Repairing peripheral nerve injury using tissue engineering techniques

Each year approximately 360,000 people in the United States suffer a peripheral nerve injury （PNI）, which is a leading source of lifelong disability （Kelsey et al., 1997; Noble et al., 1998）. The most frequent cause of PNIs is motor vehicle accidents, while gunshot wounds, stabbings, and birth trauma are also common factors. Patients suffering from disabilities as a result of their PNIs are also burdensome to the healthcare system, with aver- age hospital stays of 28 days each year （Kelsey et al., 1997; Noble et al., 1998）.

Lower rotating point nutrient vessels of sural nerve flap with distant pedicled repairing soft tissue defect of foot and ankle

To explore lower rotating potint nutrient vessels of sural nerve flap with distant pedicled repairing the soft tissue defect of foot and ankle.Methods Lay a foundation of anatomic studying from february 2003 to March 2004,using lower rotating point nutrient vessels of sural nerve flap with distant pedicled repairing the soft tissue defect of foot and ankle in 11 cases.Cause of injuring:traffic accident 7 cases,crushing 1 case,saw injury 1 case,skin cancer 1 case,chronic ulcer 1 case.Areas:foot heel 6 cases,shank lower section 2 cases,heel tendon 2 cases,the distant back of the foot 1 case.Using the flap axis point was 1～3 cm above the pin of the external heel,average 2 cm.The scope of the flap was 6.0 cm×8.0 cm～12.0 cm～18.0 cm.Results All sural nerve flaps were alive.Of them,2 cases have distant part necrosis,accompanying with subcutaneous tissue,1 case heels after change dressings,another heels after skin grafting.All case can walk as usual,the flap was wear-resisting and keenly feel.Conclusion Lower rotating point nutrient vessels of sural nerve flap,donner area was fine,available area was large,skin in the pink,easy grafting,without main blood vessel damage,survival rate high,it is a good donner area in repairing around heel,foot and shank lower section.7 refs,1 tab.

Mesenchymal stem cells： a new strategy for immunosuppression and tissue repair

Mesenchymal stem cells （MSCs） have great potential for treating various diseases, especially those related to tissue damage involving immune reactions. Various studies have demonstrated that MSCs are strongly immunosuppressive in vitro and in vivo. Our recent studies have shown that un-stimulated MSCs are indeed incapable of immunosuppression; they become potently immunosuppressive upon stimulation with the supernatant of activated lymphocytes, or with combinations of IFN-γ, with TNF-α, IL-1α or IL-1β. This observation revealed that under certain circumstances, inflammatory cytokines can actually become immunosuppressive. We showed that there is a species variation in the mechanisms of MSC-mediated immunosuppression： immunosuppression by cytokine-primed mouse MSCs is mediated by nitric oxide （NO）, whereas immunosuppression by cytokine-primed human MSCs is executed through indoleamine 2, 3-dioxygenase （IDO）. Additionally, upon stimulation with the inflammatory cytokines, both mouse and human MSCs secrete several leukocyte chemokines that apparently serve to attract immune cells into the proximity with MSCs, where NO or IDO is predicted to be most active. Therefore, immunosuppression by inflammatory cytokine-stimulated MSCs occurs via the concerted action of chemokines and immune-inhibitory NO or IDO produced by MSCs. Thus, our results provide novel information about the mechanisms of MSC-mediated immunosuppression and for better application of MSCs in treating tissue injuries induced by immune responses.

Repair cell first,then regenerate the tissues and organs

Wound healing,tissue repair and regenerative medicine are in great demand,and great achievements in these fields have been made.The traditional strategy of tissue repair and regeneration has focused on the level of tissues and organs directly;however,the basic process of repair at the cell level is often neglected.Because the cell is the basic unit of organism structure and function;cell damage is caused first by ischemia or ischemia-reperfusion after severe trauma and injury.Then,damage to tissues and organs occurs with massive cell damage,apoptosis and even cell death.Thus,how to achieve the aim of perfect repair and regeneration?The basic process of tissue or organ repair and regeneration should involve repair of cells first,then tissues and organs.In this manuscript,it is my consideration about how to repair the cell first,then regenerate the tissues and organs.

