logoYe SHG-AF Imaging

NIH-Funded COBRE Targeted Research Projects | Phase 2

Kara Powder
Kara Powder, Ph.D.

Research Project Lead
SC TRIMH Project 1: "Origins of sexual dimorphism in the craniofacial skeleton"

Phenotypic differences between males and females, termed sexual dimorphism, are a critical biological variable. Sex-based variation produces distinct biting kinematics, differential prevalence and severity of musculoskeletal conditions, and a variety of medical issues often requiring surgery. Despite these data indicating a clear impact of sex on craniofacial function and health, a critical gap in our knowledge includes the developmental stage at which males and females begin to differ in phenotype, including in common model organisms such as mice, chickens, and fishes. Further, we do not know the underlying mechanisms that generate variation in sexual dimorphism, such as the effects of genetic background and hormone signaling, particularly in early facial development. We model human sexual dimorphism using cichlid fishes, which have evolved exceptional craniofacial variation, enable easy manipulation of embryonic development through immersion of animals in chemicals, and mirror human sexual dimorphism in terms of effects on the mandible and variation due to genetic background. Given that the molecules that control facial development are highly conserved across vertebrates, this work may identify new mechanisms and genes that regulate musculoskeletal variation in humans. For example, Pdgfra regulates orofacial clefting in humans, mice, and fishes. The central question of this project is how sex generates functional variation in shape of the craniofacial skeleton. This Phase 2 application will focus on morphology, developmental time, and candidate genes to lay the foundations for future R01 applications focused on cellular and molecular mechanisms. In Aim 1, we will assess developmental origins of sexual dimorphism in bone shape and material properties between the sexes. We will also evaluate genetic risk factors that add further variation to sex-based phenotypes. These data will define when sex generates variation in the craniofacial skeleton and identify specific bones, timepoints, and candidate genes for a future R01 grant. In Aim 2, we will assess the morphological role of sex hormones in embryonic bone development. We predict that these hormones not only regulate bone patterning in both sexes, but variation in hormone signaling drives male-female differences and species-specific presentation of sexual dimorphism. Completion of this aim will extend our knowledge of hormones in adult bone biology to embryonic stages, which is currently a major gap in our understanding. We will also identify developmental windows and critical cell types for future mechanistic study in an R01 application. This project was conceptualized for an initial SC-TRIMH due to potential integration within this group and utilizes the Pre-clinical Assessment Core (PAC), Multiscale Computational Modeling (MCM) core, Advanced Fabrication & Testing (AFT) core, and the Administrative Core. It also synergizes with two other COBRES at Clemson University that support the Clemson University Genomics and Bioinformatics Facility which is important for Aim 1.2.

Zhaoxu Meng
Zhaoxu Meng, Ph.D.

Research Project Lead
SC TRIMH Project 2: "Effects of Smoking on the Rotator Cuff Tendon-Bone Enthesis"

Rotator cuff tendon tears account for more than 4.5 million physician visits and over 300,000 surgical repairs annually in the US. The healing rates of the tendon-bone interface, i.e., enthesis, remain low, despite continual improvements in fixation techniques. Moreover, pre-existing degeneration at the rotator cuff enthesis puts an estimated 17 million Americans at increased risk for rotator cuff impairment and tearing. A growing body of evidence indicates that cigarette smoking is an important risk factor. CDC data show that almost 13% of US adults smoke cigarettes, yet South Carolina rates are even higher at nearly 18%, with high school youth smoking cigarettes in SC at more than 3 times the US rate. Despite this significant impact, we still lack a fundamental understanding of the effects of cigarette smoking on the mechanical properties of the enthesis and the biomechanic mechanisms. Obstacles in formulating such understanding are partly attributed to (i) challenges in creating a realistic smoke exposure environment using well-controlled animal studies and (ii) the difficulties in characterizing the small-scale structural changes and correlating the structural changes with the deterioration of mechanical properties. We propose to utilize our custom-built automatic smoking chamber that resembles realistic cigarette smoking on a rat model, plus adopt an integrated experimental and computational approach to systematically understand the structure-function relationship of rat supraspinatus tendon-humerus enthesis and how it is impacted by cigarette smoking. The proposed studies will test the hypothesis that smoking directly affects the structure of collagen fibers plus the mineral gradient and distributions at the enthesis, all of which we further hypothesize will lead to deterioration of the enthesis by changing the microscopic deformation patterns. The specific aims are (1) to characterize the impact of smoking on the mechanical properties of the rotator cuff tendon-bone enthesis; (2) to delineate the changes from smoking on the multiphasic structures at the tendonbone enthesis; (3) to construct a multiscale modeling framework that bridges the structures with the mechanical properties. We will integrate tissue biomechanics, bioimaging, and multiscale modeling to characterize the structure-function relationship of the enthesis, provide novel mechanistic data that will inform rotator cuff injury risk associated with cigarette smoking, and understand the underlying mechanisms. Once this approach is successfully applied, the tools and insights from this project can be transferred to other soft tissue-bone interfaces. Moreover, the new knowledge generated from this project, particularly the degenerative impact of smoking on rotator cuff tendon-bone enthesis, will lay the foundation for innovating treatment strategies for repairing the interfaces and improving the surgical outcomes of high-risk and/or rural area patients.

