Targeting gut microbial nitrogen recycling and cellular uptake of ammonium to improve bortezomib resistance in multiple myeloma.

The gut microbiome has been found to play a crucial role in the treatment of multiple myeloma (MM), which is still considered incurable due to drug resistance. In previous studies, we demonstrated that intestinal nitrogen-recycling bacteria are enriched in patients with MM. However, their role in MM relapse remains unclear. This study highlights the specific enrichment of Citrobacter freundii (C. freundii) in patients with relapsed MM. Through fecal microbial transplantation experiments, we demonstrate that C. freundii plays a critical role in inducing drug resistance in MM by increasing levels of circulating ammonium. The ammonium enters MM cells through the transmembrane channel protein SLC12A2, promoting chromosomal instability and drug resistance by stabilizing the NEK2 protein. We show that furosemide sodium, a loop diuretic, downregulates SLC12A2, thereby inhibiting ammonium uptake by MM cells and improving progression-free survival and curative effect scores. These findings provide new therapeutic targets and strategies for the intervention of MM progression and drug resistance.

ODAD1 variants resulting from splice-site mutations retain partial function and cause primary ciliary dyskinesia with outer dynein arm defects.

Primary ciliary dyskinesia (PCD) is a genetically heterogeneous disorder caused by defects in motile ciliary function and/or structure. Outer dynein arm docking complex subunit 1 (ODAD1) is an important component of the outer dynein arm docking complex (ODA-DC). To date, 13 likely pathogenic mutations of ODAD1 have been reported. However, the pathogenesis of ODAD1 mutations remains elusive. To investigate the pathogenesis of splice-site mutations in ODAD1 discovered in this study and those reported previously, molecular and functional analyses were performed. Whole-exome sequencing revealed a compound mutation in ODAD1 (c.71-2A>C; c.598-2A>C) in a patient with PCD, with c.598-2A>C being a novel mutation that resulted in two mutant transcripts. The compound mutation in ODAD1 (c.71-2A>C; c.598-2A>C) led to aberrant splicing that resulted in the absence of the wild-type ODAD1 and defects of the outer dynein arm in ciliary axonemes, causing a decrease in ciliary beat frequency. Furthermore, we demonstrated that the truncated proteins resulting from splice-site mutations in ODAD1 could retain partial function and inhibit the interaction between wild-type ODAD1 and ODAD3. The results of this study expand the mutational and clinical spectrum of PCD, provide more evidence for genetic counseling, and offer new insights into gene-based therapeutic strategies for PCD.

Localized Giant Cell Tumor of the Tendon Sheath of the Upper Cervical Spine: A Case Report.

Introduction: Giant cell tumor of the tendon sheath (GCTTS) is commonly seen in the appendicular skeleton, and rarely arises from the axial skeleton. We describe a rare case of GCTTS in an adolescent in the upper cervical spine. Case Presentation: A previously healthy 16-year-old boy presented with a 6-month history of numbness of right upper extremity, and had experienced a neck pain 4 months ago. Spinal MRI demonstrated a small syrinx at C2 level and a well-circumscribed extradural mass with contrast enhancement extending from the posterior arch of C1 to C2. The extradural mass was totally resected, and the syrinx underwent clinical and imaging surveillance. Discussion: GCTTS should be considered in the differential diagnosis of the axial skeletal lesion although very rare. Gross-total resection is advocated in GCTTS of the upper cervical spine, and subtotal resection with meticulous lesion monitoring should be performed in unresectable cases.

[Three-Dimensional Nonlinear Finite Element Modeling and Analysis of Concomitant Atlanto-Occipital Fusion and Atlantoaxial Joint Dislocation].

