Kiyohito Takamatsu

Transplantation of induced pluripotent stem cell-derived neurospheres for peripheral nerve repair.

In spite of the extensive research using induced pluripotent stem (iPS) cells, the therapeutic potential of iPS cells in the treatment of peripheral nerve injury is largely unknown. In this study, we repaired peripheral nerve gaps in mice using tissue-engineered bioabsorbable nerve conduits coated with iPS cell-derived neurospheres. The secondary neurospheres derived from mouse iPS cells were suspended in each conduit (4000,000 cells per conduit) and cultured in the conduit in three-dimensional (3D) culture for 14 days. We then implanted them in the mouse sciatic nerve gaps (5 mm) (iPS group; n=10). The nerve conduit alone was implanted in the control group (n=10). After 4, 8 and 12 weeks, motor and sensory functional recovery in mice were significantly better in the iPS group. At 12 weeks, all the nerve conduits remained structurally stable without any collapse and histological analysis indicated axonal regeneration in the nerve conduits of both groups. However, the iPS group showed significantly more vigorous axonal regeneration. The bioabsorbable nerve conduits created by 3D-culture of iPS cell-derived neurospheres promoted regeneration of peripheral nerves and functional recovery in vivo. The combination of iPS cell technology and bioabsorbable nerve conduits shows potential as a future tool for the treatment of peripheral nerve defects.

Acceleration of peripheral nerve regeneration using nerve conduits in combination with induced pluripotent stem cell technology and a basic fibroblast growth factor drug delivery system

Various modifications including addition of Schwann cells or incorporation of growth factors with bioabsorbable nerve conduits have been explored as options for peripheral nerve repair. However, no reports of nerve conduits containing both supportive cells and growth factors have been published as a regenerative therapy for peripheral nerves. In the present study, sciatic nerve gaps in mice were reconstructed in the following groups: nerve conduit alone (control group), nerve conduit coated with induced pluripotent stem cell (iPSc)-derived neurospheres (iPSc group), nerve conduit coated with iPSc-derived neurospheres and basic fibroblast growth factor (bFGF)-incorporated gelatin microspheres (iPSc + bFGF group), and autograft. The fastest functional recovery and the greatest axon regeneration occurred in the autograft group, followed in order by the iPSc + bFGF group, iPSc group, and control group until 12 weeks after reconstruction. Thus, peripheral nerve regeneration using nerve conduits and functional recovery in mice was accelerated by a combination of iPSc-derived neurospheres and a bFGF drug delivery system. The combination of all three fundamental methodologies, iPSc technology for supportive cells, bioabsorbable nerve conduits for scaffolds, and a bFGF drug delivery system for growth factors, was essential for peripheral nerve regenerative therapy.

A ganglion within the ulnar nerve and communication with the distal radioulnar joint via an articular branch: case report.

An intraneural ganglion is rare, and involvement of an articular nerve may suggest a possible pathogenesis. We report an intraneural ganglion of the ulnar nerve with a connection to the distal radioulnar joint via the articular branch. We excised the ganglion, the stalk, and the articular branch. To date, there has been no recurrence.

A tissue-engineered bioabsorbable nerve conduit created by three-dimensional culture of induced pluripotent stem cell-derived neurospheres

We previously reported a bioabsorbable nerve conduit coated with Schwann cells for the treatment of peripheral nerve defects. Since there have been dramatic developments in induced pluripotent stem (iPS) cells in recent years, the purpose of the present study was to create a tissue-engineered nerve conduit coated with iPS cell-derived neurospheres. Such a conduit was constructed by three-dimensional (3D)-culture of these cells using a bioabsorbable polymer conduit as a scaffold. The nerve conduit was composed of a mesh of poly L-lactide, and a porous sponge of 50% poly L-lactide and 50% poly ε-caprolactone. The primary and secondary neurospheres (PNS and SNS, respectively) induced from iPS cells were suspended in individual conduits. The conduits were incubated for 7 or 14 days in vitro and then evaluated using immunohistochemistry. All of the 7- and 14-day differentiated PNS and SNS were observed to have adhered to the inner surface of the conduits and to have migrated into the inner porous sponge. The engrafted cells were positive for anti-Tuj1, -S-100 and -GFAP antibodies, indicating that their pluripotent ability to form neural or glial cells was maintained. These findings indicate the feasibility of creating nerve conduits coated with a 3D-culture of iPS cell-derived neurospheres for the treatment of peripheral nerve defects.

