Identification of unapproved orthopedic regenerative medicine: Usefulness of the Act on Safety of Regenerative Medicine.

In Japan, the Act on Safety of Regenerative Medicine regulates unapproved regenerative medicine. Other nations market regenerative medicine products, bypassing regulatory approval. To identify unapproved orthopedic regenerative medicine, we have used data based on the Act. Platelet-rich plasma was often used. The common target was the knee. Prices averaged $2,490.

Homo-trimeric structure of the ribonuclease for rRNA processing, FAU-1, from Pyrococcus furiosus.

Crystal structure of a ribonuclease for ribosomal RNA processing, FAU-1, from Pyrococcus furiosus was determined with the resolution of 2.57 Å in a homo-trimeric form. The monomer structure consists of two domains: N-terminal and C-terminal domains. C-terminal domain forms trimer and each N-terminal domain locates outside of the trimer core. In the obtained crystal, a dinucleotide, pApUp, was bound to the N-terminal domain, indicating that N-terminal domain has the RNA-binding ability. The affinities to RNA of FAU-1 and a fragment corresponding to the N-terminal domain, FAU-ΔC, were confirmed by polyacrylamide gel electrophoresis and nuclear magnetic resonance (NMR). Interestingly, well-dispersed NMR signals were observed at 318K, indicating that the FAU-ΔC-F18 complex form an ordered structure at higher temperature. As predicted in our previous works, FAU-1 and ribonuclease (RNase) E show a structural similarity in their RNA-binding regions. However, structural similarity between RNase E and FAU-1 could be found in the limited regions of the N-terminal domain. On the other hand, structural similarity between C-terminal domain and some proteins including a phosphatase was found. Thus, it is possible that the catalytic site is located in C-terminal domain.

Regulatory and Ethical Aspects of Orthobiologic Therapies.

Orthobiologic therapies show significant promise to improve outcomes for patients with musculoskeletal pathology. There are considerable research efforts to develop strategies that seek to modulate the biological environment to promote tissue regeneration and healing and/or provide symptomatic relief. However, the regulatory pathways overseeing the clinical translation of these therapies are complex, with considerable worldwide variation. The introduction of novel biologic treatments into clinical practice raises several ethical dilemmas. In this review, we describe the process for seeking approval for biologic therapies in the United States, Europe, and Japan. We highlight a number of ethical issues raised by the clinical translation of these treatments, including the design of clinical trials, monitoring outcomes, biobanking, "off-label" use, engagement with the public, marketing of unproven therapies, and scientific integrity.

Study protocol for periodontal tissue regeneration with a mixture of autologous adipose-derived stem cells and platelet rich plasma: A multicenter, randomized, open-label clinical trial.

Introduction: Adipose-derived stem cells (ASCs) secrete various growth factors to promote wound healing and to regenerate various tissues, such as bone, cartilage, and fat tissue. Subcutaneous adipose tissue is a considerable cell source in clinical practice and can be collected relatively easily and safely under local anesthesia. Moreover, platelet-rich plasma (PRP), a plasma component containing many platelets purified by centrifuging the collected blood, also promotes wound healing. PRP can be easily gelled and is therefore attracting attention as a scaffolding material for transplanted cells. The usefulness of a mixture of ASCs and PRP for periodontal tissue regeneration has been in vitro demonstrated in our previous study. The aim of this study is to present the protocol of translation of tissue regeneration with ASCs and PRP into practical use, evaluating its efficacy. Methods: This study is a multicenter, randomized, open-label comparative clinical trial. Fifteen patients will be randomly assigned to the treatment with mixture of ASCs and PRP or enamel matrix derivate administration into periodontal tissue defects. Increase in height of new alveolar bone in the transplanted area will be evaluated. The evaluation will be performed using dental radiographs after 36 weeks of transplantation. Occurrence of adverse events will be evaluated as secondary outcome. Results: This clinical study was initiated after meeting the regulations to be complied with, including ethical review and regulatory notifications. Conclusions: If effective, this cell therapy using autologous mesenchymal stem cells can represent a useful medical technology for regeneration of periodontal defects.

