Wen-Shiang Chen

• M.D., Ph.D.
• Professor (Full) at National Taiwan University

Aims This study aimed to investigate the regional modulation effect of low‐intensity focused ultrasound (LIFU) on cerebrospinal fluid (CSF) influx dynamics, focusing on the differential changes between hemispheres in a mouse model of unilateral ischemic stroke. Methods LIFU was administered with a commercial transducer at the unilateral M1 cortex...

Background Mirror therapy (MT) and augmented reality (AR) are gaining popularity in stroke rehabilitation. MT uses mirror visual feedback to promote bilateral brain coupling and increase primary motor cortex excitability. AR offers an interactive context of practice for promoting motor and cognitive recovery. MT and AR may complement each other for...

Recently, the glymphatic system has been proposed as a mechanism for waste clearance from the brain parenchyma. Glymphatic dysfunction has previously been shown to be associated with several neurological diseases, including Alzheimer's disease, traumatic brain injury, and stroke. As such, it may serve as an important target for therapeutic interven...

Background Extracorporeal shockwave therapy (ESWT) has been proven beneficial for post-stroke spasticity (PSS) of ankle plantar flexor muscles. This study aims to investigate the dose-response effectiveness of focused-ESWT and the duration of its effect on the treatment of ankle PSS in stroke patients. Methods In this double-blinded randomized con...

Background Stroke is a leading cause of long-term disability among stroke survivors. Despite the availability of numerous stroke rehabilitative therapies, such as mirror therapy, bilateral arm training, and robot-assisted therapy, the recovery of motor function after stroke remains incomplete. Bilateral arm function is a key component in stroke pat...

Introduction Traumatic brain injury (TBI) is a major cause of neurodisability worldwide, with notably high disability rates among moderately severe TBI cases. Extensive previous research emphasizes the critical need for early initiation of rehabilitation interventions for these cases. However, the optimal timing and methodology of early mobilizatio...

Background Early mobilization (EM) within 24 to 72 hours post-stroke may improve patients’ performance and ability. However, after intravenous thrombolysis (IVT) or mechanical thrombectomy (MT), the increased risk of hemorrhagic complications impacts the implementation of early out-of-bed mobilization. Few studies have investigated EM after IVT or...

Osteoarthritis is a degenerative condition that is highly prevalent and primarily affects the joints. The knee is the most commonly affected site, impacting the lives of over 300 million individuals worldwide. This study presents a potential solution to address the unmet need for a minimally invasive technique in the treatment of osteoarthritis: a...

Objective: To examine the effects of bilateral robotic priming combined with mirror therapy (R-mirr) versus bilateral robotic priming combined with bilateral arm training (R-bilat), relative to the control approach of bilateral robotic priming combined with movement-oriented training (R-mov) in patients with stroke. Design: A single-blind, preli...

Many stroke survivors demonstrate arm nonuse despite good arm motor function. This retrospective secondary analysis aims to identify predictors of arm nonusers with good arm motor function after stroke rehabilitation. A total of 78 participants were categorized into 2 groups using the Fugl-Meyer Assessment Upper Extremity Scale (FMA-UE) and the Mot...

Recently, the glymphatic system has been proposed as a mechanism for waste clearance from the brain parenchyma. Glymphatic dysfunction has been associated with several neurological diseases such as Alzheimer’s disease, traumatic brain injury, and stroke. Therefore, it may be an important target for therapeutic interventions. In this study, we demon...

Contrast-enhanced ultrasound (CEUS) uses an intravascular contrast agent to enhance blood flow signals and assess microcirculation in different parts of the human body. Over the past decade, CEUS has become more widely applied in musculoskeletal (MSK) medicine, and the current review aims to systematically summarize current research on the applicat...

Transcranial focused shockwave (FSW) is a novel noninvasive brain stimulation that can open blood-brain barriers (BBB) and blood-cerebrospinal fluid barriers (BCSFB) with a single low-energy (energy flux density 0.03 mJ/mm²) pulse and low-dose microbubbles (2 × 10⁶/kg). Similar to focused ultrasound, FSW deliver highly precise stimulation of discre...