Long-term efficacy and safety outcomes of transplantation of induced pluripotent stem cell-derived neurospheres with bioabsorbable nerve conduits for peripheral nerve regeneration in mice.

The induced pluripotent stem cell (iPSc) offers great potential for cell-based therapy in regenerative medicine. We previously developed tissue-engineered bioabsorbable nerve conduits coated with iPSc-derived neurospheres for use in peripheral nerve repair. Here, we examine the long-term efficacy and safety of using nerve conduits with iPSc technology for peripheral nerve repair in mice. The nerve conduit consisted of an outer layer of a poly L-lactide mesh and an inner layer of porous sponge composed of 50% L-lactide and 50% ε-caprolactone. Secondary neurospheres were derived from mouse iPScs, resuspended and cultured within the conduit for 14 days. Conduits were implanted within surgically administered 5-mm defects in the left sciatic nerve of mice (iPSc group; n = 14). The defects in the control group (n = 13) were reconstructed using the nerve conduit alone. At 4, 8, 12, 24 and 48 weeks postsurgery, motor and sensory functional recovery in the iPSc group had improved significantly more than in the control group. At 24 and 48 weeks, histological analysis revealed axonal regeneration in the nerve conduits of both groups. However, axonal regeneration and myelination were significantly enhanced in the iPSc group. No teratomas were identified in the iPSc group at any time point. Therefore, we here demonstrate that bioabsorbable nerve conduits coated with iPSc-derived neurospheres promote enhanced regeneration of peripheral nerves and functional recovery without teratoma formation in the long term. This combination of iPSc technology and bioabsorbable nerve conduits has the potential to be a safe future tool for the treatment of peripheral nerve defects.

Clinical outcomes of primary skin closure with Y-V and Z-plasties for Dupuytren's contracture: Use of one-stage skin closure

Abstract Y-V or Z-plasties are a useful one-stage technique for skin closure after aponeurotomy. However, we know no details about postoperative improvement, particularly at each joint. The purpose of this study was to evaluate the clinical outcomes of primary skin closure with Y-V and Z-plasties for Dupuytrens contracture. We retrospectively reviewed the postoperative results of 23 patients (25 hands, 29 fingers). The preoperative severity of the contracture evaluated by the Meyerding classification was grade I in 11 fingers, II in two fingers, and III in 16 fingers. In total, 26 metacarpophalangeal (MP) joints and 27 proximal interphalangeal (PIP) joints were treated. In each finger we assessed clinical outcomes according to the percentage improvement in extension and a modified version of Tubianas classification. Primary wound closure was possible in all cases. The mean contracture values were improved from 46.5° preoperatively to 4.2° postoperatively for the MP joint and from 43.9° to 22.4° for the PIP joint. The mean percentage improvement in extension for the MP joint was 92% and for the PIP joint 56%. The rate for the PIP joint of the little finger was 40% and for the other fingers 78%. In total, 83% of the fingers had satisfactory results. For Dupuytrens contracture, primary skin closure with Y-V and Z-plasties gives satisfactory results, more so with involvement of the MP than the PIP joint and less so with involvement of the little finger.

Solitary neurolymphomatosis of the brachial plexus mimicking benign nerve sheath tumour: case report.

Abstract Neurolymphomatosis typically appears as a diffuse lesion with thickening of the affected nerves on magnetic resonance imaging (MRI). MRI in the present case revealed a well-defined, solitary lesion showing continuity with brachial plexus nerves. Findings including clinical symptoms resembled benign nerve sheath tumour rather than neurolymphomatosis. Intra-operatively, the C8 root was focally swollen, corresponding to a well-circumscribed lesion on MRI. The diagnosis of neurolymphomatosis was obtained only after resection biopsy. Post-operatively, 18F-fluorodeoxyglucose positron emission tomography proved useful for follow-up evaluation. We offer the first description of the MRI characteristics of brachial plexopathy in neurolymphomatosis, along with the clinical course.