Role of endogenous Schwann cells in tissue repair after spinal cord injury

Schwann cells are glial cells of peripheral nervous system, responsible for axonal myelination and ensheathing, as well as tissue repair following a peripheral nervous system injury. They are one of several cell types that are widely studied and most commonly used for cell transplantation to treat spinal cord injury, due to their intrinsic characteristics including the ability to secrete a variety of neurotrophic factors. This mini review summarizes the recent findings of endogenous Schwann cells after spinal cord injury and discusses their role in tissue repair and axonal regeneration. After spinal cord injury, numerous endogenous Schwann cells migrate into the lesion site from the nerve roots, involving in the construction of newly formed repaired tissue and axonal myelination. These invading Schwann cells also can move a long distance away from the injury site both rostrally and caudally. In addition, Schwann cells can be induced to migrate by minimal insults （such as scar ablation） within the spinal cord and integrate with astrocytes under certain circumstances. More importantly, the host Schwann cells can be induced to migrate into spinal cord by transplantation of different cell types, such as exogenous Schwann cells, olfactory ensheathing cells, and bone marrow-derived stromal stem cells. Migration of endogenous Schwann cells following spinal cord injury is a common natural phenomenon found both in animal and human, and the myelination by Schwann cells has been examined effective in signal conduction electrophysiologically. Therefore, if the inherent properties of endogenous Schwann cells could be developed and utilized, it would offer a new avenue for the restoration of injured spinal cord.

New native tissue repair for pelvic organ prolapse:Medium-term outcomes of laparoscopic vaginal stump-round ligament fixation

BACKGROUND Laparoscopic sacrocolpopexy for pelvic organ prolapse(POP)is a new and widely used approach;however,ever since the United States Food and Drug Administration warned against the use of surgical mesh,repairs performed using patients’tissues[i.e.native tissue repair(NTR)]instead of mesh have attracted much attention.At our hospital,laparoscopic sacrocolpopexy(the Shull method)was introduced in 2017.However,patients with more severe POP who have a long vaginal canal and overextended uterosacral ligaments may not be candidates for this procedure.AIM To validate a new NTR treatment for POP,we examined patients undergoing laparoscopic vaginal stump–round ligament fixation(the Kakinuma method).METHODS The study patients were 30 individuals with POP who underwent surgery using the Kakinuma method between January 2020 and December 2021 and who were followed up for>12 mo after surgery.We retrospectively examined surgical outcomes for surgery duration,blood loss,intraoperative complications,and incidence of recurrence.The Kakinuma method involves round ligament suturing and fixation on both sides,effectively lifting the vaginal stump after laparoscopic hysterectomy.RESULTS The patients’mean age was 66.5±9.1(45-82)years,gravidity was 3.1±1.4(2-7),parity was 2.5±0.6(2-4)times,and body mass index was 24.5±3.3(20.9-32.8)kg/m2.According to the POP quantification stage classification,there were 8 patients with stage Ⅱ,11 with stage Ⅲ,and 11 with stage Ⅳ.The mean surgery duration was 113.4±22.6(88-148)min,and the mean blood loss was 26.5±39.7(10-150)mL.There were no perioperative complications.None of the patients exhibited reduced activities of daily living or cognitive impairment after hospital discharge.No cases of POP recurrence were observed 12 mo after the operation.CONCLUSION The Kakinuma method,similar to conventional NTR,may be an effective treatment for POP.

Extracellular matrix based biomaterials for central nervous system tissue repair: the benefits and drawbacks

Functional repair of injured tissue in the adult central nervous system （CNS） still remains a big challenge for current biomed- ical research and its upcoming clinical translation. The axonal regeneration of the adult CNS is generally low, and it is addi- tionally restricted after injury by the presence of inhibitory mol- ecules, generated by the glial scar.

