Local Application of Mineral-Coated Microparticles Loaded With VEGF and BMP-2 Induces the Healing of Murine Atrophic Non-Unions

Orth, Marcel; Fritz, Tobias; Stutz, Janine; Scheuer, Cláudia; Ganse, Bergita; Bullinger, Yannik; Lee, J. S.; Murphy, William L.; Laschke, Matthias W.; Menger, Michael D.; Pohlemann, Tim

doi:10.3389/fbioe.2021.809397

Cited by 3 publications

(4 citation statements)

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“…Bone morphogenetic proteins (BMPs) are thought to initiate fracture healing and to thereby reduce nonunions ( 85 ). Local intraoperative application of mineral-coated microparticles loaded with VEGF and BMP-2 induced the healing of atrophic nonunion in mice ( 100 ). In rats, a single percutaneous injection of recombinant human BMP-2 accelerated fracture repair ( 101 ).…”

Section: Pharmacologic Interventionsmentioning

confidence: 99%

Methods to accelerate fracture healing – a narrative review from a clinical perspective

Ganse

2024

Front. Immunol.

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Bone regeneration is a complex pathophysiological process determined by molecular, cellular, and biomechanical factors, including immune cells and growth factors. Fracture healing usually takes several weeks to months, during which patients are frequently immobilized and unable to work. As immobilization is associated with negative health and socioeconomic effects, it would be desirable if fracture healing could be accelerated and the healing time shortened. However, interventions for this purpose are not yet part of current clinical treatment guidelines, and there has never been a comprehensive review specifically on this topic. Therefore, this narrative review provides an overview of the available clinical evidence on methods that accelerate fracture healing, with a focus on clinical applicability in healthy patients without bone disease. The most promising methods identified are the application of axial micromovement, electromagnetic stimulation with electromagnetic fields and direct electric currents, as well as the administration of growth factors and parathyroid hormone. Some interventions have been shown to reduce the healing time by up to 20 to 30%, potentially equivalent to several weeks. As a combination of methods could decrease the healing time even further than one method alone, especially if their mechanisms of action differ, clinical studies in human patients are needed to assess the individual and combined effects on healing progress. Studies are also necessary to determine the ideal settings for the interventions, i.e., optimal frequencies, intensities, and exposure times throughout the separate healing phases. More clinical research is also desirable to create an evidence base for clinical guidelines. To make it easier to conduct these investigations, the development of new methods that allow better quantification of fracture-healing progress and speed in human patients is needed.

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Section: Pharmacologic Interventionsmentioning

confidence: 99%

Methods to accelerate fracture healing – a narrative review from a clinical perspective

Ganse

2024

Front. Immunol.

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“…M2 macrophages orchestrate the healing process via interleukin-1 (IL1), IL6, IL12, and tumor necrosis factor α (TNF-α) [11]. The newly developing vasculature is stimulated by vascular endothelial growth factor (VEGF) and bone morphogenetic protein 2 (BMP2) [35], and erythrocytes as well as platelets form the initial clot in which the callus is formed. Created with BioRender.com.…”

Section: Cellular Components Contributing To (Impaired) Bone Healingmentioning

confidence: 99%

“…The importance of vascularization for the healing fracture has been highlighted in several studies [35,75,76]. Indeed, microparticle-delivered VEGF and bone morphogenetic proteins (BMP)-2 improved bone healing in murine atrophic non-unions, evidenced by enhanced stiffness and bone volume within the callus [35].…”

Section: Vasculaturementioning

confidence: 99%

Bone Healing Gone Wrong: Pathological Fracture Healing and Non-Unions—Overview of Basic and Clinical Aspects and Systematic Review of Risk Factors

et al. 2023

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Bone healing is a multifarious process involving mesenchymal stem cells, osteoprogenitor cells, macrophages, osteoblasts and -clasts, and chondrocytes to restore the osseous tissue. Particularly in long bones including the tibia, clavicle, humerus and femur, this process fails in 2–10% of all fractures, with devastating effects for the patient and the healthcare system. Underlying reasons for this failure are manifold, from lack of biomechanical stability to impaired biological host conditions and wound-immanent intricacies. In this review, we describe the cellular components involved in impaired bone healing and how they interfere with the delicately orchestrated processes of bone repair and formation. We subsequently outline and weigh the risk factors for the development of non-unions that have been established in the literature. Therapeutic prospects are illustrated and put into clinical perspective, before the applicability of biomarkers is finally discussed.