This narrative review summarises ongoing challenges and progress in the care and prevention of fragility fractures across the Asia Pacific region since mid-2019. The approaches taken could inform development of national bone health improvement Road Maps to be implemented at scale during the United Nations ‘Decade of Healthy Ageing’.PurposeThis narr...

Background: The aim of the study was to evaluate the feasibility of convolutional neural network (CNN)-based deep learning (DL) algorithms to dichotomize shoulder ultrasound (US) images with or without supraspinatus calcific tendinopathy (SSCT). Methods: This was a retrospective study pertaining to US examinations that had been performed by 18 p...

Background: Brain plasticity evoked by environmental enrichment through early mobilization may improve sensorimotor functions of patients with moderate-to-severe traumatic brain injury (TBI). Increasing evidence also suggests that early mobilization increases verticalization, which is beneficial to TBI patients in critical care. However, there are...

Parkinson’s disease (PD) is the second most common chronic neurodegenerative disease globally; however, it lacks effective treatment at present. Focused ultrasound (FUS) combined with microbubbles could increase the efficacy of drug delivery to specific brain regions and is becoming a promising technology for the treatment of central nervous system...

Alzheimer’s disease (AD) is the most common type of dementia but lacks effective treatment at present. Gastrodin (GAS) is a phenolic glycoside extracted from the traditional Chinese herb—Gastrodia elata—and has been reported as a potential therapeutic agent for AD. However, its efficiency is reduced for AD patients due to its limited BBB permeabili...

Background The blood-cerebrospinal fluid (CSF) barrier (BCSFB) is critically important to the pathophysiology of the central nervous system (CNS). However, this barrier prevents the safe transmission of beneficial drugs from the blood to the CSF and thus the spinal cord and brain, limiting their effectiveness in treating a variety of CNS diseases....

CNS neurons have no sensory function, protected by the skull. For this reason, brain neuromodulation by ultrasound were either done at a high intensity or through auditory nerves. We demonstrate in this study CNS neurons react to ultrasound stimulation at an intensity (5 mW/cm ² ) far lower than typical therapeutic ultrasound (>30 mW/cm ² ). Using...

The blood-cerebrospinal fluid barrier (BCSFB) is another gatekeeper between systemic circulation and the central nervous system (CNS), mainly present at the boundary between choroid plexuses and the ventricular system. This study demonstrates BCSFB opening in rats by single pulse of low-energy focused shockwave (FSW, energy flux density 0.03 mJ/mm²...

Background Glioblastoma multiforme (GBM) is currently the most devastating brain tumor globally and produces a high mortality rate. GBM is also challenging to eradicate using surgery due to its invasive characteristics. Moreover, the blood-brain barrier (BBB) increases the difficulty of transporting most therapeutic drugs to tumor sites. The use of...

Background: Early out-of-bed mobilization may improve acute post-intracerebral hemorrhage (ICH) outcomes, but hemodynamic instability may be a concern. Some recent studies have showed that an increase in mean systolic blood pressure (SBP) and high blood pressure variability (BPV), high standard deviation of SBP, may lead to negative ICH outcomes....

Entrapment neuropathy (EN) is a prevalent and debilitative condition caused by a complex pathogenesis that involves a chronic compression–edema–ischemia cascade and perineural adhesion that results in excessive shear stress during motion. Despite decades of research, an easily accessible and surgery-free animal model mimicking the mixed etiology is...

The use of physical agent modalities dates back to the early days in the development of the field of physical and rehabilitation medicine. The term physiatrist is derived from the Greek words physis, pertaining to physical phenomena, and iatreia, referring to healer or physician. Thus a physiatrist is a physician who uses physical agents to relieve...

Repigmentation of vitiligo relies on the proliferation and migration of melanoblasts from hair follicles to the epidermis to replenish epidermal melanin. Our previous study has demonstrated low‐intensity pulsed ultrasound (LIPUS) can stimulate melanoblast migration in vitro. We sought to evaluate the potential additive efficacy and safety of LIPUS...