Self-healing hydrogel for tissue repair in the central nervous system

Neurological disorders are diseases of the central and peripheral nervous systems.These disorders include Alzheimer＇s disease,epilepsy,brain tumor,and cerebrovascular diseases（stroke,migraine and other headache disorders,multiple sclerosis,Parkinson＇s disease,and neuroinfections）.

Analysis of the Cicatricial Acceleration Method (MAC®) in Skin Repair in Wistar Rattus norvegicus with Induced Chemical Burns

Introduction: The cicatricial acceleration method (MAC®) promotes photobiological effects of an anti-inflammatory and healing nature. Its therapeutic radiation is emitted, producing photobiostimulant effects that result in rapid tissue repair and better tissue quality. The treatment of burns has always been a challenge, which involves both performing surgery and controlling and guiding scar regeneration, avoiding possible morbidities. Objective: To evaluate the effects of applying the MAC methodology with an AlGa (aluminum, gallium arsenide) laser on the time and quality of tissue repair in the skin of rats after induced chemical burns. Method: 22 adult male rats were subjected to a second-degree chemical burn on the back using 50% trichloroacetic acid. After the burns, the animals were randomly separated into 2 groups: control and experimental. The control group (G1) received placebo laser therapy and the laser group (G2) underwent laser irradiation with an energy density of 100 J/cm2. Histological analysis and macroscopic evaluation were carried out by means of the paper template method. Results: Group G1 showed (53%) of the necrosis area and group G2 showed (11%) necrosis area. Conclusion: The cicatricial acceleration method (MAC®) favored the repair of wounds caused by a 2nd-degree chemical burn, optimizing time and improving quality.

Developing fibrin-based biomaterials/scaffolds in tissue engineering

Tissue engineering technology has advanced rapidly in recent years, offering opportunities to construct biologicallyactive tissues or organ substitutes to repair or even enhance the functions of diseased tissues and organs.Tissue-engineered scaffolds rebuild the extracellular microenvironment by mimicking the extracellular matrix.Fibrin-based scaffolds possess numerous advantages, including hemostasis, high biocompatibility, and gooddegradability. Fibrin scaffolds provide an initial matrix that facilitates cell migration, differentiation, proliferation,and adhesion, and also play a critical role in cell-matrix interactions. Fibrin scaffolds are now widelyrecognized as a key component in tissue engineering, where they can facilitate tissue and organ defect repair.This review introduces the properties of fibrin, including its composition, structure, and biology. In addition, themodification and cross-linking modes of fibrin are discussed, along with various forms commonly used in tissueengineering. We also describe the biofunctionalization of fibrin. This review provides a detailed overview of theuse and applications of fibrin in skin, bone, and nervous tissues, and provides novel insights into future researchdirections for clinical treatment.

L-arginine loading porous PEEK promotes percutaneous tissue repairthrough macrophage orchestration

Infection and poor tissue repair are the key causes of percutaneous implantation failure. However, there is a lackof effective strategies to cope with due to its high requirements of sterilization, soft tissue healing, andosseointegration. In this work, L-arginine (L-Arg) was loaded onto a sulfonated polyetheretherketone (PEEK)surface to solve this issue. Under the infection condition, nitric oxide (NO) and reactive oxygen species (ROS) areproduced through catalyzing L-Arg by inducible nitric oxide synthase (iNOS) and thus play a role in bacteriasterilization. Under the tissue repair condition, L-Arg is catalyzed to ornithine by Arginase-1 (Arg-1), whichpromotes the proliferation and collagen secretion of L929 and rBMSCs. Notably, L-Arg loading samples couldpolarize macrophages to M1 and M2 in infection and tissue repair conditions, respectively. The results in vivoshow that the L-Arg loading samples could enhance infected soft tissue sealing and bone regeneration. Insummary, L-Arg loading sulfonated PEEK could polarize macrophage through metabolic reprogramming,providing multi-functions of antibacterial abilities, soft tissue repair, and bone regeneration, which gives a newidea to design percutaneous implantation materials.