First-in-human randomised trial and follow-up study of Plasmodium falciparum blood-stage malaria vaccine BK-SE36 with CpG-ODN(K3).

BACKGROUND: BK-SE36 is blood-stage malaria vaccine candidate that is undergoing clinical trials. Here, the safety and immunogenicity of BK-SE36 with a novel adjuvant, CpG-ODN(K3) (thus, BK-SE36/CpG) was assessed in a phase 1a trial in Japan. METHODS: An investigator-initiated, randomised, single-blind, placebo-controlled, dose-escalation study was conducted at Osaka University Hospital with 26 healthy malaria naïve Japanese male adults. The trial was conducted in two stages: Stage/Group 1, half-dose (n = 7 for BK-SE36/CpG and n = 3 for control) and Stage/Group 2, full-dose (n = 11 for BK-SE36/CpG and n = 5 for control). There were two intramuscular vaccinations 21 days apart for both half-dose (0.5 ml: 50 µg SE36 + 500 µg aluminum + 500 µg K3) and full-dose (1.0 ml: 100 µg SE36 + 1000 µg aluminum + 1000 µg K3). A one-year follow-up was done to monitor changes in autoimmune markers and vaccine-induced antibody response. RESULTS: BK-SE36/CpG was well tolerated. Vaccination site reactions were similar to those observed with BK-SE36. During the trial and follow-up period, no subject had clinical evidence of autoimmune disease. The full-dose group had significantly higher titres than the half-dose group (Student's t-test, p = 0.002) at 21 days post-second vaccination. Antibody titres remained above baseline values during 12 months of follow-up. The vaccine induced antibody was mostly composed of IgG1 and IgM, and recognised epitopes close to the polyserine region located in the middle of SE36. CONCLUSIONS: BK-SE36/CpG has an acceptable safety profile. Use of CpG-ODN(K3) greatly enhanced immunogenicity in malaria naïve Japanese adults when compared to BK-SE36 alone. The utility of BK-SE36/CpG is currently under evaluation in a malaria endemic setting in West Africa. TRIAL REGISTRATION: JMACCT Clinical Trial Registry JMA-IIA00109.

Hydrogen Production System by Light-Induced α-FeOOH Coupled with Photoreduction.

Invited for the cover of this issue is Tetsuya Yamada, Ken-ichi Katsumata and co-workers at Tokyo Institute of Technology and Tokyo University of Science. The image depicts rust producing hydrogen and purifying the pollutants at the same time by photocatalytic reaction. Read the full text of the article at 10.1002/chem.201903642.

Combination of Electrospun Nanofiber Sheet Incorporating Methylcobalamin and PGA-Collagen Tube for Treatment of a Sciatic Nerve Defect in a Rat Model.