Accumulating evidence has shown transcranial low-intensity ultrasound can be potentially a non-invasive neural modulation tool to treat brain diseases. However, the underlying mechanism remains elusive, because the majority of studies on animal models applying rather high-intensity ultrasound that cannot be safely used in humans. Here we showed low...

Introduction: Numerous studies have shown the ability of low-energy acoustic waves such as focused ultrasound or shockwave to transiently open blood-brain barrier (BBB) and facilitate drug delivery to the brain. Preclinical and clinical evidences have well demonstrated the efficacy and safety in treating various brain disorders. However, the molec...

Focused extracorporeal shockwave (FSW), one kind of focused high-intensity pulsed ultrasound, has been shown to induce blood-brain barrier (BBB) opening in targeted brain areas in rat animal models with minimal detrimental effects below threshold intensity levels or iterations. In the current study, we found that the thresholds could be further red...

Extracorporeal shockwave therapy (ESWT) is proposed to be effective in reducing pain and improving functional outcome in chronic plantar fasciitis. However, no long-term reports exist on the changes in plantar fascia (PF) elasticity after ESWT. We aimed to evaluate the changes in PF stiffness in patients with plantar fasciitis undergoing ESWT. The...

Background. Few studies have addressed early out-of-bed mobilization specifically in acute intracerebral hemorrhage (ICH) patients. Patient benefit in such cases is unclear, with early intervention timing and duration identical to those in standard care. Objective. We investigated the efficacy of an early mobilization (EM) protocol, administered wi...

Melanin is known to provide strong third-harmonic generation (THG) contrast in human skin. With a high concentration in basal cell cytoplasm, THG contrast provided by melanin overshadows other THG sources in human skin studies. For better understanding of the THG signals in keratinocytes without the influence of melanin, an in vivo THG microscopy (...

Tendon injuries or tendinopathy are common painful and disabling conditions resulting from overuse and aging. Tendinopathy remains a challenging clinical problem since response to different treatment modalities is usually unsatisfactory and recovery is slow. We performed an extensive literature review focusing on non-surgical treatment options for...

Episodic release of bioactive compounds is often necessary for appropriate biological effects under specific physiological conditions. Here, we aimed to develop an injectable, biocompatible, and thermosensitive hydrogel system for ultrasound (US)-triggered drug release. An mPEG-PLGA-BOX block copolymer hydrogel was synthesized. The viscosity of 15...

Traumatic cerebral contusion and intracerebral hemorrhages (ICH) commonly result from traumatic brain injury and are associated with high morbidity and mortality rates. Current animal models require craniotomy and provide less control over injury severity. This study proposes a highly reproducible and controllable traumatic contusion and ICH model...

The oxidised hyaluronic acid/adipic acid dihydrazide hydrogel (oxi-HA/ADH) is a biocompatible and biodegradable hydrogel that has been applied in tissue engineering in musculoskeletal medicine. The present study investigated the feasibility of using oxi-HA/ADH as a drug carrier to incorporate cytoprotective medications for possible tendinopathy tre...

Because of limitations in the current understanding of the exact pathogenesis of tendinopathy, and the lack of an optimal experimental model, effective therapy for the disease is currently unavailable. This study aims to prove that repression of oxidative stress modulates the differentiation of tendon-derived cells (TDCs) sustaining excessive tensi...

Background Gadolinium‐based contrast agents can be used to identify the blood–brain barrier (BBB) opening after inducing a focused ultrasound (FUS) cavitation effect in the presence of microbubbles. However, the use of gadolinium may be limited for frequent routine monitoring of the BBB opening in clinical applications. Purpose To use a gradient‐e...

Objective We investigated adding lower limb transcutaneous nerve stimulation or neuromuscular electrical stimulation to standard early rehabilitation in acute stroke patients. Design An assessor-blinded, randomized controlled pilot study. Setting A medical stroke center. Subjects First-stroke patients aged 20–80 years admitted to the stroke cent...

