Regenerative medicine in orthopaedic surgery

Corsi, Karin A.; Schwarz, Edward M.; Mooney, David J.; Huard, Johnny

doi:10.1002/jor.20432

Cited by 37 publications

(29 citation statements)

References 72 publications

(90 reference statements)

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“…A single supraphysiological dose of BMP does not induce the complex pattern of growth factor and cytokine production required for optimal fracture repair. Ex vivo expansion of mesenchymal stromal cells transduced to express BMPs (8,9) have been shown to promote fracture healing in experimental animal models (10). However, the clinical benefits of these complex and costly strategies are unclear.…”

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confidence: 99%

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TNF-α promotes fracture repair by augmenting the recruitment and differentiation of muscle-derived stromal cells

Glass

Chan

Freidin³

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

340

295

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With an aging population, skeletal fractures are increasing in incidence, including the typical closed and the less common open fractures in normal bone, as well as fragility fractures in patients with osteoporosis. For the older age group, there is an urgent unmet need to induce predictable bone formation as well as improve implant fixation in situations such as hip joint replacement. Using a murine model of slow-healing fractures, we have previously shown that coverage of the fracture with muscle accelerated fracture healing and increased union strength. Here, we show that cells from muscle harvested after 3 d of exposure to an adjacent fracture differentiate into osteoblasts and form bone nodules in vitro. The osteogenic potential of these cells exceeds that of adipose and skinderived stromal cells and is equivalent to bone marrow stromal cells. Supernatants from human fractured tibial bone fragments promote osteogenesis and migration of muscle-derived stromal cells (MDSC) in vitro. The main factor responsible for this is TNF-α, which promotes first MDSC migration, then osteogenic differentiation at low concentrations. However, TNF-α is inhibitory at high concentrations. In our murine model, addition of TNF-α at 1 ng/mL at the fracture site accelerated healing. These data indicate that manipulating the local inflammatory environment to recruit, then differentiate adjacent MDSC, may be a simple yet effective way to enhance bone formation and accelerate fracture repair. Our findings are based on a combination of human specimens and an in vivo murine model and may, therefore, translate to clinical care.

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confidence: 99%

“…Thus, contributions from adjacent skeletal muscle (9,13,14), fat (15), and skin (16) may be vital (17)(18)(19). We have previously compared the effect of muscle with fasciocutaneous tissue in exclusive contact with fractured, periosteally stripped, and endosteally reamed bone in a murine model of open fracture (20).…”

mentioning

confidence: 99%

TNF-α promotes fracture repair by augmenting the recruitment and differentiation of muscle-derived stromal cells

Glass

Chan

Freidin³

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

340

295

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“…In traditional tissue engineering approaches, these elements are generally applied ex vivo to induce tissue-specific lineage commitment and matrix formation. Although promising strategies for developing bone, cartilage, tendon, and muscle tissue substitutes based on this paradigm exist (7)(8)(9), these approaches require extensive in vitro manipulation of engineered replacements. Furthermore, upon implantation in vivo, the ability to further specify or modify cell fate is lost.…”

mentioning

confidence: 99%

Scaffold-mediated lentiviral transduction for functional tissue engineering of cartilage

Brunger

Huynh

Guenther

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

116

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The ability to develop tissue constructs with matrix composition and biomechanical properties that promote rapid tissue repair or regeneration remains an enduring challenge in musculoskeletal engineering. Current approaches require extensive cell manipulation ex vivo, using exogenous growth factors to drive tissue-specific differentiation, matrix accumulation, and mechanical properties, thus limiting their potential clinical utility. The ability to induce and maintain differentiation of stem cells in situ could bypass these steps and enhance the success of engineering approaches for tissue regeneration. The goal of this study was to generate a self-contained bioactive scaffold capable of mediating stem cell differentiation and formation of a cartilaginous extracellular matrix (ECM) using a lentivirus-based method. We first showed that poly-L-lysine could immobilize lentivirus to poly(e-caprolactone) films and facilitate human mesenchymal stem cell (hMSC) transduction. We then demonstrated that scaffoldmediated gene delivery of transforming growth factor β3 (TGF-β3), using a 3D woven poly(e-caprolactone) scaffold, induced robust cartilaginous ECM formation by hMSCs. Chondrogenesis induced by scaffold-mediated gene delivery was as effective as traditional differentiation protocols involving medium supplementation with TGF-β3, as assessed by gene expression, biochemical, and biomechanical analyses. Using lentiviral vectors immobilized on a biomechanically functional scaffold, we have developed a system to achieve sustained transgene expression and ECM formation by hMSCs. This method opens new avenues in the development of bioactive implants that circumvent the need for ex vivo tissue generation by enabling the long-term goal of in situ tissue engineering.biomaterials | regenerative medicine | genetic engineering | gene therapy | chondrocyte

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“…As investigators' interests increase about tissue engineering with different sources of cells, many cells have been tried to show the regeneration potential for orthopedic disorders [2,3] . Cell adhesion studies, mechanical stimulation and cytokine stimulation of cells have been reported to elucidate the mechanism of action [4,5] .…”

Section: History Of Cellular Therapy As Tissue Engineeringmentioning

confidence: 99%

Orthopedic cellular therapy: An overview with focus on clinical trials

Noh¹

2015

WJO

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In this editorial, the authors tried to evaluate the present state of cellular therapy in orthopedic field. The topics the authors try to cover include not only the clinical trials but the various research areas as well. Both the target diseases for cellular therapy and the target cells were reviewed. New methods to activate the cells were interesting to review. Most advanced clinical trials were also included because several of them have advanced to phase Ⅲ clinical trials. In the orthopedic field, there are many diseases with a definite treatment gap at this time. Because cellular therapies can regenerate damaged tissues, there is a possibility for cellular therapies to become disease modifying drugs. It is not clear whether cellular therapies will become the standard of care in any of the orthopedic disorders, however the amount of research being performed and the number of clinical trials that are on-going make the authors believe that cellular therapies will become important treatment modalities within several years.

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Regenerative medicine in orthopaedic surgery

Cited by 37 publications

References 72 publications

TNF-α promotes fracture repair by augmenting the recruitment and differentiation of muscle-derived stromal cells

TNF-α promotes fracture repair by augmenting the recruitment and differentiation of muscle-derived stromal cells

Scaffold-mediated lentiviral transduction for functional tissue engineering of cartilage

Orthopedic cellular therapy: An overview with focus on clinical trials

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