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Healing of Ligaments and Tendons: Tissue Engineering and Models

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Materials Science".

Deadline for manuscript submissions: closed (30 April 2022) | Viewed by 25712

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Special Issue Editor

Prof. Dr. Gundula Schulze-Tanzil

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Guest Editor

Institute of Anatomy and Cell Biology, Paracelsus Medical University, Nuremberg and Salzburg, 90419 Nuremberg, Germany
Interests: ligament/tendon; cartilage; tissue engineering and reconstruction
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

This Special Issue on “Healing of Ligaments and Tendons: Tissue Engineering and Models” will cover a selection of recent research topics and current review articles related to novel insight in the healing of ligaments and tendons. Up-to-date review articles, commentaries, and experimental manuscripts are all welcome.

This Special Issue will present insights into novel approaches for tendon and ligament reconstruction based on tissue engineering or cell-free strategies using natural or synthetic biomaterials. As natural biomaterials for tendon/ligament reconstruction collagen-based scaffolds, decellularized tendons/ligaments or other dense connective tissue-derived extracellular matrices are of high interest. Valuable three-dimensional in vitro models including the application of bioreactors and versatile mechano-stimulatory devices which are known to promote in vitro teno-/ligamentogenesis should be presented for initial testing of implants, but also preclinical in vivo implantation models are welcome which allow monitoring of the complex healing process. In addition to reconstruction of the midsubstance of tendons/ligaments, the neoformation of an enthesis-like interface between tendon/ligament and bone is an important prerequisite for stable reconstruction; hence, this unique transition tissue may also be addressed. A particular challenge is presented in the reconstruction of the anterior cruciate ligament (ACL) as an intraarticular ligament prone to the inflammatory milieu of the injured joint. For this reason, the influence of inflammation on the healing response shall be analyzed in more detail.

Prof. Dr. Gundula Schulze-Tanzil
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

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Keywords

tendon/ligament tissue engineering
tendon/ligament reconstruction
repair
tendon/ligament healing
ligamentogenesis
decellularized extracellular matrix
mechanostimulation
anterior cruciate ligament
inflammation
enthesis

Related Special Issue

Healing of Ligaments and Tendons: Tissue Engineering and Models 2.0 in International Journal of Molecular Sciences (4 articles)

Published Papers (10 papers)

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Research

20 pages, 7410 KiB

Open AccessArticle

Co-Culture of Mesenchymal Stem Cells and Ligamentocytes on Triphasic Embroidered Poly(L-lactide-co-ε-caprolactone) and Polylactic Acid Scaffolds for Anterior Cruciate Ligament Enthesis Tissue Engineering

by Clemens Gögele, Julia Vogt, Judith Hahn, Annette Breier, Ricardo Bernhardt, Michael Meyer, Michaela Schröpfer, Kerstin Schäfer-Eckart and Gundula Schulze-Tanzil

Int. J. Mol. Sci. 2023, 24(7), 6714; https://doi.org/10.3390/ijms24076714 - 4 Apr 2023

Cited by 7 | Viewed by 2061

Abstract

Successful anterior cruciate ligament (ACL) reconstructions strive for a firm bone-ligament integration. With the aim to establish an enthesis-like construct, embroidered functionalized scaffolds were colonized with spheroids of osteogenically differentiated human mesenchymal stem cells (hMSCs) and lapine (l) ACL fibroblasts in this study. These triphasic poly(L-lactide-co-ε-caprolactone) and polylactic acid (P(LA-CL)/PLA) scaffolds with a bone-, a fibrocartilage transition- and a ligament zone were colonized with spheroids directly after assembly (DC) or with 14-day pre-cultured lACL fibroblast and 14-day osteogenically differentiated hMSCs spheroids (=longer pre-cultivation, LC). The scaffolds with co-cultures were cultured for 14 days. Cell vitality, DNA and sulfated glycosaminoglycan (sGAG) contents were determined. The relative gene expressions of collagen types I and X, Mohawk, Tenascin C and runt-related protein (RUNX) 2 were analyzed. Compared to the lACL spheroids, those with hMSCs adhered more rapidly. Vimentin and collagen type I immunoreactivity were mainly detected in the hMSCs colonizing the bone zone. The DNA content was higher in the DC than in LC whereas the sGAG content was higher in LC. The gene expression of ECM components and transcription factors depended on cell type and pre-culturing condition. Zonal colonization of triphasic scaffolds using spheroids is possible, offering a novel approach for enthesis tissue engineering. Full article