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“…In addition, other biological adjuvants are being investigated on their own or even in combination with different BMPs to overcome potential downsides. Interesting examples are the combination with melatonin to avoid later bone resorption by reducing osteoclastogenes 145 , dual release with IGF-1 to promote cell proliferation and respond with collagen type I synthesis 146,147 or with VEGF to promote angiogenesis and neovascularization 148 . In any case, the vast majority of biological molecules that have been explored or are thought to be of considerable benefit in bone regeneration are hydrophilic.…”

Section: Microparticles For Btementioning

confidence: 99%

Optimization of mimetic periosteum autografts for the treatment of nonunions

Juan Antonio

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Bone presents truly regenerative capacity being able to regenerate into a native state in response to injuries. Despite this self-renewal potential, bone healing is not absent of complications and different conditions can interfere with the regenerative process, leading to delayed fracture and in some cases fracture nonunion. Fracture nonunion is a major cause of chronic pain and disability and, despite the low incidence of nonunion and delayed union fractures (5-10%), the numerous fractures that take place globally (~180 million every year) emphasizes the huge economic burden that fracture nonunion represents. Once detected, fracture nonunion requires a surgical approach, and the use of bone autografts that provide and osteoinductive, osteogenic and osteoconductive environment for a successful repair. However, the availability of bone grafts is limited. The scarcity of bone tissue that can be used for autografts have consolidated the need for novel tissue engineering approaches as potential candidates for the treatment of nonunion and for long bone defects, prone to evolve to nonunions. Tissue engineering strategies allow for the combination of novel tunable materials along with different biological adjuvants, including growth factors and cells. During the bone regenerative response, the periosteum, a fibrous layer surrounding the bone, plays a key role delivering osteochondroprogenitor cells and crucial growth factors into the injured tissue. Thus, we developed a tissue engineering strategy where biocompatible, 3D melt-electro-written polycaprolactone membrane would act as a mimetic periosteum. The engineered mimetic periosteum allows vascularization of the construct either when implanted ectopically or orthotopically. Additionally, we demonstrated its capacity to be functionalized with rhBMP-2, the most important morphogen for bone regeneration, both exposed on the membrane surface attached through PEA-hFN or encapsulated in microparticles covalently bound to the PCL membrane. When functionalized with low doses of rhBMP-2 the mimetic periosteum demonstrated great osteogenic potential in vitro, inducing human MSCs differentiation into osteoblasts. More importantly, in vivo results indicate that the functionalization of the mimetic periosteum with rhBMP-2 allows regenerative properties able to heal critical size femoral defects in SD rats with high efficiency and reproducibility using unpreceded low doses of rhBMP-2. Ultimately, the mimetic periosteum demonstrated its ability to deliver key mesenchymal progenitor cells into the injured site. All these results indicate that our engineered mimetic periosteum represents an efficient system for rhBMP-2 and progenitor cells delivery with important translational potential.

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Local Application of Mineral-Coated Microparticles Loaded With VEGF and BMP-2 Induces the Healing of Murine Atrophic Non-Unions

Cited by 3 publications

References 50 publications

Methods to accelerate fracture healing – a narrative review from a clinical perspective

Methods to accelerate fracture healing – a narrative review from a clinical perspective

Bone Healing Gone Wrong: Pathological Fracture Healing and Non-Unions—Overview of Basic and Clinical Aspects and Systematic Review of Risk Factors

Optimization of mimetic periosteum autografts for the treatment of nonunions

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