CLINICAL APPLICATION OF BONE MORPHOGENETIC PROTEIN ON FRACTURE HEALING PROCESS

Delayed union or non-union often occurs in bone healing fracture process. The clinical application of Bone Morphogenetic Proteins (BMPs) has helped an increasing number of patients achieve bone regeneration in clinical area lacking simple solutions for difficult bone healing situations. Many researches has proved that BMPs improved fracture healing regeneration. In this review article, introduction and current clinical issues are summarized on efficacy and function of BMPs. Currently, rhBMP-2 and rhBMP-7 have shown clinical significance but other subfamily members of BMPs still lacked of evidence.

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Physiology of fracture healing: New aspects

Medicinski pregled ◽

10.2298/mpns0302039g ◽

2003 ◽

Vol 56 (1-2) ◽

pp. 39-42 ◽

Cited By ~ 2

Author(s):

Djordje Gajdobranski ◽

Dragana Zivkovic

Keyword(s):

Fracture Healing ◽

Animal Studies ◽

Healing Process ◽

Contemporary Literature ◽

Delayed Union ◽

Functional Restoration ◽

Bone Fracture Healing ◽

Non Union ◽

Impaired Healing ◽

High Incidence

Introduction Skeletal system has a great regenerative potential, but it isn't the case with other tissues. Bone fracture healing includes a complex cascade of processes at cellular and biochemical levels, ending with a complete structural and functional restoration of the damaged bone. Impaired healing occurs in 5-10% of all fractures, manifesting as delayed union or non-union Such a high incidence of impaired healing certainly presents a problem, and therefore, permanent research regarding physiology of fracture healing is justified. Phases of fracture healing In this paper we described four phases of fracture healing. They are not clearly separated, but overlap. These data are based on contemporary literature and newest achievements in the field of fracture healing. Discussion Many data regarding this phenomenon were obtained from animal studies, but they may also be applied in human medicine since there is a great similarity between fracture healing in animal models and humans. Conclusion Full and complete knowledge of mechanisms of bioregulation of normal fracture healing process certainly presents the basic prerequisite for successful surgical and orthopedic treatment.

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Can Optimizing the Mechanical Environment Deliver a Clinically Significant Reduction in Fracture Healing Time?

Biomedicines ◽

10.3390/biomedicines9060691 ◽

2021 ◽

Vol 9 (6) ◽

pp. 691

Author(s):

Jan Barcik ◽

Devakara R. Epari

Keyword(s):

Fracture Healing ◽

Bone Healing ◽

Mechanical Stimulation ◽

Callus Formation ◽

Weight Bearing ◽

Healing Process ◽

Healing Time ◽

Mechanical Environment ◽

Clinically Significant ◽

The Impact

The impact of the local mechanical environment in the fracture gap on the bone healing process has been extensively investigated. Whilst it is widely accepted that mechanical stimulation is integral to callus formation and secondary bone healing, treatment strategies that aim to harness that potential are rare. In fact, the current clinical practice with an initially partial or non-weight-bearing approach appears to contradict the findings from animal experiments that early mechanical stimulation is critical. Therefore, we posed the question as to whether optimizing the mechanical environment over the course of healing can deliver a clinically significant reduction in fracture healing time. In reviewing the evidence from pre-clinical studies that investigate the influence of mechanics on bone healing, we formulate a hypothesis for the stimulation protocol which has the potential to shorten healing time. The protocol involves confining stimulation predominantly to the proliferative phase of healing and including adequate rest periods between applications of stimulation.

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Mechanical Failure of Angle Locking Plates in Distal Comminuted Tibial Fractures

Key Engineering Materials ◽

10.4028/www.scientific.net/kem.695.118 ◽

2016 ◽

Vol 695 ◽

pp. 118-122 ◽

Cited By ~ 2

Author(s):

Razvan Ene ◽

Zsombor Panti ◽

Mihai Nica ◽

Marian Pleniceanu ◽

Patricia Ene ◽

...

Keyword(s):

