In Vivo Intelligent Fluorescence Endo-Microscopy by Varifocal Meta-Device and Deep Learning.

Endo-microscopy is crucial for real-time 3D visualization of internal tissues and subcellular structures. Conventional methods rely on axial movement of optical components for precise focus adjustment, limiting miniaturization and complicating procedures. Meta-device, composed of artificial nanostructures, is an emerging optical flat device that can freely manipulate the phase and amplitude of light. Here, an intelligent fluorescence endo-microscope is developed based on varifocal meta-lens and deep learning (DL). The breakthrough enables in vivo 3D imaging of mouse brains, where varifocal meta-lens focal length adjusts through relative rotation angle. The system offers key advantages such as invariant magnification, a large field-of-view, and optical sectioning at a maximum focal length tuning range of ≈2 mm with 3 µm lateral resolution. Using a DL network, image acquisition time and system complexity are significantly reduced, and in vivo high-resolution brain images of detailed vessels and surrounding perivascular space are clearly observed within 0.1 s (≈50 times faster). The approach will benefit various surgical procedures, such as gastrointestinal biopsies, neural imaging, brain surgery, etc.

Update of Contrast-enhanced Ultrasound in Musculoskeletal Medicine: Clinical Perspectives - A Review.

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 application of CEUS in the MSK field, focusing on 67 articles published between January 2001 and June 2021 in online databases including PubMed, Scopus, and Embase. CEUS has been widely used for the clinical assessment of muscle microcirculation, tendinopathy, fracture nonunions, sports-related injuries, arthritis, peripheral nerves, and tumors, and can serve as an objective and quantitative evaluation tool for prognosis and outcome prediction. Optimal CEUS parameters and diagnostic cut off values for each disease category remain to be confirmed.

Three Ways to Improve Arm Function in the Chronic Phase After Stroke by Robotic Priming Combined With Mirror Therapy, Arm Training, and Movement-Oriented Therapy.

OBJECTIVE: To examine the effects of bilateral robotic priming combined with mirror therapy (R-mirr) vs 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, preliminary, randomized controlled trial. SETTING: Four outpatient rehabilitation settings. PARTICIPANTS: Outpatients with stroke and mild to moderate motor impairment (N=63). INTERVENTIONS: Patients received 6 weeks of clinic-based R-mirr, R-bilat, or R-mov for 90 min/d, 3 d/wk, plus a transfer package at home for 5 d/wk. MAIN OUTCOME MEASURES: Fugl-Meyer Assessment Upper Extremity subscale (FMA-UE), ABILHAND, and Stroke Impact Scale v3.0 scores before, immediately after, and 3 months after treatment as well as lateral pinch strength and accelerometry before and immediately after treatment. RESULTS: The posttest results favored R-mirr over R-bilat and R-mov on the FMA-UE score (P<.05). Follow-up analysis revealed that significant improvement in FMA-UE score was retained at the 3-month follow-up in the R-mirr over R-bilat or R-mov (P<.05). Significant improvements were not observed in the R-mirr over R-bilat and R-mov on other outcomes. CONCLUSIONS: Between-group differences were only detected for the primary outcome, FMA-UE. R-mirr was more effective at enhancing upper limb motor improvement, and the effect has the potential to be maintained at 3 months of follow-up.

Plantar Fasciitis: An Updated Review.

Plantar fasciitis (PF) is a common musculoskeletal disease. Histologic findings of patients with PF showed mainly chronic degenerative processes rather than inflammation. In addition to mechanical factors, such as repetitive stress and reduced ankle dorsiflexion, PF is also linked to rheumatologic diseases and genetic factors. Ultrasound is becoming a standard imaging technique for assessing PF. Major sonographic findings included increased plantar fascia thickness and hypoechoic plantar fascia. In addition to traditional B-mode ultrasound, sonoelastography can also be utilized to diagnose PF. Ultrasound can also be used to guide therapeutic interventions. Over 80% of patients with PF improved under nonsurgical treatment. Treatment options for PF include physical therapy, modalities (laser, therapeutic ultrasound), extracorporeal shock wave therapy (ESWT), injections, transcatheter arterial embolization, and surgery. For injections, corticosteroid was mostly used in the past but has been replaced gradually by other techniques such as platelet-rich plasma or dextrose prolotherapy. There is also more and more evidence about ESWT in treating PF. Surgery serves as an option for recalcitrant PF cases, and endoscopic fasciotomy seemed to have good outcomes. Ultrasound plays an important role in diagnosing of PF and evaluating the treatment effect, and the use of sonoelastography in addition to traditional B-mode ultrasound may help in the early detection of PF and assessment of the treatment effect.