BACKGROUND: For peripheral nerve defects, autografting is considered the therapeutic gold-standard treatment. However, this procedure leads to donor-site morbidity. While various artificial conduits have been recently developed, treatment outcome has been demonstrated to be poorer than that with autograft. In our previous study using a rat sciatic nerve crush injury model, we demonstrated that the delivery of electrospun nanofiber sheets incorporating methylcobalamin (MeCbl sheet) to the local site of a peripheral nerve injury promoted peripheral nerve regeneration. In this study, we examined the effects of combination therapy using an MeCbl sheet and a polyglycolic acid tube filled with collagen sponge (PGA-c) in a rat model of a 10-mm sciatic nerve defect. METHODS: The rats were divided into 4 groups: (1) sham group (n = 10); (2) PGA-c group (n = 9), in which the gap was bridged using a PGA-c; (3) PGA-c/Sheet group (n = 8), in which the gap was bridged using a PGA-c wrapped in an MeCbl sheet; and (4) autograft group (n = 10), in which the gap was bridged using a reversed autograft. Motor and sensory function were evaluated, electrophysiological analysis was performed, and histomorphological findings were analyzed at 12 weeks postoperatively. RESULTS: Compared with the PGA-c group, the PGA-c/Sheet group demonstrated significant improvements in the paw-withdrawal threshold expressed as a ratio relative to the contralateral side (mean difference [MD], -1.51; 95% confidence interval [CI], -2.64 to -0.38), terminal latency (MD, -0.86 ms; 95% CI, -1.56 to -0.16 ms), myelinated axon area (MD, 4.97%; 95% CI, 0.14% to 9.80%), proportion of myelinated axons (MD, 8.453%; 95% CI, 0.001% to 16.905%), and g-ratio (MD, -0.018; 95% CI, -0.035 to -0.001). No significant improvements were observed regarding motor function, electrophysiological findings with the exception of terminal latency, and axon numbers. CONCLUSIONS: An MeCbl sheet in combination with a PGA-c significantly accelerated recovery with respect to sensory function, electrophysiology, and histomorphometry. CLINICAL RELEVANCE: An MeCbl sheet may represent an effective therapeutic strategy for promoting regeneration across a nerve gap bridged with an artificial conduit.

Hydrogen Production System by Light-Induced α-FeOOH Coupled with Photoreduction.

Solar-driven catalysts on semiconductors to produce hydrogen are considered as a means to solve environmental issues. In this study, H2 production coupling with oxygen consumption by noble metal-free α-FeOOH was demonstrated even though the conduction band edge was lower than the reduction potential of H+ to H2 . For activation of α-FeOOH, an electron donor, Hg-Xe irradiation, and low pH (ca. 5) were indispensable factors. The H2 production from H2 O was confirmed by GC-MS using isotope-labeled water (D2 O) and deuterated methanol. The α-FeOOH synthesized by coprecipitation method showed 25 times more active than TiO2 . The photocatalytic activity was stable for over 400 h. Our study suggests that α-FeOOH known as rust can produce H2 by light induction.

Three-Dimensional Corrective Osteotomy for Malunited Fractures of the Upper Extremity Using Patient-Matched Instruments: A Prospective, Multicenter, Open-Label, Single-Arm Trial.

BACKGROUND: Medical image processing has facilitated simulation of 3-dimensional (3-D) corrective osteotomy, and 3-D rapid prototyping technology has further enabled the manufacturing of patient-matched surgical guides and implants (patient-matched instruments, or PMIs). However, 3-D corrective osteotomy using these technologies has not been the standard procedure. We aimed to prospectively verify the efficacy and safety of PMIs in corrective osteotomy for deformities of the upper extremity. METHODS: We enrolled 16 patients with a total of 17 bone deformities in the upper extremity. Eight patients had distal radial malunion; 5, distal humeral malunion; and 3, forearm diaphyseal malunion. All cases underwent 3-D corrective osteotomy with PMIs. The primary end point was the residual maximum deformity angle (MDA), which was calculated from 2 deformity angles-1 on the anteroposterior and 1 on the lateral postoperative radiograph. Secondary end points included the deformity angle on radiographs, 3-D error between the preoperative planning model and the postoperative result, range of motion, grip strength, pain measured with a visual analog scale (VAS), patient satisfaction, and Disabilities of the Arm, Shoulder and Hand (DASH) score. RESULTS: The average MDA significantly improved from 25.5° preoperatively to 3.3° at the final follow-up (p < 0.001). The angular deformity was within 5° in all cases, except for 1 with distal radial malunion who had a higher angle on the anteroposterior radiograph. The error between the correction seen on the postoperative 3-D bone model and the planned correction was <1° and <1 mm. Flexion and extension of the wrist and pronation of the forearm of the patients treated for distal radial malunion improved significantly, and pronation improved for those treated for forearm diaphyseal malunion. The average VAS score, grip strength, and DASH score significantly improved as well. Of the 16 patients, 15 were very satisfied or satisfied with the outcomes. CONCLUSIONS: Corrective osteotomy using PMIs achieved accurate correction and good functional recovery in the upper extremity. Although our study was limited to cases without any deformity on the contralateral side, 3-D corrective osteotomy using PMIs resolved treatment challenges for complex deformities in upper extremities. LEVEL OF EVIDENCE: Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence.