OBJECTIVE: To establish, with finite element technology, a three-dimensional nonlinear finite element model of the normal occipital bone, atlas and axis and a three-dimensional nonlinear finite element model of concomitant atlanto-occipital fusion and atlantoaxial dislocation, providing a biomechanical method for clinical research on the upper cervical spine. METHODS: Finite element analysis was conducted with the CT data of a 27-year-old male volunteer, and a three-dimensional nonlinear finite element model, i.e., the normal model, of the normal occipital bone, atlas and axis was established accordingly. Finite element analysis was conducted with the CT data of a 35-year-old male patient with concomitant atlanto-occipital fusion and atlantoaxial dislocation. Then, the ideal state of a simple ligament rupture under high load was generated by computer simulation, and a three-dimensional nonlinear finite element model of concomitant atlanto-occipital fusion and atlantoaxial dislocation was established, i.e., the atlanto-occipital fusion with atlantoaxial dislocation model. For both models, a vertical upward torque of 1.5 N·m was applied on the upper surface of the occipital bone. Through comparative analysis of the two models under stress, the data of the range of motion (ROM) for flexion, extension, lateral bending, and rotation were examined. In addition, stress and deformation analysis with 1.5 N·m torque load was conducted to validate the effectiveness of the two three-dimensional nonlinear finite element models established in the study. RESULTS: When the normal model established in the study was under 1.5 N·m torque load, it exhibited a maximum ROM for each unit of flexion, extension, and the ROM approximated the experimental measurement results of human mechanics, confirming the validity of the simulation. The stress and deformation results of the model were consistent with the basic principles of mechanics. The moment-angular displacement of the model showed obvious nonlinear characteristics. Compared with the normal model, the atlanto-occipital fusion with atlantoaxial dislocation model showed reduced ROM of the atlanto-occipital joint under a torque of 1.5 N·m, while the ROM of the C1-C2 joint for the four conditions of flexion, posterior extention, lateral bending, and rotation under load, with the exception of rotating motion, was greatly increased compared with that of the normal model, which was in line with the actual clinical performance of the patient. CONCLUSION: The atlanto-occipital fusion with atlantoaxial dislocation model and the three-dimensional nonlinear finite element model of the normal occipital bone, atlas and axis were successfully established by finite element technology. The models had valid simulation and reliable kinematic characteristics, and could be used as a reliable tool to simulate clinical diseases.

Lymphoplasmacyte-rich meningioma in the central nervous system: An unusual case report.

RATIONALE: Lymphoplasmacyte-rich meningioma (LPRM) is a rare meningioma characterized by significant infiltration of plasma cells and lymphocytes, and changes in the ratio of meningeal epithelial components. According to the World Health Organization, tumors of the central nervous system are classified as grade I tumors. PATIENT CONCERNS: A 44-year-old man presented to our department with complaints of limb weakness accompanied by hand numbness. Half a month before admission, the patient's limb weakness worsened and he could not walk and raise his hands, with limb sensory disturbance and incontinence. DIAGNOSIS: Magnetic resonance imaging of the head and cervical spinal cord showed a diffuse extramedullary mass creeping on the tentorium and skull base meninges along the clivus down to the sixth cervical spinal meninges. The cervical spinal cord was enveloped and pressed (Fig. 1A-C). Postoperative histopathological examination showed meningothelial areas admixed with lymphocytes and plasma cells (Fig. 2D-H), indicating that the mass was a LPRM. INTERVENTION: Suboccipital craniotomy, C1 laminectomy, and C2-C6 laminoplasty were performed for this patient, and postsurgical pathology showed that the tumor was a LPRM with large amounts of lymphocytes and plasma cells. OUTCOME: After 2 weeks of active treatment, the patient died of worsening pneumonia. LESSONS: LPRM is a rare variant of meningioma, and it is more unusual that the lesions involve the intracranial dura mater and the entire cervical spinal meninges. So far, surgical resection has been the main treatment for LPRM, but according to its own characteristics of lymphoplasmacyte-rich, immunotherapy may become a new treatment option.

Central nervous system hemangioblastomas: An age-stratified analysis.

BACKGROUND: Hemangioblastomas (HBs) are rare and understudied. The impact of age on clinical features, optimal treatment, and postoperative outcome in HBs has not been systemically studied. MATERIALS AND METHODS: We performed an institutional study in the West China Hospital, including patients diagnosed with hemangioblastomas between October 2011 and October 2016. Clinical data and surgical outcomes were compared among three different age groups (0-20, 21-59, and ≥ 60 years). We also studied surgical prognostic factors. RESULTS: 187 patients (102 males and 85 females) were identified. HBs in spinal locations were more prevalent in children and adolescents, while the most common site in young and old-age adults was the cerebellum (P = 0.023). Risk of Von Hippel-Lindau syndrome (VHL) was negatively correlated with patient age (P = 0.003). 47.6 % of patients aged 0-20, 23 % of patients aged 21-59, and 6.45 % of patients aged ≥60 years were diagnosed with VHL. Older aged patients had a significantly lower risk of VHL and had a lower tumor recurrence rate. Surgical resection was an adequate and sufficient procedure in all age groups with a favorable surgical outcome (P = 0.823). Solid tumor, VHL disease, and localization in the brainstem were associated with poor outcome in patients with hemangioblastomas. CONCLUSIONS: Our study showed that HBs in elderly patients were mostly included in the cerebellum and had a solid configuration and large size, while HBs in children were mainly localized in the spinal cord. VHL disease was more common in children and adolescents but rare in patients older than 60 years. The present study found no excess surgical mortality and risks for HBs in elderly patients or children than in younger adults.