Internal Fixation ◽

Bone Healing ◽

Tibial Fracture ◽

Weight Bearing ◽

Healing Process ◽

Biomechanical Properties ◽

Implant Failure ◽

Locking Plates ◽

Non Union ◽

Tibial Pilon

Distal comminuted tibial fracture with or without intra-articular involvement is a very common injury of the lower limb, especially in younger patients due to high energy trauma. The anatomical and biomechanical properties of this segment of tibia, makes this pathology a major surgical challenge with a preserved clinical outcome. The aim of this study is to present different outcome of tibial fracture, treated with open reduction and internal fixation (ORIF) with titanium angle locking plates (ALP) and to underline the physiological and non-physiological bone healing effects on implants. In this study we included 48 patients with tibial pilon fracture who underwent to ORIF, applying ALP in the Orthopedics and Trauma department of the University Emergency Hospital in Bucharest. Due to preserved biomechanical properties of ALP and this anatomical region, weight bearing is not allowed till 6 to 8 weeks. Comminuted fracture of this part of tibia often have de-vascularized bony fragments which leads to delayed union or non-union. These complications often lead to implant failure, improper bone healing or non-union. Internal fixation with angle stable screws, offers a good stability of reduction in the early postoperative period. Titanium angle locking plates offers good anatomical reduction and stable fixation in the early period of healing process. Due to its rigid, fixed position of the screws in the plates, bone remodelling during healing process and early weight bearing, increases the mechanical failure of implant.Keywords: tibial pilon fractures, angle locking plates, implant failure.

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Insights into the Cellular and Molecular Mechanisms That Govern the Fracture-Healing Process: A Narrative Review

Journal of Clinical Medicine ◽

10.3390/jcm10163554 ◽

2021 ◽

Vol 10 (16) ◽

pp. 3554

Author(s):

Dionysios J. Papachristou ◽

Stavros Georgopoulos ◽

Peter V. Giannoudis ◽

Elias Panagiotopoulos

Keyword(s):

Fracture Healing ◽

Bone Repair ◽

Molecular Mechanisms ◽

Current Knowledge ◽

Healing Process ◽

Bone Architecture ◽

Multi Stage ◽

Stage Process ◽

And Function ◽

The Impact

Fracture-healing is a complex multi-stage process that usually progresses flawlessly, resulting in restoration of bone architecture and function. Regrettably, however, a considerable number of fractures fail to heal, resulting in delayed unions or non-unions. This may significantly impact several aspects of a patient’s life. Not surprisingly, in the past few years, a substantial amount of research and number of clinical studies have been designed, aiming at shedding light into the cellular and molecular mechanisms that regulate fracture-healing. Herein, we present the current knowledge on the pathobiology of the fracture-healing process. In addition, the role of skeletal cells and the impact of marrow adipose tissue on bone repair is discussed. Unveiling the pathogenetic mechanisms that govern the fracture-healing process may lead to the development of novel, smarter, and more effective therapeutic strategies for the treatment of fractures, especially of those with large bone defects.

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Treatment of Avulsion Fractures of the Base of the Fifth Metatarsal with Walking Boot and Hard-Soled Shoes: A Comparative Study

Foot & Ankle Orthopaedics ◽

10.1177/2473011419s00322 ◽

2019 ◽

Vol 4 (4) ◽

pp. 2473011419S0032

Author(s):

Danilo Ryuko Cândido Nishikawa ◽

Fernando Aires Duarte ◽

Guilherme Honda Saito ◽

Augusto César Monteiro ◽

Cesar de Cesar Netto ◽

...

Keyword(s):

Comparative Study ◽

Fracture Healing ◽

Joint Disease ◽

Function Evaluation ◽

Avulsion Fractures ◽

Non Union ◽

Fracture Consolidation ◽

And Gender ◽

American Orthopaedic ◽

And Function

Category: Midfoot/Forefoot, Trauma Introduction/Purpose: Acute avulsion fractures of the base of the fifth metatarsal are common and usually treated non- surgically with satisfactory outcomes. Forms of conservative treatments are described such as elasticated bandaging, immobilization in a cast, walking boot and hard-soled-shoes. The aim of this study was to compare the clinical and functional outcomes, time to return to the previous activities, time and rate of fracture healing of the patients with avulsion fracture of the base of the fifth metatarsal treated in a hard-soled-shoes (HSS) or in a walking boot (WB). Our null hypothesis is that a less rigid immobilization without restriction of the ankle yields the same final results. Methods: A retrospective and comparative study of 72 patients with acute avulsion fractures of the base of the fifth metatarsal treated with the WB or the HSS, from March 2014 to November 2018. The average age of the patients was 41,25 (range, 11-88) and there were 56 female and 16, male. 39 were treated with the WB and 33, with the HSS. Patients with comorbities that could interfere in the rate and time of bony healing (diabetes and inflammatory joint disease), associated ankle ligament lesions and loss of follow-up were excluded. Patients were followed regularly until they were clinically asymptomatic and able to return to their previous activities (work, daily activities, sports). We retrospectively reviewed medical records containing the visual analogue scale (VAS) for pain and the american orthopaedic foot and ankle society (AOFAS) score of each visit as well as radiographic exams to evaluate time and rate of fracture healing. Results: Patients of both groups had similar VAS and AOFAS scores in 8 (p=0,34 and p=0,83) and 12 (p=0,25 and p=0,79) weeks. Age and gender distribution in the two groups were equal (p=0,23 and p=0,34, respectively). Time taken to return to the previous activities were not significant different between both groups, with the HSS group taking 8,33 weeks and the WB taking 9,73 weeks (p=0,10). The mean time for bone consolidation was significant higher in the HSS group, taking 8,64 weeks while in the WB took 7,18 weeks (p<0,001). Only 1 case of non-union was observed in the WB group and none in the HSS group. Conclusion: Our study concluded that avulsion fractures of the base of the fifth metatarsal can be treated equally with the HSS or the WB. Both types of immobilization showed to be equivalent in terms of clinical and function evaluation, return to the previous activities without difference in the rate of the fracture consolidation.

