Therapeutics for tendon regeneration: a multidisciplinary review of tendon research for improved healing.
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ABSTRACT:
SUBMITTER: Paredes JJ
PROVIDER: S-EPMC5560267 | biostudies-other | 2016 Nov
REPOSITORIES: biostudies-other
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Project description:Ligament and tendon injuries are common problems in orthopedics. There is a need for treatments that can expedite nonoperative healing or improve the efficacy of surgical repair or reconstruction of ligaments and tendons. Successful biologically-based attempts at repair and reconstruction would require a thorough understanding of normal tendon and ligament healing. The inflammatory, proliferative, and remodeling phases, and the cells involved in tendon and ligament healing will be reviewed. Then, current research efforts focusing on biologically-based treatments of ligament and tendon injuries will be summarized, with a focus on stem cells endogenous to tendons and ligaments. Statement of clinical significance: This paper details mechanisms of ligament and tendon healing, as well as attempts to apply stem cells to ligament and tendon healing. Understanding of these topics could lead to more efficacious therapies to treat ligament and tendon injuries. © 2019 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 38:7-12, 2020.
| S-EPMC7307866 | biostudies-literature
Project description:Tendons are commonly injured connective soft tissues characterized by an ineffective healing response that results in scar formation and loss of functional and structural properties. Naturally occurring extracellular matrix (ECM) constructs have become a promising therapeutic for tendon injuries due to their capacity to harness a complex biological environment. However, in tendon, the ECM properties needed for improved healing remain unknown. Interestingly, we have determined that the improved tendon healing response of the scarless-healing MRL/MpJ is driven by intrinsic properties with therapeutic potential to modulate the proliferative and morphological behavior of cells derived from a canonically healing model in vitro. We hypothesize that a distinct composition of ECM deposited during the early healing response of the MRL/MpJ will harnesses the biological cues to stimulate improved structure and function in vivo of canonically healing B6 mice. Accordingly, MRL/MpJ and B6 patellar tendons were injured via midsubstance punch defects. Healing tendons were isolated after 3 or 7 days and encapsulated in PEG-4MAL hydrogels to develop ECM-derived therapeutic constructs. Constructs were then introduced into B6 mice as a treatment following full thickness midsubstance-punch injuries. Treatment with ECM-derived constructs from MRL/MpJ tendons after 7-days post-injury (M7) resulted in improved matrix alignment, tissue stiffness, decreased collagen III content and improved cell morphology in B6 tendons after 6 weeks post-injury. Furthermore, proteomic analysis showed that M7 contained a unique compositional profile rich in glycoproteins, thereby elucidating a valuable naturally-derived platform for the treatment of tendon injuries. Overall this work highlights promising targets for future therapeutic development and tissue engineering applications.
| S-EPMC7680300 | biostudies-literature
Project description:To date, the cell and molecular mechanisms regulating tendon healing are poorly understood. Here, we establish a novel model of tendon regeneration using neonatal mice and show that neonates heal via formation of a 'neo-tendon' that differentiates along the tendon specific lineage with functional restoration of gait and mechanical properties. In contrast, adults heal via fibrovascular scar, aberrant differentiation toward cartilage and bone, with persistently impaired function. Lineage tracing identified intrinsic recruitment of Scx-lineage cells as a key cellular mechanism of neonatal healing that is absent in adults. Instead, adult Scx-lineage tenocytes are not recruited into the defect but transdifferentiate into ectopic cartilage; in the absence of tenogenic cells, extrinsic αSMA-expressing cells persist to form a permanent scar. Collectively, these results establish an exciting model of tendon regeneration and uncover a novel cellular mechanism underlying regenerative vs non-regenerative tendon healing.