Contribution of TLR signaling to the pathogenesis of colitisassociated cancer in inflammatory bowel disease

In the intestine a balance between proinflammatory and repair signals of the immune system is essential for the maintenance of intestinal homeostasis. The innate immunity ensures a primary host response to microbial invasion, which induces an inflammatory process to localize the infection and prevent systemic dissemination of pathogens. The key elements of this process are the germline encoded pattern recognition receptors including Toll-like receptors (TLRs). If pathogens cannot be eliminated, they may elicit chronic inflammation, which may be partly mediated via TLRs. Additionally, chronic inflammation has long been suggested to trigger tissue tumorous transformation. Inflammation, the seventh hallmark of cancer, may affect all phases of tumor development, and evade the immune system. Inflammation acts as a cellular stressor and may trigger DNA damage or genetic instability. Furthermore, chronic inflammation can provoke genetic mutations and epigenetic mechanisms that promote malignant cell transformation. Colorectal cancers in inflammatory bowel disease patients are considered typical examples of inflammation-related cancers. Although data regarding the role of TLRs in the pathomechanism of cancer-associated colitis are rather conflicting, functionally these molecules can be classified as ”largely antitumorigenic” and ”largely pro-tumorigenic” with the caveat that the underlying signaling pathways are mainly context (i.e., organ-, tissue-, cell-) and ligand-dependent.

The use of hydrogel-delivered extracellular vesicles in recovery of motor function in stroke:a testable experimental hypothesis for clinical translation including behavioral and neuroimaging assessment approaches

Neural tissue engineering,nanotechnology and neuroregeneration are diverse biomedical disciplines that have been working together in recent decades to solve the complex problems linked to central nervous system(CNS)repair.It is known that the CNS demonstrates a very limited regenerative capacity because of a microenvironment that impedes effective regenerative processes,making development of CNS therapeutics challenging.Given the high prevalence of CNS conditions such as stroke that damage the brain and place a severe burden on afflicted individuals and on society,it is of utmost significance to explore the optimum methodologies for finding treatments that could be applied to humans for restoration of function to pre-injury levels.Extracellular vesicles(EVs),also known as exosomes,when derived from mesenchymal stem cells,are one of the most promising approaches that have been attempted thus far,as EVs deliver factors that stimulate recovery by acting at the nanoscale level on intercellular communication while avoiding the risks linked to stem cell transplantation.At the same time,advances in tissue engineering and regenerative medicine have offered the potential of using hydrogels as bio-scaffolds in order to provide the stroma required for neural repair to occur,as well as the release of biomolecules facilitating or inducing the reparative processes.This review introduces a novel experimental hypothesis regarding the benefits that could be offered if EVs were to be combined with biocompatible injectable hydrogels.The rationale behind this hypothesis is presented,analyzing how a hydrogel might prolong the retention of EVs and maximize the localized benefit to the brain.This sustained delivery of EVs would be coupled with essential guidance cues and structural support from the hydrogel until neural tissue remodeling and regeneration occur.Finally,the importance of including nonhuman primate models in the clinical translation pipeline,as well as the added benefit of multi-modal neuroimaging analysis to establish non-invasive,in vivo,quantifiable imagingbased biomarkers for CNS repair are discussed,aiming for more effective and safe clinical translation of such regenerative therapies to humans.