Resulting from accumulative microtrauma, impaired healing and oxidative stress, tendinopathy is a debilitating and relentlessly deteriorating disease that greatly affects daily function and quality of life. Current therapy usually provides symptomatic relief only. Sufferers undergo repetitive and protracted treatment courses that rarely alter the d...

Background Glenohumeral idiopathic adhesive capsulitis (GHIAC) is a common shoulder condition that hinders functionality. Addressing the pathology has been extensively researched. Ultrasound (US) guided injections have shown their efficacy. However, no study has been conducted to compare anatomical accuracy between different approaches in targeting...

Abstract Focused ultrasound (FUS) with the presence of microbubbles induces blood brain barrier (BBB) opening in targeted areas and facilitates drug delivery. However, recent studies have indicated that FUS-BBB opening with excessive exposure levels may be associated with inflammatory response and cellular/tissue damage. Multiple weekly FUS exposur...

Background: The incidence of falls on inpatient oncology units indicated the need for quality improvement. This project aimed to reduce falls by implementing a fall reduction plan including the "Traffic Light" Fall Risk Assessment Tool (TL-FRAT). Local problem: We retrospectively reviewed the oncology unit fall data from January 2013 to Septembe...

Transcranial pulsed ultrasound with microbubbles has been shown to temporally open the blood–brain barrier (BBB) to allow therapeutic agents to penetrate into the CNS for improved therapeutic efficacy. Recent studies have shown the feasibility of using passive cavitation detection (PCD) for monitoring or real-time control of the BBB opening in a fo...

Sonoporation, the use of ultrasound to alter the permeability of cell membranes, is a non-viral technique used to facilitate gene delivery, possibly by opening transient pores in the cell membrane. However, sonoporation may have negative bio-effects on cells, such as causing apoptosis, which limits its efficacy in gene delivery. In this study, we i...

Despite extensive efforts in recent years, the blood-brain barrier (BBB) remains a significant obstacle for drug delivery. This study proposes using a clinical extracorporeal shockwave instrument to open the BBB, combined with a laser assisted bi-axial locating platform to achieve non-invasive, controllable-focus and reversible BBB opening in the b...

Background: The International Knee Documentation Committee Subjective Knee Form (IKDC) and the Knee Injury and Osteoarthritis Outcome Score (KOOS) are knee-specific questionnaires that have been widely used and translated into numerous languages. However, the differences in the psychometric properties between the Chinese IKDC and KOOS remain uncle...

In the aim of limiting the destructive effects of collapsing bubbles, the regime of stable cavitation activity is currently targeted for sensitive therapeutic applications such as blood-brain barrier opening by ultrasound. This activity is quantified through the emergence of the subharmonic component of the fundamental frequency. Due to the intrins...

The effect of nanotopographies on cell adhesion, migration, proliferation, differentiation and/or apoptosis have been studied over the last two decades. However, the effect of nanotopography on gene transfection of adhered cells is far from understood. One key phenomenon of using nanotopography is mimicry of native cell morphology in vitro such as...

Cavitation plays a substantial role in the clinical effects of extracorporeal shock wave therapy (ESWT). It is also generally accepted as a major mechanism in sonophoresis. To identify the enhancing effect of extracorporeal shock wave-mediated transdermal drug delivery, 24 Wistar rats were randomly assigned to four groups: (i) topical application o...

The efficacy of genomic medicine depends on gene transfer efficiency. In this area, electroporation has been found to be a highly promising method for physical gene transfer. However, electroporation raises issues related to electrical safety, tissue damage, and the number of required wounds. Concentric-type needle electrodes seek to address these...

Although PEGylated polyplexes for gene delivery are widespread, there is a need for in-depth investigation on the role of the PEGylation degree on the delivery efficiency of the systems. For this, a low-toxicity series of polymers for gene delivery was designed via Michael addition of poly(ethylene glycol) methyl ether methacrylate (PEGMA) onto bra...