Shangping Wang
Shangping Wang, Ph.D.

Research Project Lead
SC TRIMH Project 3: "Ice-free Cryopreservation with Nanowarming for Banking of Viable Meniscal Transplants"

Nearly a million Americans suffer from meniscus tears every year, and 80% of patients who undergo partial or total meniscus removal subsequently develop pain, transient effusion, and knee osteoarthritis. Currently, meniscal allograft transplantation (MAT) with human cadaver tissues is considered medically necessary for treatments with symptomatic post meniscectomy knees with major meniscus loss. Although MAT enables favorable outcomes in the long term, the challenge of donor-recipient size-matching strongly limits broad implementation of MAT since ineffective preservation techniques restrict the number of available fresh grafts. Our ultimate, long-term objective is to maintain cell viability, tissue structure and biomechanical integrity of meniscal allografts for the purpose of long-term storage, thereby overcoming the size-matching challenge. Our previous studies have demonstrated that ice-free cryopreservation by vitrification combined with nanowarming is a promising preservation method for preserving living cells and matrix structure in large avascular tissues. However, this method has encountered critical challenges when applied to meniscal tissues, the major hurdle being the transport limitation of cryoprotectant (CPA) molecules in the meniscus. The large and complex meniscal structure and ECM composition prevents uniform distribution of CPA throughout the tissue, thereby causing ice crystal formation during cooling, which damages living cells and tissue structure. To overcome the CPA transport limitation, two critical knowledge gaps need to be filled: 1) location-specific mass transport mechanism of CPA molecules in the whole meniscus, 2) location-specific effects of CPA concentration and exposure time (CPA toxicity) on meniscal viability. Herein, we hypothesize that meniscal allografts loaded with adequate and toxically tolerable CPAs can be preserved without the loss of viability and functionality by vitrification integrated with nanowarming compared to conventionally cryopreserved allografts. Specifically, we aim to 1) determine location-specific porcine meniscal structure- and composition-dependent CPA transport properties in the whole porcine meniscus, 2) investigate location-specific effects of CPA concentration and exposure time on meniscal viability and optimize both parameters to achieve optimal viability after vitrification, and 3) evaluate in vivo functionality of vitrified meniscal allografts in a 4-month preclinical transplant study using a porcine model. Collectively, these aims will demonstrate our concept that the vitrification method can be used to preserve living cells and tissue structures in meniscal allografts in a pig model. Future work will combine the developed methodologies and our computational model to optimize viability of human meniscal allografts after CPA addition and vitrification to identify the optimal CPA loading and vitrification protocol for each donor graft. Further, by incorporating patient-specific meniscus anatomies and morphology, this work will break therapeutic limitations in meniscal replacement.

Sarah Floyd
Sarah Floyd, Ph.D.

Research Project Lead
SC TRIMH Project 4: "The Application of Deep Learning Methods for Proximal Humerus Fracture Feature Identification"