Individualized management of giant anterior meningoceles-case series.

RATIONALE: Anterior spinal meningoceles are rare neuroanatomic abnormality formed by protrusion of the spinal meninges through a defect in the vertebral column. Presently, therapeutic options for anterior spinal meningoceles are still controversial. The objective of this study is to discuss the individualized management of giant anterior spinal meningoceles. PATIENT CONCERNS AND DIAGNOSES: We analyzed 4 patients with anterior spinal meningoceles between 2007 and 2014 in our department by retrospective chart review, two of whom were anterior sacral meningoceles (ASMs), and another2 were intrathoracic meningoceles (ITMs). INTERVENTIONS AND OUTCOMES: Patients mainly presented with compressive symptoms including rectal irritation, dyspnea (patient 3) and fixed neurologic deficits (patient 4). Three out of 4 patients received surgical treatment, one of which underwent reoperation. After surgery, meningoceles in 1 patient completely disappeared. Two patients acquired the stability of the size of the meningoceles. LESSONS: Management of anterior spinal meningoceles often requires precise treatment based on the different conditions of each patient. Surgical intervention has been proposed for the treatment of symptomatic anterior spinal meningoceles. The goal of surgery is to safely disconnect the linkage between the cyst and CSF from subarachnoid space to prevent further enlargement of the cyst or reaccumulating of cystic fluid.

Surgical Treatment of Scoliosis-Associated with Syringomyelia: The Role of Syrinx Size.

BACKGROUND: The treatment of the syrinx prior to correction of the scoliosis in syringomyelia-associated scoliosis (SMS) patients remains controversial. The aim of this study is to evaluate the role of the syrinx size in the management of SMS patients. MATERIALS AND METHODS: This was a retrospective study of 36 SMS patients. They were divided into 2 groups: Group A (26 with a small syrinx, syrinx(S)/spinal cord(C) ratio ≤0.7) and Group B (10 with a large syrinx, S/C ratio >0.7). Patients with a large syrinx accepted prophylactic neurosurgery prior to scoliosis surgery. They were evaluated at baseline, 1-week and last follow-up after correction surgery for changes in curve correction, global coronal balance, thoracic kyphosis (TK), sagittal vertical axis (SVA), and Scoliosis Research Society (SRS)-22 scores. RESULTS: The syrinx size of patients in Group A was significantly smaller than that of in Group B. The syrinx size was significantly decreased after prophylactic neurosurgery in Group B. The radiographic parameters of scoliosis at baseline, 1-week and last follow-up after scoliosis surgery were comparable between two groups. No abnormal signal was detected during the process of neuromonitoring in both groups. Pre- and postoperative SRS-22 scores were similar between two groups. CONCLUSIONS: Prophylactic neurosurgery may be beneficial for decreasing the risk of correction surgery in SMS patients with large syrinx (S/C ratio >0.7). After the intervention of syrinx prior to scoliosis correction, SMS patients with large syrinx could obtain similar clinical and radiographic outcomes of treatment with pedicle-screw-based spinal instrumentation and fusion compared to the patients with small syrinx.

[A Case Report of Ectopic Sweat Duct Ectasia of Conus Medullaris].

A healthy 52-year-old woman presented with 10-days history of back pain. Neurologic testing failed to detect any functional deficits in the upper and lower extremities, and the patient had a full range of cervical spine motion without associated pain. Spinal CT and MRI revealed a well-circumscribed intradural mass located at conus medullaris. The operation of L1 hemilaminectomy was performed, and pathological examination discovered dilatation of sweat ducts and suggested the diagnosis of ectopic sweat duct ectasia. IHC staining in epithelia immunophenotype showed: pan-cytokeratin (PCK)(+), epithelia membrane antigen (EMA)(+), P63(+), cytokeratin 5/6 (CK5/6)(+), gross cystic disease fluid protein 15 (GCDFP15)(-). Intraspinal ectopic sweat duct ectasia is extremely rare, which has not been reported in the literature to date.

Differential circular RNA expression profiles of invasive and non-invasive non-functioning pituitary adenomas: A microarray analysis.

