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Tendon tissue engineering: adipose-derived stem cell and GDF-5 mediated regeneration using electrospun matrix systems.

ABSTRACT: Tendon tissue engineering with a biomaterial scaffold that mimics the tendon extracellular matrix (ECM) and is biomechanically suitable, and when combined with readily available autologous cells, may provide successful regeneration of defects in tendon. Current repair strategies using suitable autografts and freeze-dried allografts lead to a slow repair process that is sub-optimal and fails to restore function, particularly in difficult clinical situations such as zone II flexor tendon injuries of the hand. We have investigated the effect of GDF-5 on cell proliferation and gene expression by primary rat adipose-derived stem cells (ADSCs) that were cultured on a poly(DL-lactide-co-glycolide) PLAGA fiber scaffold and compared to a PLAGA 2D film scaffold. The electrospun scaffold mimics the collagen fiber bundles present in native tendon tissue, and supports the adhesion and proliferation of multipotent ADSCs. Gene expression of scleraxis, the neotendon marker, was upregulated seven- to eightfold at 1 week with GDF-5 treatment when cultured on a 3D electrospun scaffold, and was significantly higher at 2 weeks compared to 2D films with or without GDF-5 treatment. Expression of the genes that encode the major tendon ECM protein, collagen type I, was increased by fourfold starting at 1 week on treatment with 100 ng mL(-1) GDF-5, and at all time points the expression was significantly higher compared to 2D films irrespective of GDF-5 treatment. Thus stimulation with GDF-5 can modulate primary ADSCs on a PLAGA fiber scaffold to produce a soft, collagenous musculoskeletal tissue that fulfills the need for tendon regeneration.

SUBMITTER: James R

PROVIDER: S-EPMC3206634 | biostudies-literature | 2011 Apr

REPOSITORIES: biostudies-literature

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Tendon tissue engineering: adipose-derived stem cell and GDF-5 mediated regeneration using electrospun matrix systems.

James R R Kumbar S G SG Laurencin C T CT Balian G G Chhabra A B AB

Biomedical materials (Bristol, England) 20110324 2

Tendon tissue engineering with a biomaterial scaffold that mimics the tendon extracellular matrix (ECM) and is biomechanically suitable, and when combined with readily available autologous cells, may provide successful regeneration of defects in tendon. Current repair strategies using suitable autografts and freeze-dried allografts lead to a slow repair process that is sub-optimal and fails to restore function, particularly in difficult clinical situations such as zone II flexor tendon injuries ...[more]

PMID: 21436509

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Project description:Many surgical tendon repairs fail despite advances in surgical materials and techniques. Tendon repair failure can be partially attributed to the tendon's poor intrinsic healing capacity and the repurposing of sutures from other clinical applications. Electrospun materials show promise as a biological scaffold to support endogenous tendon repair, but their relatively low tensile strength has limited their clinical translation. It is hypothesized that combining electrospun fibers with a material with increased tensile strength may improve the suture's mechanical properties while retaining biophysical cues necessary to encourage cell-mediated repair. This article describes the production of a hybrid electrospun-extruded suture with a sheath of submicron electrospun fibers and a core of melt-extruded fibers. The porosity and tensile strength of this hybrid suture is compared with an electrospun-only braided suture and clinically used sutures Vicryl and polydioxanone (PDS). Bioactivity is assessed by measuring the adsorbed serum proteins on electrospun and melt-extruded filaments using mass spectrometry. Human hamstring tendon fibroblast attachment and proliferation were quantified and compared between the hybrid and control sutures. Combining an electrospun sheath with melt-extruded cores created a hybrid braid with increased tensile strength (70.1 ± 0.3N) compared with an electrospun only suture (12.9 ± 1 N, p < 0.0001). The hybrid suture had a similar force at break to clinical sutures, but lower stiffness and stress. The Young's modulus was 772.6 ± 32 MPa for the hybrid suture, 1693.0 ± 69 MPa for PDS, and 3838.0 ± 132 MPa for Vicryl, p < 0.0001. Hybrid sutures had lower overall porosity than electrospun-only sutures (40 ± 4% and 60 ± 7%, respectively, p = 0.0018) but had a significantly larger overall porosity and average pore diameter compared with surgical sutures. There were similar clusters of adsorbed proteins on electrospun and melt-extruded filaments, which were distinct from PDS. Tendon fibroblast attachment and cell proliferation on hybrid and electrospun sutures were significantly higher than on clinical sutures. This study demonstrated that a bioactive suture with increased tensile strength and lower stiffness could be produced by adding a core of 10 μm melt-extruded fibers to a sheath of electrospun fibers. In contrast to currently used sutures, the hybrid sutures promoted a bioactive response: serum proteins adsorbed, and fibroblasts attached, survived, grew along the sutures, and adopted appropriate morphologies.