(This article belongs to the Special Issue Healing of Ligaments and Tendons: Tissue Engineering and Models)

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16 pages, 3100 KiB

Open AccessArticle

Therapeutic Effects of Platelet-Derived Extracellular Vesicles in a Bioengineered Tendon Disease Model

by Ana L. Graça, Rui M. A. Domingues, Isabel Calejo, Manuel Gómez-Florit and Manuela E. Gomes

Int. J. Mol. Sci. 2022, 23(6), 2948; https://doi.org/10.3390/ijms23062948 - 9 Mar 2022

Cited by 9 | Viewed by 2235

Abstract

Tendon injuries represent over 30–50% of musculoskeletal disorders worldwide, yet the available therapies do not provide complete tendon repair/regeneration and full functionality restoring. Extracellular vesicles (EVs), membrane-enclosed nanoparticles, have emerged as the next breakthrough in tissue engineering and regenerative medicine to promote endogenous tissue regeneration. Here, we developed a 3D human in vitro model mimicking the signature of pathological tendon and used it to evaluate the influence that different platelet-derived EVs might have in tendon tissue repair mechanisms. For this, different EV populations isolated from platelets, small EVs (sEVs) and medium EVs (mEVs), were added to the culture media of human tendon-derived cells (hTDCs) cultured on isotropic nanofibrous scaffolds. The platelet-derived EVs increased the expression of tenogenic markers, promoted a healthy extracellular matrix (ECM) remodeling, and the synthesis of anti-inflammatory mediators. These findings suggest that platelet EVs provided relevant biochemical cues that potentiated a recovery of hTDCs phenotype from a diseased to a healthy state. Thus, this study opens new perspectives for the translation of platelet-derived EVs as therapeutics. Full article

(This article belongs to the Special Issue Healing of Ligaments and Tendons: Tissue Engineering and Models)

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16 pages, 2202 KiB

Open AccessArticle

Secretome from In Vitro Mechanically Loaded Myoblasts Induces Tenocyte Migration, Transition to a Fibroblastic Phenotype and Suppression of Collagen Production

by Xin Zhou, Junhong Li, Antonios Giannopoulos, Paul J. Kingham and Ludvig J. Backman

Int. J. Mol. Sci. 2021, 22(23), 13089; https://doi.org/10.3390/ijms222313089 - 3 Dec 2021

Cited by 3 | Viewed by 2224

Abstract

It is known that mechanical loading of muscles increases the strength of healing tendon tissue, but the mechanism involved remains elusive. We hypothesized that the secretome from myoblasts in co-culture with tenocytes affects tenocyte migration, cell phenotype, and collagen (Col) production and that the effect is dependent on different types of mechanical loading of myoblasts. To test this, we used an in vitro indirect transwell co-culture system. Myoblasts were mechanically loaded using the FlexCell^® Tension system. Tenocyte cell migration, proliferation, apoptosis, collagen production, and several tenocyte markers were measured. The secretome from myoblasts decreased the Col I/III ratio and increased the expression of tenocyte specific markers as compared with tenocytes cultured alone. The secretome from statically loaded myoblasts significantly enhanced tenocyte migration and Col I/III ratio as compared with dynamic loading and controls. In addition, the secretome from statically loaded myoblasts induced tenocytes towards a myofibroblast-like phenotype. Taken together, these results demonstrate that the secretome from statically loaded myoblasts has a profound influence on tenocytes, affecting parameters that are related to the tendon healing process. Full article

(This article belongs to the Special Issue Healing of Ligaments and Tendons: Tissue Engineering and Models)

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18 pages, 1146 KiB

Open AccessArticle

Mesenchymal Stromal Cells Adapt to Chronic Tendon Disease Environment with an Initial Reduction in Matrix Remodeling

by Carla U. Doll, Sabine Niebert and Janina Burk

Int. J. Mol. Sci. 2021, 22(23), 12798; https://doi.org/10.3390/ijms222312798 - 26 Nov 2021