Proximal humerus fractures (PHFs) are the third most common fracture in the elderly, with an estimated 200,000 occurring each year in the United States. PHFs can lead to pain, poor shoulder function, plus short and longterm disability for patients. Substantial controversy persists regarding initial treatment for elderly adults with this injury. PHFs can be managed conservatively or surgically and great controversy exists over which patients should be treated surgically. A unique challenge with PHFs is that they have variable presentation and range in complexity. Unlike the management of other major joint fractures, the initial treatment choice for PHF is highly dependent on the fracture characteristics. Treatment effectiveness evidence is needed to guide clinical care for individual patients with PHF. The Neer Classification, first developed in 1970, is the most widely used framework to describe and classify PHFs. Although the Neer Classification is the most widely used in practice, it is outdated, incomplete, often incorrectly applied, and suffers from poor interobserver reliability. The absence of a universally accepted, standardized fracture classification system is a critical barrier in the development of treatment effectiveness evidence for PHF. The application of deep learning (DL) computational models can automate and standardize the fracture classification process and identify all relevant fracture characteristics. DL image analysis models have been shown to be highly accurate at identifying features of interest on diagnostic images. An automated, standardized PHF classification system will enhance our ability to universally standardize fracture classification across all orthopaedic clinical care settings, improve the precision and efficiency in fracture care and generate treatment effectiveness evidence to guide clinical practice. The overall objective for this application, is to develop and validate a DL computational model capable of identifying fracture features using X-ray images. Our central hypothesis is that we can develop a DL model that will be as accurate as expert shoulder specialists in identifying important fracture features on X-ray images. In Aim 1 we will modify the Neer Classification framework for fracture feature identification. Aim 2 will be the development of a gold standard dataset for deep learning DL fracture feature identification, and finally Aim 3 will be the training and testing of a DL model to identify fracture features on X-rays.

Graduated Targeted Research Project Leaders

The following Targeted Research Project Leaders have successfully graduated from the SC TRIMH Program based upon their receipt of meritorious independent peer-reviewed funding and significant contributions in the field of musculoskeletal health and health care research.

Yongren Wu
Yongren Wu, Ph.D.

SC TRIMH Research Project Lead
“Estrogen Effect on Beak Ligament Structure and Function in Thumb Basal Joint”

Yongren Wu, Ph.D., Assistant Professor of Bioengineering, is the Leader for Project 2 “Estrogen Effect on Beak Ligament Structure and Function in Thumb Basal Joint.” Osteoarthritis of the basal thumb joint is a significant cause of pain and suffering and socio-economic burden in the US. Despite extensive pathophysiological studies performed to date, the causes of the 10-20-fold increase in basal thumb joint osteoarthritis seen in post-menopausal women remains unclear. In this SC TRIMH study, Dr. Wu will examine morphological, mechanoelectrical, and biochemical changes of the beak ligament insertions in relationship to estrogen levels, and further determine the impact of beak ligament laxity/detachment on kinematics and local mechanical environment of the thumb basal joint. The overall goal of this work is to identify osteoarthritis at early onset and to develop therapeutic strategies to improve functional outcomes.

As Principal Investigator of the Orthopaedic Bioengineering Lab at Clemson, Dr. Wu’s research focuses on soft tissue and bone interface: 1) determining the structure-function relationship in the interface; 2) revealing the mechano-adaptive remodeling mechanism in the interface; 3) advancing strategies for better diagnosis, treatment, and rehabilitation.

Tong Ye
Tong Ye, Ph.D.

SC TRIMH Research Project Lead
“Development of Nonlinear Endomicroscopy: Toward Assessing Articular Cartilage Repair in Vivo”

Tong Ye, Ph.D., Associate Professor of Bioengineering, is the Leader for Project 3 “Development of Nonlinear Endomicroscopy: Toward Assessing Articular Cartilage Repair in Vivo.” As Principal Investigator of the Nano and Functional Imaging Lab at Clemson, Dr. Ye’s laboratory develops novel superresolution optical microscopy (stimulated emission depletion), nonlinear optical microscopy (multiphoton fluorescence and second harmonics 3D tissue imaging) and functional optical imaging (intravital imaging, 3D calcium imaging, 3D cell and particle tracking, and laser speckle contrast imaging) techniques that allow us to visualize heretofore unseen structures and events.

In this SC TRIMH study, Dr. Ye will determine whether two-photon excitation autofluorescence and second harmonic generation imaging can provide sensitive measures to assess the healthiness of articular cartilage and to build a compact endomicroscopy system for clinical use. The ultimate goal of this work is to provide orthopaedic surgeons the ability to identify the structural definition of cartilage tissue, at both surface and sub-surface levels, and the ability to assess living versus dead tissue at the time of arthroscopy.

Melinda Harman
Melinda Harman, Ph.D.