Focused Ultrasound Promotes the Delivery of Gastrodin and Enhances the Protective Effect on Dopaminergic Neurons in a Mouse Model of Parkinson's Disease.

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 diseases. In this study, we explored the therapeutic potential of FUS-mediated blood-brain barrier (BBB) opening of the left striatum to deliver gastrodin (GAS) in a subacute PD mouse model induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). The concentration of GAS in the left hemisphere was detected by ultra-high performance liquid chromatography electrospray Q-Orbitrap mass spectrometry (UHPLC/ESI Q-Orbitrap) and the distribution of tyrosine hydroxylase (TH) neurons was detected by immunohistochemical staining. The expression of TH, Dopamine transporter (DAT), cleaved-caspase-3, B-cell lymphoma 2 (Bcl-2), brain-derived neurotrophic factor (BDNF), postsynaptic density protein 95 (PSD-95), and synaptophysin (SYN) protein were detected by western blotting. Analysis showed that the concentration of GAS in the left hemisphere of PD mice increased by approximately 1.8-fold after the BBB was opened. FUS-mediated GAS delivery provided optimal neuroprotective effects and was superior to the GAS or FUS control group. In addition, FUS enhanced GAS delivery significantly increased the expression of Bcl-2, BDNF, PSD-95, and SYN protein in the left striatum (P < 0.05) and reduced the levels of cleaved-caspase-3 remarkably (P = 0.001). In conclusion, the enhanced delivery by FUS effectively strengthened the protective effect of GAS on dopaminergic neurons which may be related to the reinforcement of the anti-apoptotic activity and the expression of synaptic-related proteins in the striatum. Data suggests that FUS-enhanced GAS delivery may represent a new strategy for PD treatment.

Facilitating drug delivery in the central nervous system by opening the blood-cerebrospinal fluid barrier with a single low energy shockwave pulse.

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. METHODS: This study demonstrates a method on SD rats for reversible and site-specific opening of the BCSFB via a noninvasive, low-energy focused shockwave (FSW) pulse (energy flux density 0.03 mJ/mm2) with SonoVue microbubbles (2 × 106 MBs/kg), posing a low risk of injury. RESULTS: By opening the BCSFB, the concentrations of certain CNS-impermeable indicators (70 kDa Evans blue and 500 kDa FITC-dextran) and drugs (penicillin G, doxorubicin, and bevacizumab) could be significantly elevated in the CSF around both the brain and the spinal cord. Moreover, glioblastoma model rats treated by doxorubicin with this FSW-induced BCSFB (FSW-BCSFB) opening technique also survived significantly longer than untreated controls. CONCLUSION: This is the first study to demonstrate and validate a method for noninvasively and selectively opening the BCSFB to enhance drug delivery into CSF circulation. Potential applications may include treatments for neurodegenerative diseases, CNS infections, brain tumors, and leptomeningeal carcinomatosis.

Investigation of the Therapeutic Effect of Doxorubicin Combined With Focused Shockwave on Glioblastoma.

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 transcranial focused ultrasound (FUS) has recently been investigated for opening the BBB to facilitate drug delivery. A special form of FUS, the shockwave (SW), has also been shown to open BBB efficiently. SW has several advantages including no heating effect, less reactive oxygen species production, good transcranial ability, and no need to supply microbubbles. METHODS: We employed a commercial SW device, which is a common tool used for musculoskeletal disorders, to improve doxorubicin delivery across the BBB and evaluated its therapeutic efficacy on GBM rat models. SW emits relatively short but stronger mechanical pulses comparing with FUS. RESULTS: The results demonstrated that doxorubicin combined with SW treatment substantially inhibited tumor growth and prolonged overall survival. CONCLUSIONS: The present study shows the non-invasive transcranial SW may have potential for the treatment of GBM in future clinical setting.

Pathogenic Hydrogel? A Novel-Entrapment Neuropathy Model Induced by Ultrasound-Guided Perineural Injections.

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 currently lacking, thus limiting our understanding of the disease and the development of effective therapies. In this proof-of-concept study, we used ultrasound-guided perineural injection of a methoxy poly(ethylene glycol)-b-Poly(lactide-co-glycoilide) carboxylic acid (mPEG-PLGA-BOX) hydrogel near the rat's sciatic nerve to induce EN, as confirmed sonographically, electrophysiologically, and histologically. The nerve that was injected with hydrogel appeared unevenly contoured and swollen proximally with slowed nerve conduction velocities across the injected segments, thus showing the compressive features of EN. Histology showed perineural cellular infiltration, deposition of irregular collagen fibers, and a possible early demyelination process, thus indicating the existence of adhesions. The novel method provides a surgery-free and cost-effective way to establish a small-animal model of EN that has mixed compression and adhesion features, thus facilitating the additional elucidation of the pathophysiology of EN and the search for promising treatments.