Cited by 7 | Viewed by 1681

Abstract

Tendon lesions are common sporting injuries in humans and horses alike. The healing process of acute tendon lesions frequently results in fibrosis and chronic disease. In horses, local mesenchymal stromal cell (MSC) injection is an accepted therapeutic strategy with positive influence on acute lesions. Concerning the use of MSCs in chronic tendon disease, data are scarce but suggest less therapeutic benefit. However, it has been shown that MSCs can have a positive effect on fibrotic tissue. Therefore, we aimed to elucidate the interplay of MSCs and healthy or chronically diseased tendon matrix. Equine MSCs were cultured either as cell aggregates or on scaffolds from healthy or diseased equine tendons. Higher expression of tendon-related matrix genes and tissue inhibitors of metalloproteinases (TIMPs) was found in aggregate cultures. However, the tenogenic transcription factor scleraxis was upregulated on healthy and diseased tendon scaffolds. Matrix metalloproteinase (MMPs) expression and activity were highest in healthy scaffold cultures but showed a strong transient decrease in diseased scaffold cultures. The release of glycosaminoglycan and collagen was also higher in scaffold cultures, even more so in those with tendon disease. This study points to an early suppression of MSC matrix remodeling activity by diseased tendon matrix, while tenogenic differentiation remained unaffected. Full article

(This article belongs to the Special Issue Healing of Ligaments and Tendons: Tissue Engineering and Models)

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16 pages, 3548 KiB

Open AccessArticle

Extracellular Vesicles of Adipose-Derived Stem Cells Promote the Healing of Traumatized Achilles Tendons

by Shih-Heng Chen, Zhi-Yu Chen, Ya-Hsuan Lin, Shih-Hsien Chen, Pang-Yun Chou, Huang-Kai Kao and Feng-Huei Lin

Int. J. Mol. Sci. 2021, 22(22), 12373; https://doi.org/10.3390/ijms222212373 - 16 Nov 2021

Cited by 27 | Viewed by 2776

Abstract

Healing of ruptured tendons remains a clinical challenge because of its slow progress and relatively weak mechanical force at an early stage. Extracellular vesicles (EVs) derived from mesenchymal stem cells (MSCs) have therapeutic potential for tissue regeneration. In this study, we isolated EVs from adipose-derived stem cells (ADSCs) and evaluated their ability to promote tendon regeneration. Our results indicated that ADSC-EVs significantly enhanced the proliferation and migration of tenocytes in vitro. To further study the roles of ADSC-EVs in tendon regeneration, ADSC-EVs were used in Achilles tendon repair in rabbits. The mechanical strength, histology, and protein expression in the injured tendon tissues significantly improved 4 weeks after ADSC-EV treatment. Decorin and biglycan were significantly upregulated in comparison to the untreated controls. In summary, ADSC-EVs stimulated the proliferation and migration of tenocytes and improved the mechanical strength of repaired tendons, suggesting that ADSC-EV treatment is a potential highly potent therapeutic strategy for tendon injuries. Full article

(This article belongs to the Special Issue Healing of Ligaments and Tendons: Tissue Engineering and Models)

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13 pages, 4130 KiB

Open AccessArticle

A Tendon-Specific Double Reporter Transgenic Mouse Enables Tracking Cell Lineage and Functions Alteration In Vitro and In Vivo

by Rui Chen, Xunlei Zhou and Thomas Skutella

Int. J. Mol. Sci. 2021, 22(20), 11189; https://doi.org/10.3390/ijms222011189 - 17 Oct 2021

Cited by 2 | Viewed by 2363

Abstract

We generated and characterized a transgenic mouse line with the tendon-specific expression of a double fluorescent reporter system, which will fulfill an unmet need for animal models to support real-time monitoring cell behaviors during tendon development, growth, and repair in vitro and in vivo. The mScarlet red fluorescent protein is driven by the Scleraxis (Scx) promoter to report the cell lineage alteration. The blue fluorescent protein reporter is expressed under the control of the 3.6kb Collagen Type I Alpha 1 Chain (Col1a1) proximal promoter. In this promoter, the existence of two promoter regions named tendon-specific cis-acting elements (TSE1, TSE2) ensure the specific expression of blue fluorescent protein (BFP) in tendon tissue. Collagen I is a crucial marker for tendon regeneration that is a major component of healthy tendons. Thus, the alteration of function during tendon repair can be estimated by BFP expression. After mechanical stimulation, the expression of mScarlet and BFP increased in adipose-derived mesenchymal stem cells (ADMSCs) from our transgenic mouse line, and there was a rising trend on tendon key markers. These results suggest that our tendon-specific double reporter system is a novel model used to study cell re-differentiation and extracellular matrix alteration in vitro and in vivo. Full article