Planning digital artery perforators using color Doppler ultrasonography: A preliminary report

Digital artery perforator (DAP) flaps have been applied for the coverage of finger soft tissue defects. Although an advantage of this method is that there is no scarification of the digital arteries, it is difficult to identify the location of the perforators during intraoperative elevation of the DAP flap. In this study, anatomically reliable locations of DAPs were confirmed using color Doppler ultrasonography (US) in healthy volunteers. A successful case using an adiposal-only DAP flap for the coverage of a released digital nerve using preoperative DAP mapping with color Doppler US is also described. A total of 40 digital arteries in 20 fingers of the right hands of five healthy volunteers (mean age: 32.2 years old) were evaluated. The DAPs were identified using color flow imaging based on the beat of the digital artery in the short axial view. In total, 133 perforators were detected, 76 (an average of 3.8 per finger) arising from the radial digital artery and 57 (an average of 2.9 per finger) arising from ulnar digital artery. Sixty-three perforators (an average of 3.2 per finger) in the middle phalanges and 70 (an average of 3.5 per finger) in the proximal phalanges were found. Overall, an average of 1.7 perforators from each digital artery was detected in the proximal or middle phalanges. Moreover, at least one DAP per phalanx was reliably confirmed using color Doppler US. Preoperative knowledge of DAP mapping could make elevating the DAP flap easier and safer.

Reversed lateral upper arm flap with a vascularised fragment of the humerus for reconstruction of ulna shaft fracture after resection of malignant tumour: A case report

The lateral upper arm flap (LAF) is used for a pedicled flap with the vascular arcade at the elbow. There has been no report, however, with regard to the reverse lateral upper arm flap (R-LAF) with a vascularised humerus as an osteocutaneous flap. We describe the case of a 72-year-old woman with a fracture of the ulna after wide resection of a malignant tumour at the proximal half of the forearm, which was reconstructed with an R-LAF with a vascularised fragment of the distal humerus. The flap has successfully survived and the fracture was healed without any adverse event. The R-LAF with vascularised bone is a useful option for the simultaneous treatment of soft tissue and bone defects.

Protective effect of biodegradable nerve conduit against peripheral nerve adhesion after neurolysis

OBJECTIVE Peripheral nerve adhesion caused by extraneural and intraneural scar formation after neurolysis leads to nerve dysfunction. The authors previously developed a novel very flexible biodegradable nerve conduit composed of poly(L-lactide) and poly(ε-caprolactone) for use in peripheral nerve regeneration. In the present study, they investigated the effect of protective nerve wrapping on preventing adhesion in a rat sciatic nerve adhesion model. METHODS Rat sciatic nerves were randomly assigned to one of the following four groups: a no-adhesion group, which involved neurolysis alone without an adhesion procedure; an adhesion group, in which the adhesion procedure was performed after neurolysis, but no treatment was subsequently administered; a nerve wrap group, in which the adhesion procedure was performed after neurolysis and protective nerve wrapping was then performed with the nerve conduit; and a hyaluronic acid (HA) group, in which the adhesion procedure was performed after neurolysis and nerve wrapping was then performed with a 1% sodium HA viscous solution. Six weeks postoperatively, the authors evaluated the extent of scar formation using adhesion scores and biomechanical and histological examinations and assessed nerve function with electrophysiological examination and gastrocnemius muscle weight measurement. RESULTS In the adhesion group, prominent scar tissue surrounded the nerve and strongly adhered to the nerve biomechanically and histologically. The motor nerve conduction velocity and gastrocnemius muscle weight were the lowest in this group. Conversely, the adhesion scores were significantly lower, motor nerve conduction velocity was significantly higher, and gastrocnemius muscle weight was significantly higher in the nerve wrap group than in the adhesion group. Additionally, the biomechanical breaking strength was significantly lower in the nerve wrap group than in the adhesion group and HA group. The morphological properties of axons in the nerve wrap group were preserved. Intraneural macrophage invasion, as assessed by the number of CD68- and CCR7-positive cells, was less severe in the nerve wrap group than in the adhesion group. CONCLUSIONS The nerve conduit prevented post-neurolysis peripheral nerves from developing adhesion and allowed them to maintain their nerve function because it effectively blocked scarring and prevented adhesion-related damage in the peripheral nerves.