| S-EPMC5362908 | biostudies-literature
Project description:Mechano-regulation during tendon healing, i.e. the relationship between mechanical stimuli and cellular response, has received more attention recently. However, the basic mechanobiological mechanisms governing tendon healing after a rupture are still not well-understood. Literature has reported spatial and temporal variations in the healing of ruptured tendon tissue. In this study, we explored a computational modeling approach to describe tendon healing. In particular, a novel 3D mechano-regulatory framework was developed to investigate spatio-temporal evolution of collagen content and orientation, and temporal evolution of tendon stiffness during early tendon healing. Based on an extensive literature search, two possible relationships were proposed to connect levels of mechanical stimuli to collagen production. Since literature remains unclear on strain-dependent collagen production at high levels of strain, the two investigated production laws explored the presence or absence of collagen production upon non-physiologically high levels of strain (>15%). Implementation in a finite element framework, pointed to large spatial variations in strain magnitudes within the callus tissue, which resulted in predictions of distinct spatial distributions of collagen over time. The simulations showed that the magnitude of strain was highest in the tendon core along the central axis, and decreased towards the outer periphery. Consequently, decreased levels of collagen production for high levels of tensile strain were shown to accurately predict the experimentally observed delayed collagen production in the tendon core. In addition, our healing framework predicted evolution of collagen orientation towards alignment with the tendon axis and the overall predicted tendon stiffness agreed well with experimental data. In this study, we explored the capability of a numerical model to describe spatial and temporal variations in tendon healing and we identified that understanding mechano-regulated collagen production can play a key role in explaining heterogeneities observed during tendon healing.
| S-EPMC7901741 | biostudies-literature
Project description:Background: Despite significant advances in the materials and methods development used in surgical repair and postoperative rehabilitation, the adhesion formation remains the most common clinical problem in tendon injuries. Therefore, the development of novel therapies is necessary for targeting at preventing tendon adhesion formation and improving tendon strength. Methods: We used rat fibroblasts for in vitro experiments to determine the optimal concentration of TSA in rats, and then set up negative control group, TSA intervention group, mir-29b interference adenovirus intervention group and TSA and mir-29b interference adenovirus co-intervention group. By comparing cell proliferation and protein expression in different group, we verified the effect and mechanism of drugs on fibroblast function. At the same time, the Sprague-Dawley rat Achilles tendon model in vivo was established in this study, which was divided into sham operation group and operation group. Afterwards in the operation group, mir-29b inhibitor and placebo were injected every 3 days respectively. Then the injection inhibitor group was divided into 5 groups which mean TSA was injected into the marked area at 0, 6, 24 and 72 hours after operation for 1 week, finally all of the rats were died at 3 weeks after operation. Through the observation of general properties, histological observation of Achilles tendon injury, biomechanical test and cell and protein expression in rats' tendon cell, the effect of drugs on tendon adhesion formation was analyzed. Results: We demonstrated that the combination of miR-29b inhibitor and tanshinone IIA(TSA) could prevent tendon adhesion and also enhance tendon strength. Mechanically, the miR-29b inhibitor could activate the TGF-?/Smad3 pathway to trigger endogenous pathways and induce a high proliferation of fibroblast. Subsequently, we also found adding TSA after 6 hours of miR-29b treatment gave less cell cytotoxicity in our rat model with better outcome of less tendon adhesion and enhanced strength. Conclusion: We conclude that the use of miR-29b inhibitor at the end of the tendon break could initiate endogenous repair mechanism and subsequently use of TSA should be able to inhibit the exogenous repair mechanism. Therefore, the combination of both treatments could prevent tendon adhesion and ensure tendon strength. Our findings suggested that this approach would be a feasible approach for tendon repair.
| S-EPMC7211157 | biostudies-literature
Project description:Tendon-bone interface injuries pose a significant challenge in tissue regeneration, necessitating innovative approaches. Hydrogels with integrated supportive features and controlled release of therapeutic agents have emerged as promising candidates for the treatment of such injuries. In this study, we aimed to develop a temperature-sensitive composite hydrogel capable of providing sustained release of magnesium ions (Mg2+). We synthesized magnesium-Procyanidin coordinated metal polyphenol nanoparticles (Mg-PC) through a self-assembly process and integrated them into a two-component hydrogel. The hydrogel was composed of dopamine-modified hyaluronic acid (Dop-HA) and F127. To ensure controlled release and mitigate the "burst release" effect of Mg2+, we covalently crosslinked the Mg-PC nanoparticles through coordination bonds with the catechol moiety within the hydrogel. This crosslinking strategy extended the release window of Mg2+ concentrations for up to 56 days. The resulting hydrogel (Mg-PC@Dop-HA/F127) exhibited favorable properties, including injectability, thermosensitivity and shape adaptability, making it suitable for injection and adaptation to irregularly shaped supraspinatus implantation sites. Furthermore, the hydrogel sustained the release of Mg2+ and Procyanidins, which attracted mesenchymal stem and progenitor cells, alleviated inflammation, and promoted macrophage polarization towards the M2 phenotype. Additionally, it enhanced collagen synthesis and mineralization, facilitating the repair of the tendon-bone interface. By incorporating multilevel metal phenolic networks (MPN) to control ion release, these hybridized hydrogels can be customized for various biomedical applications.