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Fracture Healing and Biomarker Expression in a Diabetic Zucker Rat Model

Journal of the American Podiatric Medical Association ◽

10.7547/0003-0538-104.5.428 ◽

2014 ◽

Vol 104 (5) ◽

pp. 428-433 ◽

Cited By ~ 6

Author(s):

Javier La Fontaine ◽

Nathan A. Hunt ◽

Stacey Curry ◽

Tyler Kearney ◽

Daniel Jupiter ◽

...

Keyword(s):

Vascular Endothelial Growth Factor ◽

Growth Factor ◽

Fracture Healing ◽

Bone Healing ◽

Rat Model ◽

Healing Process ◽

Diabetic Rats ◽

Vascular Endothelial ◽

Delayed Healing ◽

Endothelial Growth Factor

Background Persons with diabetes have a higher incidence of fractures compared with persons without diabetes. However, there is little published information concerning the deleterious effect of late-stage diabetes on fracture healing. There are no studies using animal models that evaluate the effect of advanced diabetes on fracture healing. The purpose of our study was to evaluate cytokine expression, specifically macrophage inflammatory protein 1 (MIP-1) and vascular endothelial growth factor, in fracture healing in a type 2 diabetes rat model. Methods We evaluated biomarker expression after femur fracture using a rat model. The two groups consisted of 24 Zucker diabetic rats (study group) and 12 Zucker lean rats (control group). An independent reviewer was used to assess delayed union. We evaluated serum samples 2, 4, 7, and 14 days after surgery for MIP-1, vascular endothelial growth factor, leptin, and other cytokine levels. Results At 3 weeks, Kaplan-Meier estimates showed that 45.8% of femur fractures in Zucker diabetic rats had healed, whereas 81.8% of those in Zucker lean rats had healed (P = .02). A logistic regression model to predict fast healing that included the three cytokines and diabetes status showed that the only factor achieving significance was MIP-1α. Vascular endothelial growth factor was the only biomarker to show significance compared with delayed healing. Conclusions These results confirm significant differences in biomarker expression between diabetic and nondiabetic rats during bone healing. The key factors for bone healing may appear early in the healing process, whereas differences in diabetes versus nondiabetes are seen later in the healing process. Increased levels of MIP-1α were associated with the likelihood of delayed healing.

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Treatment of a nonunion, secondary to gunshot fracture, of the distal radius with circular external fixation and rhBMP-2 in a cat

Veterinary and Comparative Orthopaedics and Traumatology ◽

10.3415/vcot-10-11-0155 ◽

2011 ◽

Vol 24 (04) ◽

pp. 289-293 ◽

Cited By ~ 2

Author(s):

P. Maitre ◽

T. Cachon ◽

C. Carozzo ◽

D. Fau ◽

J-. P. Genevois ◽

...

Keyword(s):

External Fixation ◽

Bone Healing ◽

Individual Case ◽

Skin Wound ◽

Bone Morphogenetic Protein 2 ◽

Radiographic Evaluation ◽

Bony Union ◽

Non Union ◽

Morphogenetic Protein ◽

Human Bone Morphogenetic Protein

SummaryObjective: To report the successful use of recombinant human bone morphogenetic protein-2 (rhBMP-2) in the treatment of an ante-brachial non-union, secondary to gunshot fracture, stabilized with circular external fixation in a cat.Procedure: Following a diagnosis of a highly comminuted gunshot fracture of the distal right radius and ulna, the fracture was stabilized with a circular external fixation. A two-ring frame was placed in closed fashion.Results: The skin wound healed uneventfully by second intention in 21 days. Twenty-eight weeks after external fixation, bone healing was absent. 0.8mL of 0.2mg/mL of rhBMP-2 in two collagen sponges was placed in the bone defect. Eight weeks after rhBMP-2 implantation, an early bone healing response was noted on radiographic evaluation. Sixteen weeks after rhBMP-2 implantation, fracture union was achieved.Discussion: To the authors’ knowledge, 160 ±g is the lowest reported dose of rhBMP-2 that leads to bony union in a cat. However as an individual case study, this report can not be used as evidence that rhBMP-2 at this lower dose is appropriate for use in all cats. Further studies are needed to establish the minimum efficient dose of rhBMP-2 in cats.

