New Frontiers in Peripheral Nerve Regeneration: Concerns and Remedies

Topical advances in studying molecular and cellular mechanisms responsible for regeneration in the peripheral nervous system have highlighted the ability of the nervous system to repair itself. Still, serious injuries represent a challenge for the morphological and functional regeneration of peripheral nerves, calling for new treatment strategies that maximize nerve regeneration and recovery. This review presents the canonical view of the basic mechanisms of nerve regeneration and novel data on the role of exosomes and their transferred microRNAs in intracellular communication, regulation of axonal growth, Schwann cell migration and proliferation, and stromal cell functioning. An integrated comprehensive understanding of the current mechanistic underpinnings will open the venue for developing new clinical strategies to ensure full regeneration in the peripheral nervous system.

REVIEW ON TAIL REGENERATION MECHANISM OF XENOPUS LAEVIS AND CLINOTARSUS CURTIPESAS A THERAPEUTIC MODEL FOR REGENERATIVE MEDICINE

The augmentation of regenerative capability is a powerful method for pursuing for the regulation of degeneration, traumatic injury and cancer. The tadpole, Clinotarsus curtipes and Xenopus laevis is a significant model system for addressing the fundamental regeneration mechanism that enables to understand the key aspects of regeneration medicine. The selected creatures Clinotarsus curtipes and Xenopus laevis could able to obtain both tissue regeneration and scar free healing during larval stage in spite of its predominant loss of such ability during the metamorphic process. Such transient capability associated with the evolutionary correlation with humans creates Clinotarsus curtipes and Xenopus a very good attractive model for uncovering the functional regeneration mechanisms. The study analysed the existing literatures on change in the levels of ROS that is required for the proper wnt-signaling in every regeneration system. Apart from that the paper provided the comprehensive review on the histopathological view, regeneration signals like TGFβ, FGF, BMP, Wnt etc for successful regeneration. Factors that affect the tail regeneration like O2 influx, epigenetics and HDAC activity have also been provided. Significant other such criteria like role of TRKA signaling, profiling and intracellular protein expression followed by its corresponding challenges adds value to the paper.The study presents an overview of Xenopus and Clinotarsus curtipesas a model organism for the research and highlighted the new insights.

Smart Device for Biologically Enhanced Functional Regeneration of Osteo–Tendon Interface

The spontaneous healing of a tendon laceration results in the formation of scar tissue, which has lower functionality than the original tissue. Moreover, chronic non-healing tendon injuries frequently require surgical treatment. Several types of scaffolds have been developed using the tissue engineering approach, to complement surgical procedures and to enhance the healing process at the injured site. In this work, an electrospun hybrid tubular scaffold was designed to mimic tissue fibrous arrangement and extracellular matrix (ECM) composition, and to be extemporaneously loaded into the inner cavity with human platelet lysate (PL), with the aim of leading to complete post-surgery functional regeneration of the tissue for functional regeneration of the osteo–tendon interface. For this purpose, pullulan (P)/chitosan (CH) based polymer solutions were enriched with hydroxyapatite nanoparticles (HP) and electrospun. The nanofibers were collected vertically along the length of the scaffold to mimic the fascicle direction of the tendon tissue. The scaffold obtained showed tendon-like mechanical performance, depending on HP content and tube size. The PL proteins were able to cross the scaffold wall, and in vitro studies have demonstrated that tenocytes and osteoblasts are able to adhere to and proliferate onto the scaffold in the presence of PL; moreover, they were also able to produce either collagen or sialoproteins, respectively—important components of ECM. These results suggest that HP and PL have a synergic effect, endorsing PL-loaded HP-doped aligned tubular scaffolds as an effective strategy to support new tissue formation in tendon-to-bone interface regeneration.

Boost Tendon/Ligament Repair With Biomimetic and Smart Cellular Constructs

Tendon and ligament are soft connective tissues that play essential roles in transmitting forces from muscle to bone or bone to bone. Despite significant progress made in the field of ligament and tendon regeneration over the past decades, many strategies struggle to recapitulate basic structure-function criteria of native ligament/tendon. The goal here is to provide a fundamental understanding of the structure and composition of ligament/tendon and highlight few key challenges in functional regeneration of these connective tissues. The remainder of the review will examine several biomaterials strategies including biomimetic scaffold with non-linear mechanical behavior, hydrogel patch with anisotropic adhesion and gene-activated scaffold for interactive healing of tendon/ligament. Finally, emerging technologies and research avenues are suggested that have the potential to enhance treatment outcomes of tendon/ligament injuries.

