Sports Medicine And Regenerative Therapy (SMART)

Prof. YUNG Shu-hang, Patrick (ORCID)	Prof. LI Gang (ORCID)	Prof. WANG Huating (ORCID)
Prof. ONG Tim-yun, Michael	Prof. LING Ka-kin, Samuel (ORCID)	Dr. HO Ki-wai, Kevin (ORCID)
Prof. LEE Yuk-wai, Wayne (ORCID)

Sports Medicine And Regenerative Therapy (SMART) research theme focuses on translational research to prevent and treat sports injuries, supported by the development of advanced therapy products including stem cells and biomaterials. We have two specialized research teams working together for bench-to-bedside-to-community translational research. The sports medicine research team devises novel treatments and rehabilitation protocols for patients with sports injuries to return-to-play. We also study pathogenesis and injury mechanisms of various sports injuries, and apply this knowledge for injury prevention as well as health promotion by exercise. The regenerative therapy research team investigates basic science of stem cells and strategies to facilitate stem cell therapy. Apart from circulating stem cells and controlled de-differentiation, regulation of tissue regeneration by distraction histogenesis and non-coding RNA are major research directions. In addition to graft healing in anterior cruciate ligament reconstruction (ACLR), we also work on regenerative strategies for tendon, muscle and cartilage.

ACL reconstruction (ACLR) can partially restore knee stability , but functional recovery is always compromised by poor graft healing and persistent quadriceps muscle weakness after surgery; while regain of proprioception and psychological readiness during rehabilitation also affect return-to-play. We have investigated various biological enhancements for graft healing and recently proceed to tackle muscle weakness after ACLR. As current assessments of functional recovery after ACLR are not good enough for decision making of return-to play, our applied research team strive to develop kinematic assessments of knee stability with discriminative motion tasks, which will also help to implement preventive training program to reduce risk of ACL injuries in athletes.

Bone Tendon Junction Healing
(PI: Prof. Yung SH Patrick, Prof. Ong TY Michael)

Our Concept

Bone tendon junction (BTJ) is characterized by a thin layer of fibrocartilage tissue that mediate transition of tendinous to osseous tissues. Natural healing process cannot regenerate BTJ. It is essential to promote timely tenogenic and osteogenic processes to enable reconnection of the anchoring collagen fibres.

Innovative Research

Selected Publication

Establishment of rat ACL reconstruction model

Assessment of Knee Stability and Return-To-Play
(PI: Prof. Yung SH Patrick, Prof. Ong TY Michael)

Our Concept

Knee stability is contributed by knee laxity and neuromuscular control. Objective assessment methods are necessary to assist decision making of safe return-to-play. Safeguarding muscle function by implementation of injury prevention programme is also essential.

Innovative Research

Selected Publication

Ultrasound shear wave elastography

Knee kinematics and kinetics during single leg hop landing

Pathogenesis of Tendinopathy
(PI: Prof. Yung SH Patrick, Prof. Ong TY Michael, Prof. Ling KK Samuel)

Our Concept

Pathogenesis of tendinopathy primarily involves failed tendon healing, in which normal tendon healing process is deregulated under the influences of a number of stressful conditions, which are originated from known risk factors (overuse, diabetes).

Innovative Research

Our research include analysis of clinical samples, mechanistic studies in cell culture, establishment of representative animal models and evaluation of treatment effects in tendinopathy patients.

Selected Publication

Analysis of clinical samples of tendinopathy

Prevention and Management of Rotator Cuff Tendinopathy
(PI: Prof. Yung SH Patrick)

Our Concept

Scapular dyskinesis is one of the contributing factors to rotator cuff tendinopathy. Scapular muscle deficits have been shown to alter the scapular kinematics and contribute to the reduction of the subacromial space in patients with rotator cuff tendinopathy.

Innovative Research

Our research aimed to investigate the effects of scapular-focused exercise programme on scapular kinematics, subacromial space, and shoulder pain and function in patients with rotator cuff tendinopathy.

