An update–tissue engineered nerve grafts for the repair of peripheral nerve injuries

Peripheral nerve injuries（PNI） are caused by a range of etiologies and result in a broad spectrum of disability. While nerve autografts are the current gold standard for the reconstruction of extensive nerve damage, the limited supply of autologous nerve and complications associated with harvesting nerve from a second surgical site has driven groups from multiple disciplines, including biomedical engineering, neurosurgery, plastic surgery, and orthopedic surgery, to develop a suitable or superior alternative to autografting. Over the last couple of decades, various types of scaffolds, such as acellular nerve grafts（ANGs）, nerve guidance conduits, and non-nervous tissues, have been filled with Schwann cells, stem cells, and/or neurotrophic factors to develop tissue engineered nerve grafts（TENGs）. Although these have shown promising effects on peripheral nerve regeneration in experimental models, the autograft has remained the gold standard for large nerve gaps. This review provides a discussion of recent advances in the development of TENGs and their efficacy in experimental models. Specifically, TENGs have been enhanced via incorporation of genetically engineered cells, methods to improve stem cell survival and differentiation, optimized delivery of neurotrophic factors via drug delivery systems（DDS）, co-administration of platelet-rich plasma（PRP）, and pretreatment with chondroitinase ABC（Ch-ABC）. Other notable advancements include conduits that have been bioengineered to mimic native nerve structure via cell-derived extracellular matrix（ECM） deposition, and the development of transplantable living nervous tissue constructs from rat and human dorsal root ganglia（DRG） neurons. Grafts composed of non-nervous tissues, such as vein, artery, and muscle, will be briefly discussed.

Construction of tissue-engineered vascular grafts with enhanced patency by integrating heparin,cell-adhesive peptide,and carbon monoxide nanogenerators into acellular blood vessels

Small-diameter tissue-engineered vascular grafts(sdTEVGs)have garnered significant attention as a potential treatment modality for vascular bypass grafting and replacement therapy.However,the intimal hyperplasia and thrombosis are two major complications that impair graft patency during transplantation.To address this issue,we fabricated the covalent-organic framework(COF)-based carbon monoxide(CO)nanogenerator-and co-immobilized with LXW-7 peptide and heparin to establish a multifunctional surface on TEVGs constructed from acellular blood vessels for preventing thrombosis and stenosis.The cell-adhesive peptide LXW-7 could capture endothelial-forming cells(EFCs)to promote endothelialization,while the antithrombotic molecule heparin prevented thrombus formation.The reactive oxygen species(ROS)-triggered CO release suppressed the adhesion and activation of macrophages,leading to the reduction of ROS and inflammatory factors.As a result,the endothelial-to-mesenchymal transition(EndMT)triggered by inflammation was restricted,facilitating the maintenance of the homeostasis of the neo-endothelium and preventing pathological remodeling in TEVGs.When transplanted in vivo,these vascular grafts exhibited negligible intimal hyperplasia and remained patent for 3 months.This achievement provided a novel approach for constructing antithrombotic and anti-hyperplastic TEVGs.

Advances in the differentiation of pluripotent stem cells into vascular cells

Blood vessels constitute a closed pipe system distributed throughout the body,transporting blood from the heart to other organs and delivering metabolic waste products back to the lungs and kidneys.Changes in blood vessels are related to many disorders like stroke,myocardial infarction,aneurysm,and diabetes,which are important causes of death worldwide.Translational research for new appro-aches to disease modeling and effective treatment is needed due to the huge socio-economic burden on healthcare systems.Although mice or rats have been widely used,applying data from animal studies to human-specific vascular physiology and pathology is difficult.The rise of induced pluripotent stem cells(iPSCs)provides a reliable in vitro resource for disease modeling,regenerative medicine,and drug discovery because they carry all human genetic information and have the ability to directionally differentiate into any type of human cells.This review summarizes the latest progress from the establishment of iPSCs,the strategies for differentiating iPSCs into vascular cells,and the in vivo trans-plantation of these vascular derivatives.It also introduces the application of these technologies in disease modeling,drug screening,and regenerative medicine.Additionally,the application of high-tech tools,such as omics analysis and high-throughput sequencing,in this field is reviewed.