The additive efficacy of therapeutic low-intensity pulsed ultrasound in the treatment of vitiligo: A randomized, left-right comparison clinical trial.

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 for repigmentation of vitiligo. Twenty-seven adult patients with stable generalized vitiligo on the face or trunk were recruited in this randomized, open, left-right comparison study. In each patient, two symmetric lesional sites were randomly selected; one was assigned as the target lesion, which was treated with add-on LIPUS twice weekly for 24 weeks, and the other as the control lesion, which was administrated with sham sonification. The primary outcome was the difference of repigmentation degree between the target and control lesions at week 24, based on the 7-point physician global assessment score. At the end of study, 23 patients with vitiligo on the face (n = 10) or trunk (n = 13) completed the 24-week treatment course. Enhanced repigmentation for vitiligo receiving LIPUS as compared to sham sonification was observed in 38.5% (5/13) of the patients with truncal vitiligo, but none of those with facial vitiligo. Truncal vitiligo (P = .046) and higher intensity of LIPUS administered (P = .01) were statistically significantly associated with the effectiveness of additive LIPUS treatment. The LIPUS treatment was well-tolerated without remarkable adverse effects. This pilot study showed that LIPUS could provide therapeutic benefits and could be considered as a treatment adjunct for truncal vitiligo.

A Single High-Intensity Shock Wave Pulse With Microbubbles Opens the Blood-Brain Barrier in Rats.

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 reduced by the addition of microbubbles (ultrasound contrast agents or UCA; SonoVue). FSW with 2 × 106 MBs/kg of UCA (20% of clinical dosage) at an intensity level of 0.1 (peak positive pressure 5.4 MPa; peak negative pressure -4.2 MPa; energy flux density 0.03 mJ/mm2) resulting in a 100% BBB opening rate without detectable hemorrhage or apoptosis in the brain. Significantly reduced free radical production was found compared with 0.5 MHz focused ultrasound at a peak negative pressure of 0.44 MPa (1% duty cycle and 4 × 107 MBs/kg of UCA). FSW devices offer advantages of commercial availability and high safety, and thus may facilitate future research and applications of focal BBB opening for oncological and pharmacological purposes.

Sonoelastographic evaluation of plantar fascia after shock wave therapy for recalcitrant plantar fasciitis: A 12-month longitudinal follow-up study.

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 visual analogue scale (VAS, 0-100) was used for evaluating heel pain severity. B-mode sonography and strain sonoelastography were used for evaluating the PF thickness and stiffness. The sonoelastogram was analyzed using hue histogram analysis (value: 0-255, from stiffer to softer). All evaluations were recorded before ESWT, and 1 week, 1 month, 3 months, 6 months, and 12 months after ESWT. Repeated measures ANOVA was used to compare pain VAS, PF thickness, and PF hue value at different follow-up time-points. Twenty-two participants (8 men, 14 women) completed all measurements for 12 months. The VAS of heel pain, PF thickness, and PF hue values at pre-ESWT, and 1-week, 1-month, 3-month, 6-month, and 12-month evaluations after ESWT were 62.4 ± 4.2, 49.3 ± 5.8, 38.3 ± 5.7, 27.9 ± 5.3, 18.9 ± 4.7, and 13.2 ± 3.0 (p < 0.01 in all measurements post ESWT versus pre-ESWT); 5.57 ± 0.22 mm, 5.64 ± 0.18 mm, 5.45 ± 0.24 mm, 5.37 ± 0.20 mm, 5.08 ± 0.20 mm, and 4.62 ± 0.15 mm (p < 0.01 at 6-month; otherwise p > 0.05); and 24.5 ± 2.4, 35.2 ± 3.1, 31.0 ± 4.1, 30.5 ± 3.9, 21.4 ± 2.1, and 15.9 ± 1.6 (p < 0.01 at 1-week and 6-month; otherwise p > 0.05), respectively. In conclusion, the heel pain intensity and PF thickness reduced gradually over 12 months after ESWT. The PF stiffness decreased during the first week and increased thereafter; at the 12-month follow-up, stiffness was more than at pre-ESWT.