(This article belongs to the Special Issue Healing of Ligaments and Tendons: Tissue Engineering and Models)

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16 pages, 3293 KiB

Open AccessArticle

Minispheroids as a Tool for Ligament Tissue Engineering: Do the Self-Assembly Techniques and Spheroid Dimensions Influence the Cruciate Ligamentocyte Phenotype?

by Ingrid Zahn, Tobias Braun, Clemens Gögele and Gundula Schulze-Tanzil

Int. J. Mol. Sci. 2021, 22(20), 11011; https://doi.org/10.3390/ijms222011011 - 12 Oct 2021

Cited by 5 | Viewed by 1751

Abstract

Spheroid culture might stabilize the ligamentocyte phenotype. Therefore, the phenotype of lapine cruciate ligamentocyte (L-CLs) minispheroids prepared either by hanging drop (HD) method or by using a novel spheroid plate (SP) and the option of methyl cellulose (MC) for tuning spheroid formation was tested. A total of 250 and 1000 L-CLs per spheroid were seeded as HDs or on an SP before performing cell viability assay, morphometry, gene expression (qRT-PCR) and protein immunolocalization after 7 (HD/SP) and 14 (SP) days. Stable and viable spheroids of both sizes could be produced with both methods, but more rapidly with SP. MC accelerated the formation of round spheroids (HD). Their circular areas decreased significantly during culturing. After 7 days, the diameters of HD-derived spheroids were significantly larger compared to those harvested from the SP, with a tendency of lower circularity suggesting an ellipsoid shape. Gene expression of decorin increased significantly after 7 days (HD, similar trend in SP), tenascin C tended to increase after 7 (HD/SP) and 14 days (SP), whereas collagen type 1 decreased (HD/SP) compared to the monolayer control. The cruciate ligament extracellular matrix components could be localized in all mini-spheroids, confirming their conserved expression profile and their suitability for ligament tissue engineering. Full article

(This article belongs to the Special Issue Healing of Ligaments and Tendons: Tissue Engineering and Models)

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Graphical abstract

22 pages, 5575 KiB

Open AccessArticle

CD146 Delineates an Interfascicular Cell Sub-Population in Tendon That Is Recruited during Injury through Its Ligand Laminin-α4

by Neil Marr, Richard Meeson, Elizabeth F. Kelly, Yongxiang Fang, Mandy J. Peffers, Andrew A. Pitsillides, Jayesh Dudhia and Chavaunne T. Thorpe

Int. J. Mol. Sci. 2021, 22(18), 9729; https://doi.org/10.3390/ijms22189729 - 8 Sep 2021

Cited by 10 | Viewed by 2705

Abstract

The interfascicular matrix (IFM) binds tendon fascicles and contains a population of morphologically distinct cells. However, the role of IFM-localised cell populations in tendon repair remains to be determined. The basement membrane protein laminin-α4 also localises to the IFM. Laminin-α4 is a ligand for several cell surface receptors, including CD146, a marker of pericyte and progenitor cells. We used a needle injury model in the rat Achilles tendon to test the hypothesis that the IFM is a niche for CD146+ cells that are mobilised in response to tendon damage. We also aimed to establish how expression patterns of circulating non-coding RNAs alter with tendon injury and identify potential RNA-based markers of tendon disease. The results demonstrate the formation of a focal lesion at the injury site, which increased in size and cellularity for up to 21 days post injury. In healthy tendon, CD146+ cells localised to the IFM, compared with injury, where CD146+ cells migrated towards the lesion at days 4 and 7, and populated the lesion 21 days post injury. This was accompanied by increased laminin-α4, suggesting that laminin-α4 facilitates CD146+ cell recruitment at injury sites. We also identified a panel of circulating microRNAs that are dysregulated with tendon injury. We propose that the IFM cell niche mediates the intrinsic response to injury, whereby an injury stimulus induces CD146+ cell migration. Further work is required to fully characterise CD146+ subpopulations within the IFM and establish their precise roles during tendon healing. Full article