Non-functioning pituitary adenomas (NFPAs) are the most common pituitary tumors, and some exhibit locally invasive or even clinically aggressive behavior. Circular RNAs (circRNAs) are a reinvented class of non-coding RNAs that play important roles in tumor initiation and progression.CircRNA microarray assays were performed in 4 invasive and 4 non-invasive NFPAs, and 4 typically differential expression circRNAs were selected for validation using quantitative reverse transcription-polymerase chain reaction. The diagnostic and prognostic values of tested cirRNAs were further evaluated. Bioinformatics analysis and a literature review of potential miRNAs targets involved in pituitary tumor invasion were performed.A specific circRNA expression profile was detected between invasive and non-invasive NFPAs, including 91 upregulated and 61 downregulated circRNAs in invasive tumors. The dysregulation of the 4 circRNAs has been confirmed. The expression of hsa_circRNA_102597, a downregulated circRNA, was significantly correlated with tumor diameter (P < .05) and Knosp grade (P < .01). Hsa_circRNA_102597 alone or in combined with Ki-67 index was able to accurately differentiate invasive from non-invasive NFPAs as well as predict tumor progression/recurrence. Fourteen aberrantly expressed circRNAs might be involved in the invasiveness of pituitary adenomas via seven predicted potential miRNA targets.CircRNAs are participated in pituitary tumor invasion, and may be used as novel diagnostic and prognostic biomarkers in NFPAs.

Systemic lupus erythematosus flare up as acute spinal subarachnoid hemorrhage with bilateral lower limb paralysis.

Subarachnoid hemorrhage (SAH) is an uncommon complication of systemic lupus erythematosus (SLE). Solitary association of fatal spinal SAH as a complication of SLE, has not been encountered much in literature although coexisting acute cerebral and spinal SAH have been associated with SLE. We present a 39-year old female with initial diagnosis of SLE eight years ago who suddenly developed a productive cough, acute abdomen and paralysis of the lower limbs. Magnetic resonance imaging of the spine revealed thoracic spinal SAH with varying degrees of thoracic spinal cord compression. The hemorrhage was total evacuated via surgery. She regained normal function of her lower limbers after the operation with no further neurological complications. One of the rare but fatal complications of SLE is solitary spinal SAH without cranial involvement. The best and most appropriate management of this kind of presentation is surgical decompression of the hematoma with total hemostasis. The cause of hemorrhage should be identified intra-operatively and treated appropriately.

Spinal extradural angiolipoma: a report of two cases and review of literature.

Spinal extradural angiolipomas (SEALs) are extremely extraordinary benign extradural lesions. They are infrequently encountered in normal clinical practice although several authors have report single cases or case series. We present two cases of SEAL which we successfully surgical resected with no further neurological deficits. Our cases comprise of a male and a female with ages ranging from 30 to 60 years. Their principal presenting complains were numbness and pain at the lower extremity with associated fecal and urinary incontinence. In all our cases, MRI revealed extradural spinal lesions that exerted compressive effect on the spinal cord. The male patient had an infiltrating type while the female had non-infiltrating type. We attained total resection in both cases without any further neurological complication. The diagnosis of SEALs initially can be challenging radiologically since they may mimic other spinal lesions. The gold standard treatment modality should always be surgery although total resection may not be achievable in some cases.

An infantile alantoaxial dislocation with patent foramen ovale managed with titanium cabling and allogenic bone grafts.

Atlantoaxial dislocation is a disorder that is characterized with loss of stability of the atlas and axis (C1-C2) with consequential loss of usual articulation. Although this condition is very common, no one has reported a case as young as our patients. We present a 7-month infant with bilateral paralysis of the lower limbs for four (4) months with no history of trauma. Computer tomographic (CT-scan) imaging revealed alantoaxial dislocation with severe cervical spinal cord compression. The odontoid process is displaced outwardly with no bone destruction. Doppler echocardiogram done revealed patent foramen ovale. Thorough physical examination as well as radiological evaluation revealed no feather malformations. Electrophysio - logical studies reveal normal compound muscle action potentials (CMAP) and sensory nerve action potentials (SNAPs) in all the limbs. Electromyography (EMG) also revealed normal nerves in the limbs and the trunk. We attained a stable fusion and anatomical reduction using a posterior titanium wire and an iliac bone graft harvested from his mother. This is the youngest patient reported in literature. Infantile alantoaxial dislocation should be managed at early stage to prevent long-term neurologic disorders.

Thoracolumbar spinal neurenteric cyst with tethered cord syndrome and extreme cervical lordosis in a child: A case report and literature review.