Interplay of Forces and the Immune Response for Functional Tendon Regeneration

Tendon injury commonly occurs during sports activity, which may cause interruption or rapid decline in athletic career. Tensile strength, as one aspect of tendon biomechanical properties, is the main parameter of tendon function. Tendon injury will induce an immune response and cause the loss of tensile strength. Regulation of mechanical forces during tendon healing also changes immune response to improve regeneration. Here, the effects of internal/external forces and immune response on tendon regeneration are reviewed. The interaction between immune response and internal/external forces during tendon regeneration is critically examined and compared, in relation to other tissues. In conclusion, it is essential to maintain a fine balance between internal/external forces and immune response, to optimize tendon functional regeneration.

Reprogramming adult tendon healing using regenerative neonatal regulatory T cells

Tendinopathy is a common clinical problem leading to significant musculoskeletal disability. Using a neonatal mouse model of tendon regeneration compared to adult tendon fibrosis, we identified a unique immune profile in regeneration that is associated with type 2 macrophage polarization and regulatory T cell (Treg) infiltration. Neonatal Treg ablation resulted in a dysregulated immune response leading to failed tenocyte recruitment and loss of functional regeneration. Transcriptional profiling of adult and neonatal tendon Tregs revealed distinct type 1 and type 2 immune signatures that facilitate macrophage polarization following injury. Finally, adoptive transfer of mouse and human neonatal Tregs was sufficient to improve functional regeneration, in contrast to adult Treg transfer. Collectively, these studies uncover a critical role for neonatal Tregs in controlling immune polarization to promote an environment permissive for tendon regeneration. Our findings provide a basis for immune modulating therapies to facilitate regenerative adult tendon healing.

Novel Drosophila central nervous system injury paradigm in adult: molecular, cellular and functional aspects

The mammalian central nervous system (CNS) exhibits limited regenerative capacity, and the mechanisms that mediate regeneration are not fully understood. Here we present a novel experimental design to damage the CNS using a contusion injury paradigm. The design of this novel protocol allows the study of long term and short term cellular responses including the CNS and the immune system, and the implications for functional recovery. We demonstrate for the first time that adult Drosophila undergoes spontaneous functional recovery following injury. This crush injury leads to an intermediate level of functional recovery after damage, which is ideal to screen for genes that facilitate or prevent the regeneration process. Here we validate this model and analyze the immune responses of glial cells as a central regulator of functional regeneration. Additionally, we demonstrate that glia and macrophages contribute to functional regeneration through mechanisms involving the c-Jun N-terminal kinase (JNK) pathway and Draper, characteristic of other neural injury paradigms. We show that macrophages are recruited to the injury site and are required for recovery. Further, we show that Grindelwald and Draper in glial cells mediate JNK activation, and draper expression in turn, is dependent on JNK activation. Finally, we link neuron-glia communication and the requirement of neuronal vesicular transport for JNK pathway regulation and functional recovery.

Functional regeneration and repair of tendons using biomimetic scaffolds loaded with recombinant periostin

Tendon injuries disrupt the balance between stability and mobility, causing compromised functions and disabilities. The regeneration of mature, functional tendons remains a clinical challenge. Here, we perform transcriptional profiling of tendon developmental processes to show that the extracellular matrix-associated protein periostin (Postn) contributes to the maintenance of tendon stem/progenitor cell (TSPC) functions and promotes tendon regeneration. We show that recombinant periostin (rPOSTN) promotes the proliferation and stemness of TSPCs, and maintains the tenogenic potentials of TSPCs in vitro. We also find that rPOSTN protects TSPCs against functional impairment during long-term passage in vitro. For in vivo tendon formation, we construct a biomimetic parallel-aligned collagen scaffold to facilitate TSPC tenogenesis. Using a rat full-cut Achilles tendon defect model, we demonstrate that scaffolds loaded with rPOSTN promote endogenous TSPC recruitment, tendon regeneration and repair with native-like hierarchically organized collagen fibers. Moreover, newly regenerated tendons show recovery of mechanical properties and locomotion functions.