DENSE injectable regenerative graft.
| S-EPMC9243602 | biostudies-literature
Project description:Large bone cyst of the talar body is frequently associated with an osteochondral lesion. The talar bone cyst can be an incidental radiologic finding. However, when the talus is extensively destroyed, there is a risk of pathologic fracture and damage to the articular cartilage, leading to persistent swelling and pain of the subtalar joint and ankle joint. Open debridement and bone grafting frequently requires extensive soft-tissue dissection or even different types of malleolar osteotomy for proper access to the lesion. The purpose of this Technical Note is to describes the technique of endoscopic curettage, nanofracture, and filling the cyst with injectable bone graft substitute. This minimally invasive approach has minimal disruption of the normal cartilage surface.
| S-EPMC8355510 | biostudies-literature
Project description:While the gold standard of treatment of nonunion is open autologous bone grafting, studies have shown that injecting bone marrow aspirate concentrates (BMAC) is effective in treating tibial nonunions with fracture gaps less than 5 mm.We aim to demonstrate that combining BMAC with osteoinductive agents can effectively treat delayed or nonunion regardless of fracture gap size, nonunion site, or osteoinductive agent used.In this non-randomized retrospective-prospective cohort study, 49 patients with tibial nonunion met the inclusion criteria and underwent BMAC injection with demineralized bone matrix (DBM) and/or recombinant human bone morphogenic protein-2 (rhBMP-2). Radiologic healing of the fracture was the primary outcome. Patients were followed until radiographic union was achieved or another procedure was performed. Radiographic healing was defined as bridging of three out of four cortices on anteroposterior and lateral films.There was no difference in the healing rate (p?=?0.81) between patients with fracture gaps less than and greater than 5 mm. On multivariate analysis, the use of rhBMP-2 was associated with a lower healing rate compared to DBM (p?=?0.036). Patients who underwent early intervention (within 6 months of fixation) had higher union rates (p?=?0.04).This study shows that percutaneous BMAC injection combined with either DBM and/or rhBMP-2 is a safe and effective treatment for delayed or nonunion regardless of the fracture gap size or fracture site. DBM may be superior to rhBMP-2 in this procedure.
| S-EPMC4481261 | biostudies-other
Project description:Adipose tissue is an attractive source of mesenchymal stem cells (MSCs) because of its abundance and accessibility. We have previously defined a population of native MSCs termed perivascular stem cells (PSCs), purified from diverse human tissues, including adipose tissue. Human PSCs (hPSCs) are a bipartite cell population composed of pericytes (CD146+CD34-CD45-) and adventitial cells (CD146-CD34+CD45-), isolated by fluorescence-activated cell sorting and with properties identical to those of culture identified MSCs. Our previous studies showed that hPSCs exhibit improved bone formation compared with a sample-matched unpurified population (termed stromal vascular fraction); however, it is not known whether hPSCs would be efficacious in a spinal fusion model. To investigate, we evaluated the osteogenic potential of freshly sorted hPSCs without culture expansion and differentiation in a rat model of posterolateral lumbar spinal fusion. We compared increasing dosages of implanted hPSCs to assess for dose-dependent efficacy. All hPSC treatment groups induced successful spinal fusion, assessed by manual palpation and microcomputed tomography. Computerized biomechanical simulation (finite element analysis) further demonstrated bone fusion with hPSC treatment. Histological analyses showed robust endochondral ossification in hPSC-treated samples. Finally, we confirmed that implanted hPSCs indeed differentiated into osteoblasts and osteocytes; however, the majority of the new bone formation was of host origin. These results suggest that implanted hPSCs positively regulate bone formation via direct and paracrine mechanisms. In summary, hPSCs are a readily available MSC population that effectively forms bone without requirements for culture or predifferentiation. Thus, hPSC-based products show promise for future efforts in clinical bone regeneration and repair.
| S-EPMC4181396 | biostudies-literature
Project description:Osteomyelitis is a common occurrence in orthopaedic surgery, which is caused by different bacteria. Treatment of osteomyelitis patients aims to eradicate infection by debridement surgery and local and systemic antibiotic therapy. Local treatment increases success rates and can be performed with different antimicrobial bone graft substitutes. This review is performed to assess the level of evidence of synthetic bone graft substitutes in osteomyelitis treatment. According to the PRISMA statement for reporting systematic reviews, different types of clinical studies concerning treatment of osteomyelitis with bone graft substitutes are included. These studies are assessed on their methodological quality as level of evidence and bias and their clinical outcomes as eradication of infection. In the fifteen included studies, the levels of evidence were weak and in ten out of the fifteen studies there was a moderate to high risk of bias. However, first results of the eradication of infection in these studies showed promising results with their relatively high success rates and low complication rates. Due to the low levels of evidence and high risks of bias of the included studies, these results are inconclusive and no conclusions regarding the performed clinical studies of osteomyelitis treatment with antimicrobial bone graft substitutes can be drawn.
| S-EPMC4745864 | biostudies-literature
Project description:IntroductionThe occurrence of atypical femur fractures (AFFs) in patients on prolonged bisphosphonate treatment has been gaining medical attention, but the use of pharmacotherapy for these fractures has not been explored in detail. The authors describe a case of AFFs successfully treated with once-weekly administration of 56.5 μg teriparatide (TPTD).Case presentationThe patient was a 74-year-old female patient who had been taking alendronate for approximately 6 years and who suffered with a fall while walking. X-rays revealed a subtrochanteric right femur fracture. The contralateral femur showed cortical thickening and a transverse radiolucent fracture line. Based on these specific features, the patient was diagnosed with AFF. The patient underwent osteosynthesis with intramedullary nailing for the right fracture. Alendronate treatment was discontinued. Low-intensity pulsed ultrasonography therapy did not affect the healing of the fracture with delayed union, even after 3 months of application. Prophylactic osteosynthesis was performed for the subtrochanteric left femur. Bone tissue collected from the left fracture site during surgery showed severe suppression of bone turnover. Union of bilateral femurs was achieved after 3 months of a once-weekly administration of TPTD.ConclusionOnce-weekly TPTD treatment is shown to be beneficial for improving the healing of AFFs showing delayed union.
| S-EPMC4254865 | biostudies-literature