| S-EPMC10909705 | biostudies-literature
Project description:We report RNA sequencing data from the plantaris tendons of 3-month old Sprague Dawley rats that were treated with vehicle or GSK2894631A to inhibit the HPGDS enzyme. Rats underwent a bilateral plantaris tendon tear followed by immediate repair, and samples were obtained either 7 or 21 days after surgical intervention.
2019-09-20 | GSE130276 | GEO
Project description:Extreme events have increased in frequency globally, with a simultaneous surge in scientific interest about their ecological responses, particularly in sensitive freshwater, coastal, and marine ecosystems. We synthesized observational studies of extreme events in these aquatic ecosystems, finding that many studies do not use consistent definitions of extreme events. Furthermore, many studies do not capture ecological responses across the full spatial scale of the events. In contrast, sampling often extends across longer temporal scales than the event itself, highlighting the usefulness of long-term monitoring. Many ecological studies of extreme events measure biological responses but exclude chemical and physical responses, underscoring the need for integrative and multidisciplinary approaches. To advance extreme event research, we suggest prioritizing pre- and postevent data collection, including leveraging long-term monitoring; making intersite and cross-scale comparisons; adopting novel empirical and statistical approaches; and developing funding streams to support flexible and responsive data collection.
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Project description:IntroductionTendon disorders present significant challenges in the realm of musculoskeletal diseases, affecting locomotor activity and causing pain. Current treatments often fall short of achieving complete functional recovery of the tendon. It is crucial to explore, in preclinical research, the pathways governing the loss of tissue homeostasis and its regeneration. In this context, this study aimed to establish a correlation between the unbiased locomotor activity pattern of CRL:CD1 (ICR) mice exposed to uni- or bilateral Achilles tendon (AT) experimental injuries and the key histomorphometric parameters that influence tissue microarchitecture recovery.MethodsThe study involved the phenotyping of spontaneous and voluntary locomotor activity patterns in male mice using digital ventilated cages (DVC®) with access to running wheels either granted or blocked. The mice underwent non-intrusive 24/7 long-term activity monitoring for the entire study period. This period included 7 days of pre-injury habituation followed by 28 days post-injury.Results and discussionThe results revealed significant variations in activity levels based on the type of tendon injury and access to running wheels. Notably, mice with bilateral lesions and unrestricted wheel access exhibited significantly higher activity after surgery. Extracellular matrix (ECM) remodeling, including COL1 deposition and organization, blood vessel remodeling, and metaplasia, as well as cytological tendon parameters, such as cell alignment and angle deviation were enhanced in surgical (bilateral lesion) and husbandry (free access to wheels) groups. Interestingly, correlation matrix analysis uncovered a strong relationship between locomotion and microarchitecture recovery (cell alignment and angle deviation) during tendon healing. Overall, this study highlights the potential of using mice activity metrics obtained from a home-cage monitoring system to predict tendon microarchitecture recovery at both cellular and ECM levels. This provides a scalable experimental setup to address the challenging topic of tendon regeneration using innovative and animal welfare-compliant strategies.
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Project description:Bone tissue engineering and the research surrounding peptides has expanded significantly over the last few decades. Several peptides have been shown to support and stimulate the bone healing response and have been proposed as therapeutic vehicles for clinical use. The aim of this comprehensive review is to present the clinical and experimental studies analysing the potential role of peptides for bone healing and bone regeneration.A systematic review according to PRISMA guidelines was conducted. Articles presenting peptides capable of exerting an upregulatory effect on osteoprogenitor cells and bone healing were included in the study.Based on the available literature, a significant amount of experimental in vitro and in vivo evidence exists. Several peptides were found to upregulate the bone healing response in experimental models and could act as potential candidates for future clinical applications. However, from the available peptides that reached the level of clinical trials, the presented results are limited.Further research is desirable to shed more light into the processes governing the osteoprogenitor cellular responses. With further advances in the field of biomimetic materials and scaffolds, new treatment modalities for bone repair will emerge.
| S-EPMC4940902 | biostudies-other