Improved tendon healing using bFGF, BMP-12 and TGFβ1 in a rat model

Majewski, Martin; Heisterbach, Patricia; Jaquiéry, Claude; Dürselen, Lutz; Todorov, Atanas; Martin, Ivan; Evans, Chris; Müller, Sebastian

doi:10.22203/ecm.v035a22

Cited by 29 publications

(36 citation statements)

References 46 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…There are several limitations in our study. Tgf- β 1 was often combined with other inducers for tendon differentiation [ 14 , 43 ], although its use alone had definite capability to induce tenogenic differentiation which was used to compare with the inductivity of hypoxia in this study. In addition, we did not seed fluorescent-labeled MSCs in the wound gap to investigate the role of hypoxia-induced MSCs in tenogenesis in vivo.…”

Section: Discussionmentioning

confidence: 99%

Hypoxia-Induced Mesenchymal Stem Cells Exhibit Stronger Tenogenic Differentiation Capacities and Promote Patellar Tendon Repair in Rabbits

Chen

Zhang

et al. 2020

Stem Cells International

View full text Add to dashboard Cite

Tendon injury is a common but tough medical problem. Unsatisfactory clinical results have been reported in tendon repair using mesenchymal stem cell (MSC) therapy, creating a need for a better strategy to induce MSCs to tenogenic differentiation. This study was designed to examine the effect of hypoxia on the tenogenic differentiation of different MSCs and their tenogenic differentiation capacities under hypoxia condition in vitro and to investigate the in vivo inductility of hypoxia in tenogenesis. Adipose tissue-derived MSCs (AMSCs) and bone marrow-derived MSCs (BMSCs) were isolated and characterized. The expression of hypoxia-induced factor-1 alpha (Hif-1α) was examined to confirm the establishment of hypoxia condition. qRT-PCR, western blot, and immunofluorescence staining were used to evaluate the expression of tendon-associated marker Col-1a1, Col-3a1, Dcn, and Tnmd in AMSCs and BMSCs under hypoxia condition, compared with Tgf-β1 induction. In vivo, a patellar tendon injury model was established. Normoxic and hypoxic BMSCs were cultured and implanted. Histological, biomechanical, and transmission electron microscopy analyses were performed to assess the improved healing effect of hypoxic BMSCs on tendon injury. Our in vitro results showed that hypoxia remarkably increased the expression of Hif-1α and that hypoxia not only promoted a significant increase in tenogenic markers in both AMSCs and BMSCs compared with the normoxia group but also showed higher inductility compared with Tgf-β1. In addition, hypoxic BMSCs exhibited higher potential of tenogenic differentiation than hypoxic AMSCs. Our in vivo results demonstrated that hypoxic BMSCs possessed better histological and biomechanical properties than normoxic BMSCs, as evidenced by histological scores, patellar tendon biomechanical parameters, and the range and average of collagen fibril diameters. These findings suggested that hypoxia may be a practical and reliable strategy to induce tenogenic differentiation of BMSCs for tendon repair and could enhance the effectiveness of MSCs therapy in treating tendon injury.

show abstract

Section: Discussionmentioning

confidence: 99%

Hypoxia-Induced Mesenchymal Stem Cells Exhibit Stronger Tenogenic Differentiation Capacities and Promote Patellar Tendon Repair in Rabbits

Chen

Zhang

et al. 2020

Stem Cells International

View full text Add to dashboard Cite

show abstract

“…Certain growth factors could act directly on target cells present in the injured site to facilitate the healing process. These include insulin-like growth factor-1 (IGF-1), basic fibroblast growth factor (bFGF), platelet-derived growth factor (PDGF), and transforming growth factor-β (TGF-β) [2][3][4][5][6][7][8]. However, their clinical use is still limited because of their high costs, short preservation period, and limited clinical availability.…”

Section: Introductionmentioning

confidence: 99%

Cytokine and Growth Factor Delivery from Implanted Platelet-Rich Fibrin Enhances Rabbit Achilles Tendon Healing

Wong

Huang

Chen

et al. 2020

IJMS

View full text Add to dashboard Cite

Tendons are hypocellular and hypovascular tissues, and thus, their natural healing capacity is low. In this study, we sought to evaluate the efficacy of platelet-rich fibrin (PRF) to serve as a bioactive scaffold in promoting the healing of rabbit Achilles tendon injury. For in vitro study, the essence portion of PRF was determined through bioluminescent assay. Furthermore, we analyzed the time-sequential cytokines-release kinetics of PRF and evaluated their effects on tenocytes proliferation and tenogenic gene expressions. In animal study, the rabbit Achilles tendon defect was left untreated or implanted with normal/heat-denatured PRF scaffolds. Six weeks postoperatively, the specimens were evaluated through sonographic imaging and histological analysis. The results revealed significantly more activated platelets on bottom half of the PRF scaffold. Cytokine concentrations released from PRF could be detected from the first hour to six days. For the in vitro study, PRF enhanced cell viability and collagen I, collagen III, tenomodulin, and tenascin gene expression compared to the standard culture medium. For in vivo study, sonographic images revealed significantly better tendon healing in the PRF group in terms of tissue echogenicity and homogeneity. The histological analysis showed that the healing tissues in the PRF group had more organized collagen fiber, less vascularity, and minimal cartilage formation. In conclusion, bioactive PRF promotes in vitro tenocytes viability and tenogenic phenotypic differentiation. Administration of a PRF scaffold at the tendon defect promotes tissue healing as evidenced by imaging and histological outcomes.