Project description:The rotator cuff consists of several tendons and muscles that provide stability and force transmission in the shoulder joint. Whereas most rotator cuff tears are amenable to suture repair, the overall success rate of repair is low, and massive tears are prone to re-tear. Extracellular matrix (ECM) patches are used to augment suture repair, but they have limitations. Tissue-engineered approaches provide a promising solution for massive rotator cuff tears. Previous studies have shown that, compared to nonaligned scaffolds, aligned electrospun polymer scaffolds exhibit greater anisotropy and exert a greater tenogenic effect. Nevertheless, achieving rapid cell infiltration through the full thickness of the scaffold is challenging, and scaling to a translationally relevant size may be difficult. Our goal was to evaluate whether a novel method of alignment, combining a multilayered electrospinning technique with a hybrid of several electrospinning alignment techniques, would permit cell infiltration and collagen deposition through the thickness of poly(ε-caprolactone) scaffolds following seeding with human adipose-derived stem cells. Furthermore, we evaluated whether multilayered aligned scaffolds enhanced collagen alignment, tendon-related gene expression, and mechanical properties compared to multilayered nonaligned scaffolds. Both aligned and nonaligned multilayered scaffolds demonstrated cell infiltration and ECM deposition through the full thickness of the scaffold after only 28days of culture. Aligned scaffolds displayed significantly increased expression of tenomodulin compared to nonaligned scaffolds and exhibited aligned collagen fibrils throughout the full thickness, the presence of which may account for the increased yield stress and Young's modulus of cell-seeded aligned scaffolds along the axis of fiber alignment.Statement of significanceRotator cuff tears are an important clinical problem in the shoulder, with over 300,000 surgical repairs performed annually. Re-tear rates may be high, and current methods used to augment surgical repair have limited evidence to support their clinical use due to inadequate initial mechanical properties and slow cellular infiltration. Tissue engineering approaches such as electrospinning have shown similar challenges in previous studies. In this study, a novel technique to align electrospun fibers while using a multilayered approach demonstrated increased mechanical properties and development of aligned collagen through the full thickness of the scaffolds compared to nonaligned multilayered scaffolds, and both types of scaffolds demonstrated rapid cell infiltration through the full thickness of the scaffold.

Project description:Cell-derived extracellular matrix (ECM) has been employed as scaffolds for tissue engineering, creating a biomimetic microenvironment that provides physical, chemical and mechanical cues for cells and supports cell adhesion, proliferation, migration and differentiation by mimicking their in vivo microenvironment. Despite the enhanced bioactivity of cell-derived ECM, its application as a scaffold to regenerate hard tissues such as bone is still hampered by its insufficient mechanical properties. The combination of cell-derived ECM with synthetic biomaterials might result in an effective strategy to enhance scaffold mechanical properties and structural support. Electrospinning has been used in bone tissue engineering to fabricate fibrous and porous scaffolds, mimicking the hierarchical organized fibrillar structure and architecture found in the ECM. Although the structure of the scaffold might be similar to ECM architecture, most of these electrospun scaffolds have failed to achieve functionality due to a lack of bioactivity and osteoinductive factors. In this study, we developed bioactive cell-derived ECM electrospun polycaprolactone (PCL) scaffolds produced from ECM derived from human mesenchymal stem/stromal cells (MSC), human umbilical vein endothelial cells (HUVEC) and their combination based on the hypothesis that the cell-derived ECM incorporated into the PCL fibers would enhance the biofunctionality of the scaffold. The aims of this study were to fabricate and characterize cell-derived ECM electrospun PCL scaffolds and assess their ability to enhance osteogenic differentiation of MSCs, envisaging bone tissue engineering applications. Our findings demonstrate that all cell-derived ECM electrospun scaffolds promoted significant cell proliferation compared to PCL alone, while presenting similar physical/mechanical properties. Additionally, MSC:HUVEC-ECM electrospun scaffolds significantly enhanced osteogenic differentiation of MSCs as verified by increased ALP activity and osteogenic gene expression levels. To our knowledge, these results describe the first study suggesting that MSC:HUVEC-ECM might be developed as a biomimetic electrospun scaffold for bone tissue engineering applications.