Selected Publication

Isometric scapular strength test by Digital Handheld Dynamometer

Shoulder biomechanics assessment

Ultrasound measurement of subacromial space & upper trapezius stiffness

Scapular-focused training

Tendon Derived Stem Cells
(PI: Prof. Li Gang, Prof. Yung SH Patrick)

Our Concept

Tendon injuries are difficult to manage, especially in cases of bone tendon junction healing. With the discovery of tendon derived stem cells (TDSC), we intend to construct an engineered tendon by stem cells and growth factors without exogenous scaffolds. TDSC also play an important role in failed tendon healing in tendinopathy.

Innovative Research

Tendon stem/progenitor cells, as a new cell type, was firstly identified in both human and mouse tendon tissues in 2007, and we also isolated and characterized this unique stem cell population from rat tendon tissues. We have found that tendon-derived stem cells (TDSCs) have higher mRNA expression of tenomodulin (Tnmd), scleraxis (Scx), type I collagen (Col1A1), decorin (Dcn) and biglycan (Bgn) than that of bone marrow derived mesenchymal stem cells (BMSCs). Our recent study further demonstrated TDSCs could promote earlier and better recovery after tendon injury as a new cell source for tendon repair The ectopic bone formation in tendon after transplantation of MSCs is an unwanted side effect. To avoid this potential risk, we propose that tenogenic differentiation of TDSCs in vitro may promote tendon healing and alleviate the risk of complication such as ectopic bone formation after transplantation of tenogenic TDSCs in vivo. We have successfully constructed engineering scaffold-free tendon tissue using TDSCs cell sheet in vitro,the engineered scaffold-free tendon tissue promoted tendon healing in a rat patellar tendon window injury model.

Selected Publication

Tendon-derived progenitor cells and fibroblasts

High-resolution 3-D ultrasound imaging of rat patellar tendon

Muscle Strengthening in the Elderly

Our Concept

To facilitate our biggest portion of the population to age well in our community, healthy and active lifestyle should be promoted among the young-olds and elderlies, with focus on muscle strengthening.

Innovative Research

The "Mus-fit Action" health promotion project aims at training Mus-Fit Ambassadors to coach local young olds and elderly to establish habits of regular exercise, hence promote musculoskeletal health. A set of stretching and muscle strengthening exercise is designed and coached by 'Mus-fit' ambassadors. The effectiveness of this exercise training will be evaluated by on-line musculoskeletal health survey and on-site assessment of muscle strength and fitness.

Persistent Quadriceps Weakness after ACLR
(PI: Prof. Ong TY Michael, Prof. Yung SH Patrick)

Our Concept

Apart from instability and pain, knee injuries commonly result in muscle weakness which is a major obstacle of functional recovery. Arthogenic muscle inhibition (AMI) represents long-lasting inability to fully activate the quadriceps muscle, which is thought to be contributed by joint inflammation, effusion, pain and reflex inhibition. Functional deficits due to AMI may further interact with persistent muscle atrophy which may be attributed to disturbances in myokines. We propose to tackle these clinical conditions of muscle weakness by biological intervention and preventive measures.

Innovative Research

Gene Regulation
(PI: Prof. Wang HT)

Our Concept

Gene regulatory mechanisms are crucial in determining cell identity and cell fate. Transcription factors (TFs), Enhancers, non-coding RNA (ncRNAs) and RNA binding proteins (RBPs) are key elements in regulating gene expression at transcriptional and post-transcriptional levels and they remain as the focus of our research.