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Osteogenic Potency of Secretome Bone Marrow Derived Mesenchymal Stem Cells: A Literature Review

Advanced Science Letters ◽

10.1166/asl.2018.12684 ◽

2018 ◽

Vol 24 (8) ◽

pp. 6206-6208

Author(s):

Ismail Hadisoebroto Dilogo ◽

Jessica Fiolin ◽

Petrus Aprianto

Keyword(s):

Stem Cells ◽

Mesenchymal Stem Cells ◽

Growth Factors ◽

Bone Healing ◽

Mechanical Stability ◽

Healing Process ◽

Study Groups ◽

Non Union ◽

Acute Kidney Disease ◽

Diamond Concept

Treatment of non-union bone healing has been an unsolved problem in Orthopaedic surgery despite many advances. The most commonly adapted concept is the diamond concept including the osteoprogenitor cells, osteoinductive proteins, osteoconductive scaffolds and mechanical stability. Recent study groups worldwide have been studying the Mesenchymal Stem Cells as an adjunct to increase the bone healing process. However, newer literatures have shown that only few number of MSC transplanted will integrate. This paracrine mechanism is mediated by active secretion of cytokines, growth factors and enzymes called the secretome which is produced as a byproduct during the process of MSC culture. The addition of secretome itself alone is predicted to have the similar effect as the transplantation of MSC with less cost needed, and easier to obtain. The effect of MSC secretome has shown positive result on neurodegenerative disease, acute kidney disease, and cancer; but the effect on bone regeneration itself has never been studied. The MSC secretome have been proven to contain various cytokines (TGβ, some interleukins, GCSF, and many other cytokines) and growth factors (VEGF, EGF, PDGF, IGF-1, IGF-II, PLGF, HGF, NGF, BDNF). We also suspect the osteoinductive profile of MSC secretome due to the existence of BMP-2 which can be analysed using the ELISA spectrophotometry. The osteoinductive profile of secretome MSC will be able to replace the need of recombinant human BMP-2 (rhBMP-2) transplantation in treating bone defect and diminish the risk of excessive inflammation created by BMP-2 and also the carcinogenic potency.

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Influence of high-frequency cyclical stimulation on the bone fracture-healing process: mathematical and experimental models

Philosophical Transactions of The Royal Society A Mathematical Physical and Engineering Sciences ◽

10.1098/rsta.2011.0153 ◽

2011 ◽

Vol 369 (1954) ◽

pp. 4278-4294 ◽

Cited By ~ 16

Author(s):

María José Gómez-Benito ◽

Libardo Andrés González-Torres ◽

Esther Reina-Romo ◽

Jorge Grasa ◽

Belén Seral ◽

...

Keyword(s):

Fracture Healing ◽

Bone Healing ◽

Mechanical Stimulation ◽

Bone Fracture ◽

High Frequency ◽

Endochondral Ossification ◽

Healing Process ◽

Bone Fracture Healing ◽

Bone Healing Process ◽

Low Magnitude

Mechanical stimulation affects the evolution of healthy and fractured bone. However, the effect of applying cyclical mechanical stimuli on bone healing has not yet been fully clarified. The aim of the present study was to determine the influence of a high-frequency and low-magnitude cyclical displacement of the fractured fragments on the bone-healing process. This subject is studied experimentally and computationally for a sheep long bone. On the one hand, the mathematical computational study indicates that mechanical stimulation at high frequencies can stimulate and accelerate the process of chondrogenesis and endochondral ossification and consequently the bony union of the fracture. This is probably achieved by the interstitial fluid flow, which can move nutrients and waste from one place to another in the callus. This movement of fluid modifies the mechanical stimulus on the cells attached to the extracellular matrix. On the other hand, the experimental study was carried out using two sheep groups. In the first group, static fixators were implanted, while, in the second one, identical devices were used, but with an additional vibrator. This vibrator allowed a cyclic displacement with low magnitude and high frequency (LMHF) to be applied to the fractured zone every day; the frequency of stimulation was chosen from mechano-biological model predictions. Analysing the results obtained for the control and stimulated groups, we observed improvements in the bone-healing process in the stimulated group. Therefore, in this study, we show the potential of computer mechano-biological models to guide and define better mechanical conditions for experiments in order to improve bone fracture healing. In fact, both experimental and computational studies indicated improvements in the healing process in the LMHF mechanically stimulated fractures. In both studies, these improvements could be associated with the promotion of endochondral ossification and an increase in the rate of cell proliferation and tissue synthesis.

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