A Nanofiber Sheet Incorporating Vitamin B12 Promotes Nerve Regeneration in a Rat Neurorrhaphy Model.

Outcomes of peripheral nerve repair after injury are often suboptimal. Therefore, developing biological approaches to augment nerve regeneration is important. In this in vivo study, we tested the hypothesis that augmentation with an electrospun nanofiber sheet incorporating methylcobalamin (MeCbl) would be effective for regeneration after peripheral nerve transection and repair. METHODS: Rats were divided into 3 groups that either underwent sciatic nerve repair with or without the MeCbl sheet, or a sham operation. At 4 and/or 8 weeks after the operation, sensory and motor functional recovery, along with histological findings, were compared among the groups using the toe-spreading test, mechanical and thermal algesimetry tests, tibialis anterior muscle weight measurements, electrophysiological analyses, which included nerve conduction velocity (NCV), compound muscle action potential (CMAP), and terminal latency (TL), and histological analyses involving the myelinated axon ratio, axon diameter, and total axon number. RESULTS: Compared with the repair group without the MeCbl sheet, the repair group with the MeCbl sheet showed significant recovery in terms of tibialis anterior muscle weight, NCV and CMAP, and also tended to improve in the toe-spreading test, mechanical and thermal algesimetry tests, and TL. Histological analyses also demonstrated that the myelinated axon ratios and axon diameters were significantly higher. Among these findings, the repair group with the MeCbl sheet demonstrated the same recovery in NCV as the sham group. CONCLUSION: This study demonstrated that electrospun nanofiber MeCbl sheets promoted nerve regeneration and functional recovery, indicating that this treatment strategy may be viable for human peripheral nerve injuries.

Establishment of the National Consortium for Regenerative Medicine and National Regenerative Medicine Database in Japan.

With its aim to regain the function of organs that are damaged by illness or injury, regenerative medicine has become the global focus of research. To accelerate the development and establishment of sufficient safety measures in regenerative medicine in Japan, the Pharmaceuticals and Medical Devices Act and the Act on Safety of Regenerative Medicine were enacted in 2014. Advancements in regenerative medicine are anticipated to draw attention toward the development of a system that consolidates and uses valuable data from studies performed from premarketing to postmarketing stages. Data gathered from premarketing to postmarketing stages of clinical research would promote new development avenues that would lead to the establishment of appropriate evaluation methods for new regenerative medical products by data validation. Against this background, the Japanese Society for Regenerative Medicine has been working to establish a national consortium for promoting regenerative medicine and constructing a large-scale clinical data registry, called the National Regenerative Medicine Database. This article aims to introduce the current framework of regenerative medicine in Japan, with a particular focus on the activity for establishment of a national consortium for regenerative medicine and the National Regenerative Medicine Database.

A comparison of corrective osteotomies using dorsal and volar fixation for malunited distal radius fractures.

PURPOSE: This study aimed to compare clinical results and to restore radiographic parameters of corrective osteotomy for malunited distal radius fracture using a volar locking plate with a dorsal plate. METHODS: We retrospectively studied 28 consecutive patients with symptomatic malunited distal radius fractures followed up for more than 12 months who underwent corrective osteotomy with a dorsal buttress plate (n = 9) or a volar locking plate (n = 19). Volar tilt (VT), radial inclination (RI), and ulnar variance (UV) were radiographically evaluated. Clinical examination parameters included pain, wrist and forearm ranges of motion (ROM), grip strength, and Mayo Modified Wrist Score (MMWS). RESULTS: The volar group had a significantly greater VT undercorrection for - 9.4° than did the dorsal group for - 1.2° (p < 0.001). Major complications requiring plate removal occurred in six of nine patients in the dorsal group and two of 19 patients in the volar group. The complication ratio was significantly greater in the dorsal group than in the volar group (p < 0.05). Improvements in forearm and wrist ROM, grip strength, and MMWS did not differ significantly between groups. CONCLUSIONS: Opening wedge osteotomy of the radius using a volar locking plate is preferable to dorsal buttress fixation in terms of surgical and technical demands and frequency of complications, but VT correction is insufficient. Surgeons should be aware of the mismatch between the plate and the volar surface of the malunited distal radius.