show abstract

“…The ability of this technology to accelerate healing of the transected rat Achilles tendon has been previously confirmed. 15 In the IP group, the longitudinally opened paratenon was preserved and closed together with the skin using single stitches. In the RP group, the paratenon was resected completely, 20 the GF-loaded sponge placed into the tendon defect, and the skin thoroughly closed with single stitches, while the collagen sponge was secured with the skin sutures in place.…”

Section: Methodsmentioning

confidence: 99%

“…16 Tendons were tested with a constant displacement rate of 1000 mm/min, which corresponds to dynamic loading of the Achilles tendon in vivo. 15 Force and elongation were continuously recorded, and the maximal load to failure (N) was assessed from the corresponding load-elongation graph. Tendon stiffness (N/mm) was calculated from the linear part of the force-elongation curve and correlated to the cross-sectional area and strain to determine the elastic modulus (MPa).…”

Section: Methodsmentioning

confidence: 99%

“…Excellent results with accelerated healing were found in a rat Achilles tendon transection model when bFGF, BMP-12, and TGF-β1 were loaded onto a collagen sponge and inserted into the defect. 15 Although purified GFs are not yet used clinically to enhance tendon repair, platelet-rich plasma 3,6,8,10,31 and autologous conditioned serum 2 are sometimes applied as rich sources of autologous GFs.…”

mentioning

confidence: 99%

See 1 more Smart Citation

Response of the Injured Tendon to Growth Factors in the Presence or Absence of the Paratenon

et al. 2018

View full text Add to dashboard Cite

Background: The paratenon is important for Achilles tendon healing. There is much interest in the use of exogenous growth factors (GFs) as potential agents for accelerating the healing of damaged Achilles tendons. Purpose/Hypothesis: The present study used a rat model to study the responses of the injured Achilles tendon to GFs in the presence or absence of the paratenon. The hypothesis was that responses of the injured tendon to GFs would be lower in the absence of a paratenon. Study Design: Controlled laboratory study. Methods: A 4-mm defect was created in the right Achilles tendon of 60 skeletally mature rats, which were treated with a validated combination of GFs (bFGF, BMP-12, and TGF-β1). Animals were randomly assigned to the intact paratenon (IP) group or resected paratenon (RP) group. Healing was studied anatomically, mechanically, and histologically after 1, 2, and 4 weeks. Results: IP tendons showed improved healing compared with RP tendons. IP tendons were significantly stronger (32.2 N and 48.9 N, respectively) than RP tendons (20.1 N and 31.1 N, respectively) after 1 and 2 weeks. IP tendons did not elongate as much as RP tendons and had greater cross-sectional areas (18.0 mm2, 14.4 mm2, and 16.4 mm2, respectively) after 1, 2, and 4 weeks compared with RP tendons (10.5 mm2, 8.4 mm2, and 11.9 mm2, respectively). On histology, earlier collagen deposition and parallel orientation of fibrils were found for IP tendons. Conclusion: The paratenon is essential for efficient Achilles tendon healing. Healing with GFs in this Achilles tendon defect model was superior in the presence of the paratenon. Clinical Relevance: Biological approaches to tendon engineering using GFs are in vogue and have been shown to improve healing of the rat Achilles tendon, most likely by inducing progenitor cells located within the paratenon. Clinically, resection or incision of the paratenon has been proposed for wound closure. Our data demonstrate the fundamental importance of the paratenon, which therefore should be preserved during Achilles tendon repair, especially if augmented with products such as platelet-rich plasma or autologous conditioned serum that are rich in GFs.

show abstract

Improved tendon healing using bFGF, BMP-12 and TGFβ1 in a rat model

Cited by 29 publications

References 46 publications

Hypoxia-Induced Mesenchymal Stem Cells Exhibit Stronger Tenogenic Differentiation Capacities and Promote Patellar Tendon Repair in Rabbits

Hypoxia-Induced Mesenchymal Stem Cells Exhibit Stronger Tenogenic Differentiation Capacities and Promote Patellar Tendon Repair in Rabbits

Cytokine and Growth Factor Delivery from Implanted Platelet-Rich Fibrin Enhances Rabbit Achilles Tendon Healing

Response of the Injured Tendon to Growth Factors in the Presence or Absence of the Paratenon

Contact Info

Product

Resources

About