Background/purpose: To compare shear modulus of heel pad microchamber and macrochamber layers between young and elderly people using shear wave ultrasound elastography (SWUE), with the intent to clarify age-related changes. Methods: This single-center prospective cross-sectional study was conducted between March, 2014 and March, 2016. Shear modu...

Episodic release of bioactive compounds plays an important role in biological systems. “On-demand” release systems which based on polymeric materials and activated by external stimuli may provide the necessary functionality. Here we describe an ultrasound-responsive hydrogel based on N-isopropylacrylamide (NIPAM) and N,N′-methylenebisacrylamide (MB...

It is well established that electrical-stimulation frequency is crucial to determining the scale of induced neuromodulation, particularly when attempting to modulate corticospinal excitability. However, the modulatory effects of stimulation frequency are not only determined by its absolute value but also by other parameters such as power at harmoni...

Current clinical evaluations of post-stroke upper limb spasticity are subjective and qualitative. We proposed a quantitative measurement of post-stroke spastic muscle stiffness by using shear-wave ultrasound elastography and tested its reliability. Acoustic radiation force impulse with shear wave velocity (SWV) detection was used to evaluate stiffn...

[Purpose] No literature has described a suitable method for measuring muscle strength in a supine position during acute phase after stroke. This study investigated the feasibility and reliability of using a commercial handheld dynamometer to measure the muscle strengths of the hip flexor, knee extensor, and dorsiflexor in the supine position with a...

Objective: The aims of the study were (1) to assess whether a knowledge disparity existed between physical medicine and rehabilitation residents from community hospitals versus those from medical centers, before the introduction of short-term elective training at the end of 2008 and (2), if such disparity existed, to determine whether 1-month shor...

We have previously showed that IL-1β is involved in the pathogenesis of both spontaneously occurring and passively induced IgA nephropathy (IgAN) models. However, the exact causal-relationship between NLRP3 inflammasome and the pathogenesis of IgAN remains unknown. In the present study, we showed that [1] IgA immune complexes (ICs) activated NLRP3...

Sonoporation using mid-frequency high-pressure ultrasound is a nonviral approach for in-vitro and in-vivo gene delivery. However, partially due to the unstationary behavior of cavitation microbubble cloud, sonoporation effect is usually unrepeatable, especially in low intensity conditions. This appears as a main drawback for therapeutic application...

This paper presents an assistive control system with a special kinematic structure of an upper limb rehabilitation robot embedded with force/torque sensors. A dynamic human model integrated with sensing torque is used to simulate human interaction under three rehabilitation modes: active mode, assistive mode, and passive mode. The hereby proposed r...

2-methacryloyloxy ethyl trimethyl ammonium chloride (TMA) is a potent polymeric plasma DNA (pDNA) carrier. The present study shows that TMA/pDNA polyplexes could be internalized into cells efficiently, but could not mediate gene transfection on its own. The transfection process of TMA/pDNA polyplexes is turned on only when ultrasound (US) was appli...

In this study, we aimed to determine whether the combination of electroporation (EP) and ultrasound (US) waves (sonoporation) can result in an increased intracellular delivery of anticancer drug bleomycin. CHO cells were treated with electric pulses (1 or 8 high voltage pulses of 800 or 1200 V/cm, 100 μs or 1 low voltage pulse of 100 or 250 V/cm, 1...

Imaging of the nerves in the cervical region is more complicated than those of the extremities. Although high-resolution ultrasound enables the depiction of peripheral nerves' morphology and their associations with the adjacent soft tissues, precise identification of the nerves in the neck is still challenging. Familiarization with the cervical ner...

A previous study that investigated the effect of ultrasound (US) on the transdermal permeation of the non-steroidal anti-inflammatory drug diclofenac found that therapeutic US can increase circulation in an inflamed joint and decrease arthritic pain. Transdermal drug delivery has recently been demonstrated by US combined with microbubbles (MB) cont...