Fully Depleted Ti-Nb-Ta-Zr-O Nanotubes: Interfacial Charge Dynamics and Solar Hydrogen Production.

Poor kinetics of hole transportation at the electrode/electrolyte interface is regarded as a primary cause for the mediocre performance of n-type TiO2 photoelectrodes. By adopting nanotubes as the electrode backbone, light absorption and carrier collection can be spatially decoupled, allowing n-type TiO2, with its short hole diffusion length, to maximize the use of the available photoexcited charge carriers during operation in photoelectrochemical (PEC) water splitting. Here, we presented a delicate electrochemical anodization process for the preparation of quaternary Ti-Nb-Ta-Zr-O mixed-oxide (denoted as TNTZO) nanotube arrays and demonstrated their utility in PEC water splitting. The charge-transfer dynamics for the electrodes was investigated using time-resolved photoluminescence, electrochemical impedance spectroscopy, and the decay of open-circuit voltage analysis. Data reveal that the superior photoactivity of TNTZO over pristine TiO2 originated from the introduction of Nd, Ta, and Zr elements, which enhanced the amount of accessible charge carriers, modified the electronic structure, and improved the hole injection kinetics for expediting water splitting. By modulating the water content of the electrolyte employed in the anodization process, the wall thickness of the grown TNTZO nanotubes can be reduced to a size smaller than that of the depletion layer thickness, realizing a fully depleted state for charge carriers to further advance the PEC performance. Hydrogen evolution tests demonstrate the practical efficacy of TNTZO for realizing solar hydrogen production. Furthermore, with the composition complexity and fully depleted band structure, the present TNTZO nanotube arrays may offer a feasible and universal platform for the loading of other semiconductors to construct a sophisticated heterostructure photoelectrode paradigm, in which the photoexcited charge carriers can be entirely utilized for efficient solar-to-fuel conversion.

Neurotropin® Accelerates the Differentiation of Schwann Cells and Remyelination in a Rat Lysophosphatidylcholine-Induced Demyelination Model.

Neurotropin® (NTP), a non-protein extract of inflamed rabbit skin inoculated with vaccinia virus, is clinically used for the treatment of neuropathic pain in Japan and China, although its effect on peripheral nerve regeneration remains to be elucidated. The purpose of this study was to investigate the effects of NTP on Schwann cells (SCs) in vitro and in vivo, which play an important role in peripheral nerve regeneration. In SCs, NTP upregulated protein kinase B (AKT) activity and Krox20 and downregulated extracellular signal-regulated kinase1/2 activity under both growth and differentiation conditions, enhanced the expression of myelin basic protein and protein zero under the differentiation condition. In a co-culture of dorsal root ganglion neurons and SCs, NTP accelerated myelination of SCs. To further investigate the influence of NTP on SCs in vivo, lysophosphatidylcholine was injected into the rat sciatic nerve, leading to the focal demyelination. After demyelination, NTP was administered systemically with an osmotic pump for one week. NTP improved the ratio of myelinated axons and motor, sensory, and electrophysiological function. These findings reveal novel effects of NTP on SCs differentiation in vitro and in vivo, and indicate NTP as a promising treatment option for peripheral nerve injuries and demyelinating diseases.

In Vivo 3-Dimensional Kinematics of Thumb Carpometacarpal Joint During Thumb Opposition.