RATIONALE: Neurenteric cysts, are rare benign tumors of the central nervous system that are mostly located in the spinal cord and predominantly seen in male children although adult form of the disorder also occurs. The etiology and treatment of this disorder is still a matter of debate. Our case further throws more light on the pathogenesis and treatment of this disorder. PATIENT CONCERNS: A 4-year-old boy presented with 5-month history of cervical lordosis and bilateral lower extremity pain that progressed to his abdomen and upper body. The pain was general, recurrent, non-persistent and progressive in nature with no paralysis. The pain was aggravated by trunk stretching and relieved when he assumed opisthotonos position so he preferred sleeping in this position at night. DIAGNOSES: Magnetic resonance imaging (MRI) revealed a cystic lesion at the thoracolumbar spine with tethering of spinal cord and cervical lordosis. INTERVENTIONS: He was operated on successfully and the cervical lordosis and pain resolved. OUTCOMES: The child recovered well with no tumor recurrence and massive improvement of his life. LESSONS: The gold standard treatment for this disorder is surgery although the precise surgical approach is still a matter of debate. We are of the view that surgical approach should be individualized and aim at total excision of the cyst.

Invasive intramedullary melanotic schwannoma: case report and review of the literature.

PURPOSE: Melanotic schwannoma (MS) is rare, accounting for less than 1% of primary peripheral nerve sheath tumors, and most often occurs in the paraspinal nerve roots. Intramedullary MS is exceedingly rare, and to the best of our knowledge, only nine cases have been reported in literature. METHODS AND RESULTS: We present a 47-year-old male, who underwent excision of thoracic intraspinal space-occupying lesion 6 years ago, as the 10th known case to date of intradural intramedullary MS that had a more invasive growth pattern than those reported before, and we review the diagnosis, clinicopathologic features, treatment and prognosis of intramedullary MS. CONCLUSIONS: Intramedullary MS' behavior is unpredictable and can have an aggressive clinical course such as recurrence and metastasis.

Primary Spinal Cord Glioblastoma Multiforme: A Retrospective Study of Patients at a Single Institution.

BACKGROUND AND OBJECTIVE: Primary spinal cord (PSC) glioblastoma multiforme (GBM) is extremely rare and accounts for only 1.5% of all spinal cord tumors. Therefore, its treatment is still ill defined. To elucidate prognostic factors, we performed a single-institutional retrospective review of the largest series to date of patients with PSC GBM who underwent surgical resection in West China Hospital between 2008 and 2014. A total of 14 patients with PSC GBM were reviewed. METHODS: Demographic, operative, and postoperative factors were recorded. Overall survival (OS) and progression-free survival (PFS) were calculated and compared with the Kaplan-Meier method. RESULTS: Eight males (57%) and 6 females (43%) were involved in the study. Their median age was 28 years (range, 14-56 years). Median Karnofsky Performance Status score was 60 (range, 20-90). Four patients (28.6%) received gross total resection, 5 (35.7%) partial resection, and the remaining 5 (35.7%) biopsy only. Nine patients (64.3%) received postoperative radiotherapy and chemotherapy, 3 (21.4%) chemotherapy only, and 2 (14.3%) neither. Median follow-up period was 15 months (range, 5-26 months). One-year and 2-year survival was 78.5% (11/14) and 7.1% (1/14), respectively. Median OS was 15 months, and median PFS 8 months. Univariate log-rank analysis showed that OS and PFS were significantly associated with patients' age (P = 0.007 and P = 0.04, respectively) and postoperative radiotherapy (P = 0.001 and P = 0.002, respectively). However, preoperative Karnofsky Performance Status score affected only OS and did not affect PFS (P = 0.033 and P = 0.106, respectively). CONCLUSIONS: According to our study, the combination of postoperative radiotherapy and temozolomide chemotherapy can improve prognosis and may serve as a feasible postoperative adjuvant treatment of PSC GBM.

Progesterone for acute traumatic brain injury.