In vivo third-harmonic generation microscopy study on vitiligo patients.

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 (THGM) study was first conducted on vitiliginous skin. As a result, the THG-brightness ratio between the melanin-lacking cytoplasm of basal cells and collagen fibers is about 1.106 at the dermal-epidermal junctions of vitiliginous skin, indicating high sensitivity of THGM for the presence of melanin. We further applied the in vivo THGM to assist evaluating the therapeutic outcome from the histopathological point of view for those showed no improvement under narrowband ultraviolet B therapy based on the seven-point Physician Global Assessment score. Our clinical study indicates the high potential of THGM to assist the histopathological assessment of the therapeutic efficacy of vitiligo treatments.

Fall Risk Program for Oncology Inpatients: Addition of the "Traffic Light" Fall Risk Assessment Tool.

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 September 2014 and found that the average fall incidence was high. METHODS: The project used a program evaluation design, and the process was guided by Kotter's 8-step change model. INTERVENTIONS: We implemented the TL-FRAT to classify oncology inpatients at a high risk of falling in advance. RESULTS: The average fall incidence and falls with injury during the project were reduced. CONCLUSIONS: Adding the TL-FRAT to the fall protocol on the units effectively reduced the incidence of falls related to impaired mobility. The TL-FRAT can improve nurses' sensitivity to falls related to impaired mobility and, subsequently, guide corresponding fall prevention strategies.

NLRP3 inflammasome: Pathogenic role and potential therapeutic target for IgA nephropathy.

We have previously showed that IL-1ß 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 inflammasome in macrophages involving disruption of mitochondrial integrity and induction of mitochondrial ROS, bone marrow-derived dendritic cells (BMDCs) and renal intrinsic cells; [2] knockout of NLRP3 inhibited IgA ICs-mediated activation of BMDCs and T cells; and [3] knockout of NLRP3 or a kidney-targeting delivery of shRNA of NLRP3 improved renal function and renal injury in a mouse IgAN model. These results strongly suggest that NLRP3 inflammasome serves as a key player in the pathogenesis of IgAN partly through activation of T cells and mitochondrial ROS production and that a local, kidney-targeting suppression of NLRP3 be a therapeutic strategy for IgAN.

Intracellular triggered release of DNA-quaternary ammonium polyplex by ultrasound.

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 applied 4-8h after incubating TMA/pDNA polyplexes with target cells (with a gene expression 1000 times that of the immediate US group). US is a widely used physical method for gene delivery; its transfection efficiency can be significantly enhanced when combined with cationic polymer vectors. Traditionally, US is given simultaneously with genetic materials, carriers and microbubbles to exert maximal efficacy. The unique on-off phenomenon of TMA/pDNA polyplexes, controlled by US exposure, was found to relate to the endosomal escape effect of US since the polyplexes colocalized well with the lysosome marker if no US was given or was given at inappropriate times. The proposed delivery system using US and TMA carriers has potential in many pharmaceutical applications requiring precise temporal and spatial release control.

Intracellular Delivery of Bleomycin by Combined Application of Electroporation and Sonoporation in Vitro.

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, 100 ms) and with 880 kHz US of 320 or 500 kPa peak negative pressure, 100 % duty cycle, applied for 2 s in the presence or absence of exogenously added contrast agent microbubbles. Various sequential or simultaneous combinations of EP and sonoporation were used. The results of the study showed that i) sequential treatment of cells by EP and sonoporation enhanced bleomycin electrosonotransfer at the reduced energy of electric field and US; ii) sequential combination of EP and sonoporation induced a summation effect which at some conditions was more prominent when the cells were treated first by EP and then by sonoporation; iii) the most efficient intracellular delivery of bleomycin was achieved by the simultaneous application of cell EP and sonoporation resulting in percentage of reversibly porated cells above the summation level; and iv) compared with sequential application of EP and sonoporation, simultaneous use of electric pulses and US increased cell viability in the absence of bleomycin.

Efficacy of Combined Ultrasound-and-Microbubbles-Mediated Diclofenac Gel Delivery to Enhance Transdermal Permeation in Adjuvant-Induced Rheumatoid Arthritis in the Rat.