PURPOSE: This study primarily aimed to demonstrate the screw-home rotation of the thumb carpometacarpal (CMC) joint and the function of surrounding ligaments during thumb oppositional motion. METHODS: A 3-dimensional kinematic analysis of the thumb CMC joint was conducted using data derived from computed tomography of 9 healthy volunteers. Scans were obtained in the neutral forearm and wrist position and the thumb in maximum radial abduction, maximum palmar abduction, and maximum opposition. The movements of the first metacarpal and the palmar and dorsal bases on the trapezium during thumb oppositional motion from radial abduction through palmar abduction were quantified using a coordinate system originating on the trapezium. In addition to the kinematic analyses, the length of virtual ligaments, including the anterior oblique, ulnar collateral, dorsal radial, dorsal central (DCL), and posterior oblique ligament (POL), were calculated at each thumb position. RESULTS: From radial abduction to opposition of the thumb through palmar abduction, the first metacarpal was abducted, internally rotated, and flexed on the trapezium. The palmar base of the first metacarpal moved in the palmar-ulnar direction, and the dorsal base moved in the palmar-distal direction along the concave surface of the trapezium. Although the DCL and POL lengthened, the lengths of other ligaments did not change significantly. CONCLUSIONS: During thumb oppositional motion, internal rotation of the first metacarpal occurred, with the palmar base rotating primarily with respect to the dorsal base. The DCL and POL may be strained in thumb functional positions. CLINICAL RELEVANCE: Kinematic variables indicated a screw-home rotation of the thumb CMC joint and the contribution of the dorsal ligaments to the stability of the rotation on the pivot point.

Insurance systems and reimbursement concerning research and development of regenerative medicine in Japan.

In Japan, the Act on the Safety of Regenerative Medicine and the Pharmaceuticals, Medical Devices and Other Therapeutic Products Act were enacted in November 2014, creating a new framework for clinical research and products related to regenerative medicine. Together with these regulatory frameworks, new insurance procedures were created for handling regenerative medicine in Japan. For developing regenerative medicine in Japan, understanding medical insurance greatly influences funding and venture success, particularly in the stages between clinical research and market launch. The study aimed to identify the issues and examples surrounding Japan's present medical insurance system, especially for regenerative medicine. We believe that building stronger insurance systems for regenerative medicine is essential for internationally aligning and harmonizing the progress of regenerative medicine.

Electrospun nanofiber sheets incorporating methylcobalamin promote nerve regeneration and functional recovery in a rat sciatic nerve crush injury model.

Peripheral nerve injury is one of common traumas. Although injured peripheral nerves have the capacity to regenerate, axon regeneration proceeds slowly and functional outcomes are often poor. Pharmacological enhancement of regeneration can play an important role in increasing functional recovery. In this study, we developed a novel electrospun nanofiber sheet incorporating methylcobalamin (MeCbl), one of the active forms of vitamin B12 homologues, to deliver it enough locally to the peripheral nerve injury site. We evaluated whether local administration of MeCbl at the nerve injury site was effective in promoting nerve regeneration. Electrospun nanofiber sheets gradually released MeCbl for at least 8weeks when tested in vitro. There was no adverse effect of nanofiber sheets on function in vivo of the peripheral nervous system. Local implantation of nanofiber sheets incorporating MeCbl contributed to the recovery of the motor and sensory function, the recovery of nerve conduction velocity, and the promotion of myelination after sciatic nerve injury, without affecting plasma concentration of MeCbl. STATEMENT OF SIGNIFICANCE: Methylcobalamin (MeCbl) is a vitamin B12 analog and we previously reported its effectiveness in axonal outgrowth of neurons and differentiation of Schwann cells both in vitro and in vivo. Here we estimated the effect of local administered MeCbl with an electrospun nanofiber sheet on peripheral nerve injury. Local administration of MeCbl promoted functional recovery in a rat sciatic nerve crush injury model. These sheets are useful for nerve injury in continuity differently from artificial nerve conduits, which are useful only for nerve defects. We believe that the findings of this study are relevant to the scope of your journal and will be of interest to its readership.