Chitosan/PLGA-based tissue engineered nerve grafts with SKP-SC-EVs enhance sciatic nerve regeneration in dogs through miR-30b-5p-mediated regulation of axon growth

Extracellular vesicles from skin-derived precursor Schwann cells(SKP-SC-EVs)promote neurite outgrowth in culture and enhance peripheral nerve regeneration in rats.This study aimed at expanding the application of SKPSC-EVs in nerve grafting by creating a chitosan/PLGA-based,SKP-SC-EVs-containing tissue engineered nerve graft(TENG)to bridge a 40-mm long sciatic nerve defect in dogs.SKP-SC-EVs contained in TENGs significantly accelerated the recovery of hind limb motor and electrophysiological functions,supported the outgrowth and myelination of regenerated axons,and alleviated the denervation-induced atrophy of target muscles in dogs.To clarify the underlying molecular mechanism,we observed that SKP-SC-EVs were rich in a variety of miRNAs linked to the axon growth of neurons,and miR-30b-5p was the most important among others.We further noted that miR-30b-5p contained within SKP-SC-EVs exerted nerve regeneration-promoting effects by targeting the Sin3a/HDAC complex and activating the phosphorylation of ERK,STAT3 or CREB.Our findings suggested that SKP-SC-EVs-incorporating TENGs represent a novel type of bioactive material with potential application for peripheral nerve repair in the clinic.

Micro-compound tissue grafting for repairing linear scars

This study explored the clinical application and therapeutic effect of micro-compound tissue grafting(MCTG)for linear scars.In February 2019,one patient received MCTG treatment and the recovery at 20 months postoperative was observed.The patient was completely satisfied with the results.The MCTG technique is simple and reliable and can significantly improve scar appearance.This technique may be an effective method for treating linear scars,but it requires further validation in large samples.

Fracture of ossified Achilles tendons:A review of cases

Fracture of an ossification of the Achilles tendon(OAT)is a rare entity,and its etiology,pathology,and treatment remain unclear.We reviewed and scrutinized 18 cases(16 articles)of the fracture of an OAT.The most common etiologies of the ossifications include previous surgery and trauma.The fractures often occur without any trigger or with minimal trigger.The long,>5 cm,ossification in the body of the Achilles tendon may have a higher risk of fracture.The OAT itself is often asymptomatic;however,its fracture causes severe local pain,swelling,and weakness of plantar flexion,which forces patients to undergo aggressive treatments.Regarding the treatments of the fractures,nonoperative treatment by immobilizing ankle joint could be an option for elderly patients.However,because it often cannot produce satisfactory results in younger patients,surgical treatment is typically recommended.Excision of the fractured mass and repairing the tendon is applicable if the remnant is enough.If there is a defect after the excision,reconstruction with autologous grafts or adjacent tendon transfer is performed.Gastrocnemius fascia turndown flap,hamstring tendon and tensor fascia lata are used as autologous grafts,whereas peroneus brevis and flexor hallucis longus tendons are used for the tendon transfer.If the fracture of an OAT is treated properly,the functional result will be satisfactory.

Enhanced critical-sized bone defect repair efficiency by combining deproteinized antler cancellous bone and autologous BMSCs

Previously we have demonstrated that calcinated antler cancellous bone（CACB） has great potential for bone defect repair,due to its highly similar composition and architecture to natural extracellular bone matrix.This study is aiming at seeking for an optimal strategy of combined application of CACB and bone marrow mesenchymal stem cells（BMSCs） in bone defect repair.In vitro study demonstrated that CACB promoted the adhesion,spreading and viability of BMSCs.Increased extracellular matrix production and expression of osteogenic markers in BMSCs were observed when seeded on CACB scaffolds.The cells ceased to proliferation in the dual effect of CACB and osteogenic induction at the early stage of incubation.Hence synergistic effect of CACB combined with autologous undifferentiated BMSCs in rabbit mandible critical-sized defect repair was further evaluated.Histological analysis results showed that loading the CACB with autologous BMSCs resulted in enhanced new bone formation and angiogenesis when compared with implanted CACB alone.These findings indicate that the combination of CACB and autologous BMSCs should become potential routes to improve bone repair efficiency