Review of the potential of mesenchymal stem cells for the treatment of infectious diseases

The therapeutic value of mesenchymal stem cells (MSCs) for the treatment of infectious diseases and the repair of disease-induced tissue damage has been explored extensively. MSCs inhibit inflammation, reduce pathogen load and tissue damage encountered during infectious diseases through the secretion of antimicrobial factors for pathogen clearance and they phagocytose certain bacteria themselves. MSCs dampen tissue damage during infection by downregulating thelevels of pro-inflammatory cytokines, and inhibiting the excessive recruitment ofneutrophils and proliferation of T cells at the site of injury. MSCs aid in theregeneration of damaged tissue by differentiating into the damaged cell types orby releasing paracrine factors that direct tissue regeneration, differentiation, andwound healing. In this review, we discuss in detail the various mechanisms bywhich MSCs help combat pathogens, tissue damage associated with infectiousdiseases, and challenges in utilizing MSCs for therapy.

Active Achilles tendon kinesitherapy accelerates Achilles tendon repair by promoting neurite regeneration

Active Achilles tendon kinesitherapy facilitates the functional recovery of a ruptured Achilles tendon However, protein expression during the healing process remains a controversial issue. New Zealand rabbits, aged 14 weeks, underwent tenotomy followed immediately byAchilles tendon microsurgery to repair the Achilles tendon rupture. The tendon was then immobilized or subjected to postoperative early motion treatment （kinesitherapy）. Mass spectrography results showed that after 14 days of motion treatment, 18 protein spots were differentially expressed, among which, 12 were up-regulated, consisting of gelsolin isoform b and neurite growth-related protein collapsing response mediator protein 2. Western blot analysis showed that gelsolin isoform b was up-regulated at days 7-21 of motion treatment. These findings suggest that active Achilles tendon kinesitherapy promotes the neurite regeneration of a ruptured Achilles tendon and gelsolin isoform b can be used as a biomarker for Achilles tendon healing after kinesitherapy.

Oscillating field stimulation promotes neurogenesis of neural stem cells through miR-124/Tal1 axis to repair spinal cord injury in rats

Spinal cord injury often leads to severe motor and sensory deficits,and prognosis using the currently available therapies remains poor.Therefore,we aimed to explore a novel therapeutic approach for improving the prognosis of spinal cord injury.In this study,we implanted oscillating field stimulation devices and transplanted neural stem cells into the thoracic region(T9–T10)of rats with a spinal cord contusion.Basso-Beattie-Bresnahan scoring revealed that oscillating field stimulation combined with neural stem cells transplantation promoted motor function recovery following spinal cord injury.In addition,we investigated the regulation of oscillating field stimulation on the miR-124/Tal1 axis in neural stem cells.Transfection of lentivirus was performed to investigate the role of Tal1 in neurogenesis of neural stem cells induced by oscillating field stimulation.Quantitative reverse transcription-polymerase chain reaction,immunofluorescence and western blotting showed that oscillating field stimulation promoted neurogenesis of neural stem cells in vitro and in vivo.Hematoxylin and eosin staining showed that oscillating field stimulation combined with neural stem cells transplantation alleviated cavities formation after spinal cord injury.Taking the results together,we concluded that oscillating field stimulation decreased miR-124 expression and increased Tal1 content,thereby promoting the neurogenesis of neural stem cells.The combination of oscillating field stimulation and neural stem cells transplantation improved neurogenesis,and thereby promoted structural and functional recovery after spinal cord injury.

A Systematic Review of Animal and Clinical Studies on the Use of Scaffolds for Urethral Repair

Replacing urethral tissue with functional scaffolds has been one of the challenging problems in the field of urethra reconstruction or repair over the last several decades. Various scaffold materials have been used in animal studies, but clinical studies on use of scaffolds for urethral repair are scarce. The aim of this study was to review recent animal and clinical studies on the use of different scaffolds for urethral repair, and to evaluate these scaffolds based on the evidence from these studies. Pub Med and OVID databases were searched to identify relevant studies, in conjunction with further manual search. Studies that met the inclusion criteria were systematically evaluated. Of 555 identified studies, 38 were included for analysis. It was found that in both animal and clinical studies, scaffolds seeded with cells were used for repair of large segmental defects of the urethra, such as in tubular urethroplasty. When the defect area was small, cell-free scaffolds were more likely to be applied. A lot of pre-clinical and limited clinical evidence showed that natural or artificial materials could be used as scaffolds for urethral repair. Urinary tissue engineering is still in the immature stage, and the safety, efficacy, cost-effectiveness of the scaffolds are needed for further study.