BACKGROUND: Traumatic brain injury (TBI) is a leading cause of death and disability, and the identification of effective, inexpensive and widely practicable treatments for brain injury is of great public health importance worldwide. Progesterone is a naturally produced hormone that has well-defined pharmacokinetics, is widely available, inexpensive, and has steroidal, neuroactive and neurosteroidal actions in the central nervous system. It is, therefore, a potential candidate for treating TBI patients. However, uncertainty exists regarding the efficacy of this treatment. This is an update of our previous review of the same title, published in 2012. OBJECTIVES: To assess the effects of progesterone on neurologic outcome, mortality and disability in patients with acute TBI. To assess the safety of progesterone in patients with acute TBI. SEARCH METHODS: We updated our searches of the following databases: the Cochrane Injuries Group's Specialised Register (30 September 2016), the Cochrane Central Register of Controlled Trials (CENTRAL; Issue 9, 2016), MEDLINE (Ovid; 1950 to 30 September 2016), Embase (Ovid; 1980 to 30 September 2016), Web of Science Core Collection: Conference Proceedings Citation Index-Science (CPCI-S; 1990 to 30 September 2016); and trials registries: Clinicaltrials.gov (30 September 2016) and the World Health Organization (WHO) International Clinical Trials Registry Platform (30 September 2016). SELECTION CRITERIA: We included randomised controlled trials (RCTs) of progesterone versus no progesterone (or placebo) for the treatment of people with acute TBI. DATA COLLECTION AND ANALYSIS: Two review authors screened search results independently to identify potentially relevant studies for inclusion. Independently, two review authors selected trials that met the inclusion criteria from the results of the screened searches, with no disagreement. MAIN RESULTS: We included five RCTs in the review, with a total of 2392 participants. We assessed one trial to be at low risk of bias; two at unclear risk of bias (in one multicentred trial the possibility of centre effects was unclear, whilst the other trial was stopped early), and two at high risk of bias, due to issues with blinding and selective reporting of outcome data.All included studies reported the effects of progesterone on mortality and disability. Low quality evidence revealed no evidence of a difference in overall mortality between the progesterone group and placebo group (RR 0.91, 95% CI 0.65 to 1.28, I² = 62%; 5 studies, 2392 participants, 2376 pooled for analysis). Using the GRADE criteria, we assessed the quality of the evidence as low, due to the substantial inconsistency across studies.There was also no evidence of a difference in disability (unfavourable outcomes as assessed by the Glasgow Outcome Score) between the progesterone group and placebo group (RR 0.98, 95% CI 0.89 to 1.06, I² = 37%; 4 studies; 2336 participants, 2260 pooled for analysis). We assessed the quality of this evidence to be moderate, due to inconsistency across studies.Data were not available for meta-analysis for the outcomes of mean intracranial pressure, blood pressure, body temperature or adverse events. However, data from three studies showed no difference in mean intracranial pressure between the groups. Data from another study showed no evidence of a difference in blood pressure or body temperature between the progesterone and placebo groups, although there was evidence that intravenous progesterone infusion increased the frequency of phlebitis (882 participants). There was no evidence of a difference in the rate of other adverse events between progesterone treatment and placebo in the other three studies that reported on adverse events. AUTHORS' CONCLUSIONS: This updated review did not find evidence that progesterone could reduce mortality or disability in patients with TBI. However, concerns regarding inconsistency (heterogeneity among participants and the intervention used) across included studies reduce our confidence in these results.There is no evidence from the available data that progesterone therapy results in more adverse events than placebo, aside from evidence from a single study of an increase in phlebitis (in the case of intravascular progesterone).There were not enough data on the effects of progesterone therapy for our other outcomes of interest (intracranial pressure, blood pressure, body temperature) for us to be able to draw firm conclusions.Future trials would benefit from a more precise classification of TBI and attempts to optimise progesterone dosage and scheduling.

3D-engineering of Cellularized Conduits for Peripheral Nerve Regeneration.

Tissue engineered conduits have great promise for bridging peripheral nerve defects by providing physical guiding and biological cues. A flexible method for integrating support cells into a conduit with desired architectures is wanted. Here, a 3D-printing technology is adopted to prepare a bio-conduit with designer structures for peripheral nerve regeneration. This bio-conduit is consisted of a cryopolymerized gelatin methacryloyl (cryoGelMA) gel cellularized with adipose-derived stem cells (ASCs). By modeling using 3D-printed "lock and key" moulds, the cryoGelMA gel is structured into conduits with different geometries, such as the designed multichannel or bifurcating and the personalized structures. The cryoGelMA conduit is degradable and could be completely degraded in 2-4 months in vivo. The cryoGelMA scaffold supports the attachment, proliferation and survival of the seeded ASCs, and up-regulates the expression of their neurotrophic factors mRNA in vitro. After implanted in a rat model, the bio-conduit is capable of supporting the re-innervation across a 10 mm sciatic nerve gap, with results close to that of the autografts in terms of functional and histological assessments. The study describes an indirect 3D-printing technology for fabricating cellularized designer conduits for peripheral nerve regeneration, and could lead to the development of future nerve bio-conduits for clinical use.