Compared with the upper limbs, sonographic tracking of peripheral nerves in the lower limbs is more challenging. The overlying muscles are larger, hindering visualization of the deeply embedded nerves by using a linear transducer. The use of a curvilinear transducer-providing an extended view with better penetration for the field of interest-may be...

Objective: The purposes of this study were to determine the best cutoff value for bicipital peritendinous effusion (BPE) and to test its diagnostic performance as regards shoulders with and without rotator cuff pathology. Design: We reviewed the sonographic reports of 1352 patients with suspected shoulder disorders between January 2011 and June...

Purpose: To investigate the feasibility of half-Fourier acquisition single-shot turbo spin-echo (HASTE) for real-time monitoring of signal changes because of water flow induced by inertial cavitation (IC) during microbubbles (MBs)-present focused ultrasound (FUS) exposure. Theory and methods: Strong turbulence produced in MB solution at the onse...

In this study, we describe the development of surface-modified chitosan substrates to examine topographically related Neuro-2a cell behaviors. Different functional groups can be modified on chitosan surfaces to probe Neuro-2a cell morphology. To prepare chitosan substrates with micro/nano-scaled features, we demonstrated an easy-to-handle method th...

Background: Protocols to induce motor related neuroplasticity are usually directed to central neural structures such as the motor cortex or the spinal cord. Objective: Herein, we aimed to evaluate the effects of peripheral nerve stimulation using a current intensity (stimulation intensity) approach to understand the contribution of the corticosp...

In this protocol, the patient/probe positionings, anatomical drawings and ultrasound images of commonly scanned ankle/foot structures are described. This practical guide is prepared (with an international consensus of several expert physiatrists) to serve as a uniform/standard approach especially for beginner sonographers.

Purpose: To evaluate the elasticity of the coracohumeral ligament (CHL) in healthy individuals and patients with clinical findings suggestive of unilaterally involved adhesive capsulitis of the shoulder (ACS). Materials and methods: The institutional review board approved this single-institution prospective study, which was performed between Nov...

How aging affects the elasticity of tendons has long been debated, partly because of the limited methods for in vivo evaluation, which differ vastly from those for in vitro animal studies. In this study, we tested the reliability of shear wave elastography (SWE) in the evaluation of patellar tendons and their change in elasticity with age. We recru...

To investigate plantar fascia elasticity in patients with typical clinical manifestations of plantar fasciitis but normal plantar fascia morphology on B-mode sonography. Twenty patients with plantar fasciitis (10 unilateral and 10 bilateral) and 30 healthy volunteers, all with normal plantar fascia morphology on B-mode sonography, were included in...

In this protocol, the patient/probe positionings, anatomical drawings and ultrasound images of commonly scanned wrist/hand structures are described. This practical guide is prepared (with an international consensus of several expert physiatrists) to serve as a uniform/standard approach especially for beginner sonographers.

In this protocol, the patient/probe positionings, anatomical drawings and ultrasound images of commonly scanned shoulder structures are described. This practical guide is prepared (with an international consensus of several expert physiatrists) to serve as a uniform/standard approach especially for beginner sonographers.

In this protocol, the patient/probe positionings, anatomical drawings and ultrasound images of commonly scanned elbow structures are described. This practical guide is prepared (with an international consensus of several expert physiatrists) to serve as a uniform/standard approach especially for beginner sonographers.

Ultrasound has been the most useful imaging tool for musculoskeletal disorders whereby peripheral nerve lesions constitute a substantial portion. High-resolution ultrasound enables elaboration of peripheral nerve morphology and reciprocal anatomy. However, limited literature is available for delineating standard positions and tracking skills. The p...

Polyethylenimine (PEI) and poly(2-(dimethylamino) ethyl methacrylate) (PDMAEMA) have both been used for DNA delivery. PDMAEMA has been shown to exhibit better gene transfection efficiency but lower expression ability than PEI. We mixed the two polymers at different ratios to investigate whether or not the resulting "dual" polyplex (PEI/PDMAEMA/DNA)...