Cartilage oligomeric matrix protein enhances the vascularization of acellular nerves

Vascularization of acellular nerves has been shown to contribute to nerve bridging.In this study,we used a 10-mm sciatic nerve defect model in rats to determine whether cartilage oligomeric matrix protein enhances the vascularization of injured acellular nerves.The rat nerve defects were treated with acellular nerve grafting（control group） alone or acellular nerve grafting combined with intraperitoneal injection of cartilage oligomeric matrix protein（experimental group）.As shown through two-dimensional imaging,the vessels began to invade into the acellular nerve graft from both anastomotic ends at day 7 post-operation,and gradually covered the entire graft at day 21.The vascular density,vascular area,and the velocity of revascularization in the experimental group were all higher than those in the control group.These results indicate that cartilage oligomeric matrix protein enhances the vascularization of acellular nerves.

Current status and prospects of basic research and clinical application of mesenchymal stem cells in acute respiratory distress syndrome

Acute respiratory distress syndrome(ARDS)is a common and clinically devastating disease that causes respiratory failure.Morbidity and mortality of patients in intensive care units are stubbornly high,and various complications severely affect the quality of life of survivors.The pathophysiology of ARDS includes increased alveolar–capillary membrane permeability,an influx of protein-rich pulmonary edema fluid,and surfactant dysfunction leading to severe hypoxemia.At present,the main treatment for ARDS is mechanical treatment combined with diuretics to reduce pulmonary edema,which primarily improves symptoms,but the prognosis of patients with ARDS is still very poor.Mesenchymal stem cells(MSCs)are stromal cells that possess the capacity to self-renew and also exhibit multilineage differentiation.MSCs can be isolated from a variety of tissues,such as the umbilical cord,endometrial polyps,menstrual blood,bone marrow,and adipose tissues.Studies have confirmed the critical healing and immunomodulatory properties of MSCs in the treatment of a variety of diseases.Recently,the potential of stem cells in treating ARDS has been explored via basic research and clinical trials.The efficacy of MSCs has been shown in a variety of in vivo models of ARDS,reducing bacterial pneumonia and ischemia-reperfusion injury while promoting the repair of ventilator-induced lung injury.This article reviews the current basic research findings and clinical applications of MSCs in the treatment of ARDS in order to emphasize the clinical prospects of MSCs.

Therapeutic nucleic acids in regenerative medicine and tissue repair

In the vanguard of biomedical innovation,regenerative medicine emerges as a transformative paradigm,concentrating its efforts on rectifying tissue deficits and functional aberrations in patients through the strategic augmentation of endogenous cellular processes.Central to this approach is nucleic acid therapy,which offers a novel pathway for tissue regeneration by modulating key signaling pathways.As one of the most effective ways to regulate cell function,nucleic acids are crucial for various tissue regeneration;however,their in vivo therapeutic applications face substantial challenges,including nuclease degradation,cell membrane impermeability,and targeted intracellular transport.Biomaterial-based gene delivery systems offer a solution for stable and localized drug delivery by enabling the controlled overexpression of therapeutic nucleic acids,producing functional regulatory agents.This review presents examples of nucleic acid applications in regenerative medicine,highlighting the synergy between nucleic acids and biomaterial technologies.It underlines the importance of nucleic acid delivery techniques,the choice of therapeutic nucleic acids,and biomaterials for advancing tissue repair.The latest developments in designing nucleic acid biomaterial-based delivery vehicles are explored,the mechanism of nucleic acids in tissue regeneration is elucidated,and their limitations are discussed while considering future directions for the clinical translation of nucleic acid-based therapeutics.