SC TRIMH Research Project Lead
SC TRIMH Project 4: “Soft Tissue Conditions During Total Knee Replacement”

Melinda Harman, Ph.D., Associate Professor of Bioengineering, is the Leader for Project 4 “Soft Tissue Conditions During Total Knee Replacement”. As Principal Investigator of the Laboratory for Retrieval Research and Reprocessing of Medical Devices at Clemson, Dr. Harman’s research is based in: i) Performance of Orthopaedic Devices (analysis of retrieved implants and devices, preclinical testing and simulations of joint replacements, examination of bearing surfaces and bone-biomaterial interfaces), ii) Innovation for Reprocessing and Reuse of Medical Devices (medical device design, optimization for reprocessing, verification and validation of processing protocols, reusable technology for low-resource settings) and iii) Translational Orthopaedic Research (implant registries, post-marketing surveillance, musculoskeletal biomechanics and functional assessments, and development of novel surgical instrumentation and operative techniques).

Unfortunately, a significant portion of patients receiving total knee replacement, still experience pain and mobility issues post-surgery. In this SC TRIMH study, Dr. Harman seeks to develop a new computational testing platform to assess the interoperative condition of soft tissues during implant surgery. This system will aid surgical planning and rehabilitation and will be used to elucidate the underlying biomechanical mechanisms leading to instability and poor function following total knee replacement.

Feng Ding
Feng Ding, Ph.D.

Graduated SC TRIMH Research Project Lead
“Inhibition of the osteoclast-specific V-ATPase for reduced osteoclast bone resorption activity”
Dr. Ding currently serves as a Resource Mentor in the SC TRIMH Multistage Computational Modeling Core

Feng Ding, Ph.D., Associate Professor of Physics and Astronomy, was the first Research Project Lead of the SC TRIMH program to graduate and transition from being a targeted COBRE Lead to an independently funded investigator (NIH R35GM1450409; R35GM145409). Dr. Ding currently serves as a Resource Mentor in the Multistage Computational Modeling Core utilizing his expertise in computational biophysics and structural bioinformatics to support investigators understanding the structure, dynamics and function relationship of biomolecules and molecular complexes using multiscale modeling approaches. Dr. Ding’s research focuses on understanding the disease mechanisms at the molecular level. His research interests range from methodology development to applications of these methods in protein misfolding and amyloid aggregation, molecular recognition, drug discovery, interactions between engineered nanomaterials and biomolecules at the nano-bio interface, and biosensor design.

Fei Peng
Fei Peng, Ph.D.

Graduated SC TRIMH Research Project Lead
“Development and Validation of Embedded Micro Wireless Strain Sensor Array for In Vivo Characterization of Contact Stress Distribution in Hip Replacement”
Dr. Peng currently serves as a Resource Mentor in the SC TRIMH Advanced Fabrication and Testing Core.

Fei Peng, PhD, Associate Professor of Materials Science and Engineering, served as the Project Lead for “Development and Validation of Embedded Micro Wireless Strain Sensor Array for In Vivo Characterization of Contact Stress Distribution in Hip Replacement” that developed micro strain sensors embedded in the acetabular cup liner of the total hip replacement implant for assessment and selection of hip replacement components to be used for the surgery. In 2022, Dr. Peng graduated from the SC TRIMH as Research Project Lead based on his outstanding success in obtaining peer-reviewed funding and establishing research independence.

Dr. Peng currently serves as a Resource Mentor in the Advanced Fabrication and Testing Core utilizing his expertise in additive subtractive manufacturing and production of biosensors to assist investigators with custom applications. Dr. Peng's current research projects are focused on additive manufacturing of ceramics, sensor materials for clinical surgeries, thermal and environmental barrier ceramic coatings, bioactive and biocompatible thin film and coatings, high-temperature kinetics and microstructure, ceramic nanofibers and composites, smart materials, sintering of ultra-high temperature ceramics, and the high-temperature oxidation resistance of borides and carbides.

Will Richardson
William Richardson, Ph.D.
Graduated SC TRIMH Research Project Lead
“Predicting collagen turnover for improved tendon repair strategy”
Dr. Richardson served as Co-Director of the Multistage Computational Modeling Core after graduation, until his recent relocating to Arkansas University this past year.