Innovative Research

We study gene regulatory mechanisms in the system of adult skeletal muscle regeneration and muscle stem cells. Skeletal muscle has a remarkable ability to regenerate after injury owing to its resident muscle stem cells (also called satellite cells, SCs) which normally lie quiescently beneath muscle fiber. SCs can quickly activate and proliferate following injury, then differentiate and fuse into myofiber; meanwhile a subset of SCs undergoes self-renewal and returns to quiescent state to replenish the adult stem cell pool. Each state of the myogenic lineage progression is orchestrated by complex gene regulatory networks of intrinsic and extrinsic factors/mechanisms. Disruption of the regulations may render their loss of ability to regenerate, contributing to muscle wasting conditions such as muscular dystrophy, cachexia, and sarcopenia that are prevalent in our society. Better understanding of the gene regulatory mechanisms underlying skeletal muscle regeneration through our research will aid future therapeutic development of treatment for muscle damages and diseases.

Selected Publication

De-differentiation
(PI: Prof. Li Gang, Prof. Lee YW Wayne)

Our Concept

With it multipotent differentiation ability, it is of great research interest to investigate and use MSCs for functional tissue engineering. Poor therapeutic outcome is often the hindrance to this cellular therapy. Various attempts have been suggested to enhance the survivability and differentiation ability of MSCs in vivo, but complicated manipulation and foreign genes introduction may elicit another safety concerns. With these, we propose a simple manipulation to enhance the capability of MSCs for tissue regeneration.

Innovative Research

MSCs have been proven to promote cartilage regeneration in osteoarthritis and chondral defect animal models. However, clinical trials showed that transplanted MSCs in osteoarthritis patients showed poor viability and the chondrogenic differentiation ability is still controversial. Previous study showed that two-phases differentiation procedure (de-differentiation) promoted survivability and differentiation potential of MSCs (illustrated below). With this, we aim to investigate if this de-differentiation process is also to promote the chondrogenic or osteogenic differentiation of MSCs and its survivability in vivo.

We proved that chondrogenic de-differentiated MSCs (De-chondro-MSCs) is more resistant to cytotoxic agent and showed higher chondrogenic differentiation than untreatead MSCs in vitro. Moreover, De-chondro-MSCs exhibited higher cell survivability and better cartilage regeneration in vivo. With these, we demonstrated that de-differentiation process could be an effective alternative to promote the clinical application of MSCs in tissue regeneration.

Selected Publication

Circulating Stem Cells
(PI: Prof. Li Gang, Prof. Lee YW Wayne)

Our Concept

Mesenchymal stem cells (MSCs) have been found in cord blood and peripheral blood (PB) of mammalian species including human, guinea pig, mice, rat, dog, horse and rabbit. The number of MSCs in PB (PB-MSCs) is rare and their biological role was not fully defined. PB-MSCs are new cell source of cells that may play very important roles in development, repair and disease progression. PB-MSCs may be used for disease monitoring, diagnosis, cell and gene therapy applications.

Innovative Research

We have found increased numbers of circulating MSCs in peripheral blood in patients with long bone fracture, non-union and in patients with cancers. The number of PB-MSCs was approximately 9 times higher in the cancer patients, suggesting there is systemic recruitment of MSCs during cancer development. We have compared the difference between the circulating MSCs and bone marrow derived MSCs and found that they share similar phenotype in vitro, but the gene expression profile between the two cell populations was significantly different. cDNA microarray analysis and quantitative RT-PCR confirmed some genes that are differentially expressed with more than 10 folds difference, such as cellular retinol-binding protein 1 (CRBP1), N-cadherin, SRY-box containing gene 11 (Sox11), the aquaporin 1 (AQP1), et al. These genes are now being further investigated for their role in MSCs migration, homing and multiple-differentiation potential. We have demonstrated that systemically administrated MSCs could home to tumor sites and participated tumor growth. We are now working on using MSCs as a systemic gene delivery vehicle for management of wound healing and cancer therapy, and the ways of enhancing the homing and recruitment of MSCs toward specific sites after their systemic delivery.