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) contrast agent (henceforth referred to as "US-MB"). The present study evaluated the efficacy of US-MB-mediated diclofenac delivery for treating adjuvant-induced rheumatoid arthritis (RA) in rats. RA was induced by injecting 100 µL of complete Freund's adjuvant into the ankle joint of male Sprague-Dawley rats (250-300 g) that were randomly divided into five treatment groups: (i) carbopol gel alone (the control [group C]), (ii) diclofenac-carbopol gel (group D), (iii) US plus carbopol gel (group U), (iv) US plus diclofenac-carbopol gel (group DU) and (v) US-MB plus diclofenac-carbopol gel (group DUB). The ankle width was measured over 10 d using high-frequency (40-MHz) US B-mode and color Doppler-mode imaging, covering the period before and after treatment. Longitudinal US images of the induced RA showed synovitis and neovascularity. Only a small amount of neovascularity was observed after treatment. The recovery rate on day 10 was significantly higher in group DUB (97.7% ± 2.7%, mean ± standard deviation [SD]) than in groups C (1.0% ± 2.7%), D (37.5% ± 4.6%), U (75.5% ± 4.2%) and DU (87.3% ± 5.2%) (p < 0.05). The results obtained indicate that combining US and MB can increase the skin permeability and thereby enhance the delivery of diclofenac sodium gel and thereby inhibit inflammation of the tissues surrounding the arthritic ankle. Color Doppler-mode imaging revealed that US-MB treatment induced a rapid reduction in synovial neoangiogenesis in the arthritic area.

Synergistic Effect of PEI and PDMAEMA on Transgene Expression in Vitro.

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 the resulting "dual" polyplex (PEI/PDMAEMA/DNA) could enhance both gene transfection efficiency and DNA expression ability. Experimental results showed a significant increase in DNA internalization and DNA expression for the PDMAEMA/PEI/DNA polyplexes at a ratio of 1:3 or 1:9 (PDMAEMA: PEI), depending on cell type, in comparison with PEI/DNA, PDMAEMA/DNA, and PDMAEMA/PEI/DNA at other ratios. PDMAEMA/PEI/DNA polyplexes did not reduce cell viability. In contrast to with the conventional approach using covalently modified PEI, the proposed "combination" approach provided a more convenient and effective way to improve transgene expression efficiency.

Nineteen reasons why physiatrists should do musculoskeletal ultrasound: EURO-MUSCULUS/USPRM recommendations.

This article is an eventual consensus of experts from the European Musculoskeletal Ultrasound Study Group (EURO-MUSCULUS) and the Ultrasound Study Group in Physical and Rehabilitation Medicine (USPRM) pertaining to the use of musculoskeletal ultrasound in physical and rehabilitation medicine. Nineteen important reasons (as regards general advantages, specific conditions in physical and rehabilitation medicine, as well as comparisons with other imaging tools) have been highlighted to consolidate the scenario of how/why the probe of ultrasound needs to become the stethoscope, the extended hand, and the pen of physiatrists.

Early Versus Delayed Passive Range of Motion Exercise for Arthroscopic Rotator Cuff Repair: A Meta-analysis of Randomized Controlled Trials.

BACKGROUND: Postoperative shoulder stiffness complicates functional recovery after arthroscopic rotator cuff repair. PURPOSE: To compare early passive range of motion (ROM) exercise with a delayed rehabilitation protocol with regard to the effectiveness of stiffness reduction and functional improvements and rates of improper healing in patients undergoing arthroscopic repair for torn rotator cuffs. STUDY DESIGN: Systematic review and meta-analysis. METHODS: Randomized controlled trials (RCTs) comparing both rehabilitation approaches were identified in PubMed and Scopus. Between-group differences in shoulder function were transformed to effect sizes for comparisons, whereas the effectiveness against stiffness and the risk of tendon failure were reported using standardized mean differences of ROM degrees and odds ratios (ORs) of recurrent tears, respectively. RESULTS: Six RCTs were included, consisting of 482 patients. No significant difference in shoulder function existed across both protocols. The early ROM group demonstrated more improvement in shoulder forward flexion than the delayed rehabilitation group, with a standardized mean difference of 7.45° (95% CI, 3.20°-11.70°) at 6 months and 3.51° (95% CI, 0.31°-6.71°) at 12 months. Early ROM exercise tended to cause a higher rate of recurrent tendon tears (OR, 1.43; 95% CI, 0.90-2.28), and the effect became statistically significant (OR, 1.93; 95% CI, 1.04-3.60) after excluding 2 RCTs that recruited only those patients with small to medium-sized tears. CONCLUSION: Early ROM exercise accelerated recovery from postoperative stiffness for patients after arthroscopic rotator cuff repair but was likely to result in improper tendon healing in shoulders with large-sized tears. The choice of either protocol should be based on an accommodation of the risks of recurrent tears and postoperative shoulder stiffness.