(This article belongs to the Special Issue Healing of Ligaments and Tendons: Tissue Engineering and Models)

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25 pages, 45369 KiB

Open AccessArticle

Maintenance of Ligament Homeostasis of Spheroid-Colonized Embroidered and Functionalized Scaffolds after 3D Stretch

by Clemens Gögele, Jens Konrad, Judith Hahn, Annette Breier, Michaela Schröpfer, Michael Meyer, Rudolf Merkel, Bernd Hoffmann and Gundula Schulze-Tanzil

Int. J. Mol. Sci. 2021, 22(15), 8204; https://doi.org/10.3390/ijms22158204 - 30 Jul 2021

Cited by 7 | Viewed by 2269

Abstract

Anterior cruciate ligament (ACL) ruptures are usually treated with autograft implantation to prevent knee instability. Tissue engineered ACL reconstruction is becoming promising to circumvent autograft limitations. The aim was to evaluate the influence of cyclic stretch on lapine (L) ACL fibroblasts on embroidered scaffolds with respect to adhesion, DNA and sulphated glycosaminoglycan (sGAG) contents, gene expression of ligament-associated extracellular matrix genes, such as type I collagen, decorin, tenascin C, tenomodulin, gap junctional connexin 43 and the transcription factor Mohawk. Control scaffolds and those functionalized by gas phase fluorination and cross-linked collagen foam were either pre-cultured with a suspension or with spheroids of LACL cells before being subjected to cyclic stretch (4%, 0.11 Hz, 3 days). Stretch increased significantly the scaffold area colonized with cells but impaired sGAGs and decorin gene expression (functionalized scaffolds seeded with cell suspension). Stretching increased tenascin C, connexin 43 and Mohawk but decreased decorin gene expression (control scaffolds seeded with cell suspension). Pre-cultivation of functionalized scaffolds with spheroids might be the more suitable method for maintaining ligamentogenesis in 3D scaffolds compared to using a cell suspension due to a significantly higher sGAG content in response to stretching and type I collagen gene expression in functionalized scaffolds. Full article

(This article belongs to the Special Issue Healing of Ligaments and Tendons: Tissue Engineering and Models)

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18 pages, 5765 KiB

Open AccessArticle

Molecular Mechanisms of Fetal Tendon Regeneration Versus Adult Fibrous Repair

by Iris Ribitsch, Andrea Bileck, Alexander D. Aldoshin, Maciej M. Kańduła, Rupert L. Mayer, Monika Egerbacher, Simone Gabner, Ulrike Auer, Sinan Gültekin, Johann Huber, David P. Kreil, Christopher Gerner and Florien Jenner

Int. J. Mol. Sci. 2021, 22(11), 5619; https://doi.org/10.3390/ijms22115619 - 25 May 2021

Cited by 11 | Viewed by 3957

Abstract

Tendinopathies are painful, disabling conditions that afflict 25% of the adult human population. Filling an unmet need for realistic large-animal models, we here present an ovine model of tendon injury for the comparative study of adult scarring repair and fetal regeneration. Complete regeneration of the fetal tendon within 28 days is demonstrated, while adult tendon defects remained macroscopically and histologically evident five months post-injury. In addition to a comprehensive histological assessment, proteome analyses of secretomes were performed. Confirming histological data, a specific and pronounced inflammation accompanied by activation of neutrophils in adult tendon defects was observed, corroborated by the significant up-regulation of pro-inflammatory factors, neutrophil attracting chemokines, the release of potentially tissue-damaging antimicrobial and extracellular matrix-degrading enzymes, and a response to oxidative stress. In contrast, secreted proteins of injured fetal tendons included proteins initiating the resolution of inflammation or promoting functional extracellular matrix production. These results demonstrate the power and relevance of our novel ovine fetal tendon regeneration model, which thus promises to accelerate research in the field. First insights from the model already support our molecular understanding of successful fetal tendon healing processes and may guide improved therapeutic strategies. Full article

(This article belongs to the Special Issue Healing of Ligaments and Tendons: Tissue Engineering and Models)

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