Project description:Tendon disorders are common medical conditions that could lead to significant disability, pain, healthcare costs, and a loss of productivity. Traditional approaches require long periods of treatment, and they largely fail due to the tissues weakening and the postoperative alterations of the normal joint mechanics. To overcome these limitations, innovative strategies for the treatment of these injuries need to be explored. The aim of the present work was the design of nano-fibrous scaffolds based on poly(butyl cyanoacrylate) (PBCA), a well-known biodegradable and biocompatible synthetic polymer, doped with copper oxide nanoparticles and caseinphosphopeptides (CPP), able to mimic the hierarchical structure of the tendon and to improve the tissue healing potential. These were developed as implants to be sutured to reconstruct the tendons and the ligaments during surgery. PBCA was synthetized, and then electrospun to produce aligned nanofibers. The obtained scaffolds were characterized for their structure and physico-chemical and mechanical properties, highlighting that CuO and CPP loading, and the aligned conformation determined an increase in the scaffold mechanical performance. Furthermore, the scaffolds loaded with CuO showed antioxidant and anti-inflammatory properties. Moreover, human tenocytes adhesion and proliferation to the scaffolds were assessed in vitro. Finally, the antibacterial activity of the scaffolds was evaluated using Escherichia coli and Staphylococcus aureus as representative of Gram-negative and Gram-positive bacteria, respectively, demonstrating that the CuO-doped scaffolds possessed a significant antimicrobial effect against E. coli. In conclusion, scaffolds based on PBCA and doped with CuO and CPP deserve particular attention as enhancers of the tendon tissue regeneration and able to avoid bacterial adhesion. Further investigation on the scaffold efficacy in vivo will assess their capability for enhancing the tendon ECM restoration in view of accelerating their translation to the clinic.

Project description:Many surgical tendon repairs fail despite advances in surgical materials and techniques. Tendon repair failure can be partially attributed to the tendon’s poor intrinsic healing capacity and the repurposing of sutures from use in other tissues. Electrospun materials show promise as a biological scaffold to support endogenous tendon repair, but their relatively low tensile strength has limited their clinical translation. It is hypothesized that combining electrospun fibres with a stronger material may improve the suture’s mechanical properties while retaining biophysical cues necessary to encourage cell-mediated repair. This paper describes the production of a hybrid electrospun-extruded suture with a sheath of submicron electrospun fibres and a core of melt-extruded fibres. The porosity and tensile strength of this hybrid suture is compared to an electrospun-only braided suture and clinically used sutures Vicryl and PDS. Bioactivity is assessed by measuring the adsorbed serum proteins on electrospun and melt-extruded filaments using mass spectrometry. Human hamstring tendon fibroblast attachment and proliferation was quantified and compared between the hybrid and control sutures. Combining an electrospun sheath with melt-extruded cores created a hybrid braid with increased tensile strength (70.1±0.3N) compared to an electrospun only suture (12.9±1N, p<0.0001). The hybrid suture had a similar force at break to clinical sutures, but lower stiffness and stress. The Young’s modulus was 772.6±32Mpa for the hybrid suture, 1693.0±69Mpa for PDS, and 3838.0±132MPa for Vicryl, p<0.0001. Hybrid sutures had lower overall porosity than electrospun-only sutures (40±4% and 60±7%, respectively, p=0.0018) but had a significantly larger overall porosity and average pore diameter compared to surgical sutures. There were similar clusters of adsorbed proteins on electrospun and melt-extruded filaments, which were distinct from PDS. Tendon fibroblast attachment on hybrid and electrospun sutures was significantly higher than on clinical sutures (hybrid 28±7%; electrospun 24±7%; Vicryl 10±5%; PDS 2±0.1%, p<0.0001). Cell proliferation was significantly higher on hybrid and electrospun sutures compared to on clinical sutures. Overall, this study demonstrated that a bioactive suture with increased tensile strength and lower stiffness could be produced by adding a core of 10um melt-extruded fibres to a sheath of electrospun fibres. In contrast to currently used sutures, the hybrid sutures promoted a bioactive response: serum proteins adsorbed, and fibroblasts attached, survived, grew along the sutures, and adopted appropriate morphologies.

Dataset Information

Tendon tissue engineering: adipose-derived stem cell and GDF-5 mediated regeneration using electrospun matrix systems.

Publications

Tendon tissue engineering: adipose-derived stem cell and GDF-5 mediated regeneration using electrospun matrix systems.

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