Selected Publication

Distraction Histogenesis
(PI: Prof. Li Gang, Prof. Lee YW Wayne)

Our Concept

Distraction histogenesis (DH) techniques have been widely accepted and practiced in orthopaedics, traumatology, and craniofacial surgery over the last two decades, using DH methods, many previously untreatable conditions have been successfully managed with outstanding clinical outcomes. Although the biological mechanisms of DH are still not yet fully defined, it is generally accepted that mechanical stimulation is the key in promoting and maintaining tissues' regenerating capacities.

Many genes are up- or down-regulated in bone cells responding to mechanical stimulation. The changing patterns of BMPs expression and apoptosis may regulate bone regeneration in DH. High magnitude strain promotes bone remodelling, whereas low magnitude stain stimulates osteogenesis. DH not only increases local angiogenesis, but also leads to increased expressions of VEGF and its receptors systemically. Routine radiography remains the most cost effective imaging technique to follow all aspect of the regenerate, followed by ultrasound, mechanical testing, DEXA and QCT. Under normal circumstances with adequate support of postoperative physiotherapy, DH treatment has good clinical outcome and needs no additional intervention(s).

However, if bone consolidation becomes a clinical concern, minimal non-invasive means of intervention for promoting bone consolidation are preferable, such as weight-bearing exercise, ultrasound and electromagnetic stimulation. Systemic administration of anabolic agents and hormones may also be useful and local application of growth factors such as BMPs remains the last resort, as their working mechanisms in DH are still not clearly known and are expensive.

Innovative Research

Being a great surgical technique for skeletal tissue repair and regeneration, DH also has a wider implication in understanding body's self-repair and self-regeneration potentials, and its new clinical applications are extended to functional tissue engineering, hip reconstruction surgery, management of vascular diseases and cosmetic limb lengthening surgery, etc. DH theory opens a new page of human biology and physiology, its wider applications will continue bring us more surprises. Our recent research interests in DH are:

Selected Publication

Clinical Trials of Stem Cell Therapy
(PI: Prof. Yung SH Patrick, Prof. Li Gang, Prof. Lee YW Wayne, Dr. Ho KK)

Our Concept

Pathogenesis of osteoarthritis (OA) is primarily associated with aging (degeneration) and trauma. Chondral lesion is difficult to heal due to chronic inflammation and unfavorable mechanical stress in the joint. We focus on new strategies to apply stem cell therapy for OA.

Many genes are up- or down-regulated in bone cells responding to mechanical stimulation. The changing patterns of BMPs expression and apoptosis may regulate bone regeneration in DH. High magnitude strain promotes bone remodelling, whereas low magnitude stain stimulates osteogenesis. DH not only increases local angiogenesis, but also leads to increased expressions of VEGF and its receptors systemically. Routine radiography remains the most cost effective imaging technique to follow all aspect of the regenerate, followed by ultrasound, mechanical testing, DEXA and QCT. Under normal circumstances with adequate support of postoperative physiotherapy, DH treatment has good clinical outcome and needs no additional intervention(s).

However, if bone consolidation becomes a clinical concern, minimal non-invasive means of intervention for promoting bone consolidation are preferable, such as weight-bearing exercise, ultrasound and electromagnetic stimulation. Systemic administration of anabolic agents and hormones may also be useful and local application of growth factors such as BMPs remains the last resort, as their working mechanisms in DH are still not clearly known and are expensive.

Innovative Research

Research Collaboration & Knowledge Transfer

Musculoskeletal Regeneration Research Network (MRN)

Launch of MRN - Nov 13, 2013

MRN members

Asia Knee Arthroscopy Think-tank (AKAT)

Professional Activities Engagement

Nourishing Young Researchers

Croucher Summer Course: Stem Cells Biological and Regenerative Medicine
Next course will be conducted in 2022

Field Support

On-field medical service - School, University and Community sports team

Medical support to mega event - HK game, Rugby 10s, SC marathon, etc

Health Promotion

Out-reach projects on Primary, Secondary school and Community sports team

Education

Practical Training

First Clinical Sports Trainer (CST) certificate course and CST elective module in HK

Exercise Promotion to the community