Dr. Richardson, Associate Professor of Bioengineering, served as Project Lead for “Predicting collagen turnover for improved tendon repair strategy” that employed computational modeling (systems biology) approaches fostered by SC TRIMH to identify key factors contributing to complex biological processes involved in collagen processing in tendon biology and repair. Dr. Richardson graduated from the program after receiving an NIH independent research award in 2018 (R01HL144927) using similar strategies to create patient-specific cardiac fibrosis predictions in patients suffering from heart disease. He served as the co-Director of the Multistage Computational Modeling Core assisting others using multistage modeling approaches in their work following his graduation through August 2022. Dr. Richardson currently serves as an advisor to the program in his capacity as Associate Professor of Chemical Engineering at the University of Arkansas where he remains active in NIH IDeA sponsored research.

Hugo Sanabria
Hugo Sanabria, Ph.D.

Graduated SC TRIMH Research Project Lead

“Modulation and inhibition of the osteoclast-specific V-ATPAse for bone resorption”
Dr. Sanabria currently serves as a Resource Mentor in the Multistage Computational Modeling Core.

Hugo Sanabria, PhD, Associate Professor, Department of Physics and Astronomy, served as Project Lead for “Modulation and inhibition of the osteoclast-specific V-ATPAse for bone resorption.” For this SC TRIMH study, Dr. Sanabria used single-molecule Förster Resonance Energy Transfer (FRET) methods, that capture molecular dynamics spanning from subnanoseconds to seconds, to identify functional regions of the osteoclast-specific V-ATPAse. The overall goal of this work is to develop new therapeutic strategies to control bone loss and growth.

In recognition of his developed research independence, NSF CAREER Award, and high impact works published in the study of structure, dynamics and function of biomolecules using state of the art fluorescence spectroscopic tools, Dr. Sanabria graduated from the SC TRMIH Program in 2022. His work at the molecular level has provided new insights in mechanisms of biomolecular interactions, specifically regulation of synaptic proteins and other biomolecules that hold potential use as therapeutic targets. Dr. Sanabria continues to contribute to the program by serving as a Resource Mentor in the SC TRIMH Multistage Computational Modeling Core.

NIH-Funded Targeted Pilot Projects

NIH Pilot Project 1: ““The role of kinase signaling in musculoskeletal differentiation and maintenance”

Ann C. Foley, PhD, Assistant Professor of Bioengineering, is Leader for NIH Pilot Project 1 “The role of kinase signaling in musculoskeletal differentiation and maintenance.” As Principal Investigator of the Cardiac Regenerative Medicine Laboratory at Clemson, Dr. Foley’s research uses cellular biology concepts to inform her research to (i) create newly engineered stem cell lineages, (ii) identify bioreporters involved in tissue development and maintenance and (iii) study mesoderm/substrate interactions leading to tissue specific development.

For this SC TRIMH study, Dr. Foley will study factors contributing to amyotrophic lateral sclerosis (ALS) and Parkinson’s Disease (PD); both or which involve progressive muscle wasting, resulting in impaired ability to move, speak, swallow and chew. Specifically, Dr. Foley will examine the role of Map3k7 [a kinase that (i) interacts with multiple important intracellular signaling cascades that promote muscle growth and differentiation and (ii) mediates cross talk between cellular signals that result in inflammation and cell death in muscle loss] in muscle formation and maintenance. The PI seeks to determine the mechanism by which Map3k7 drives motor neuron differentiation by (i) activating or repressing its expression in human and murine pluripotent stem cells, (ii) assessing motor neuron differentiation and the role of inflammatory pathways, (iii) and creating a transgenic mouse model with conditional expression of Map3k7 in motor neurons and other lineages. Additionally, the study seeks to determine the mechanism by which Map3k7 and kinase TKA1 activation drives skeletal muscle formation. The ultimate goal of this work is to devise new therapeutic strategies for the treatment of muscle wasting diseases.

Clemson University Funded SC TRIMH Pilot Funded Grants

The SC Center for Translational Research Improving Musculoskeletal Health was established as a National Institutes of Health Center of Biomedical Research Excellence (NIH COBRE) in 2018 (NIH P20GM121342) and formalized as a Clemson University Center in 2019. The University SC TRIMH Center, sponsors a Pilot Project Program grant funding as an active mechanism to attract both junior and more senior investigators into the field of musculoskeletal research, encourage use of research core resources and expertise, foster new collaborations, develop research teams, diversify the mentee pool, and build a pipeline of investigators. Through the Pilot Project Program, awards for a total of $500,000 were made in YR 1-4 to 22 investigators who most typically were junior faculty but also included mid-level and senior faculty and have benefited from mentoring and research core usage, and obtained $7.1M in external funding collectively for a ROI of >14:1. These awards included multiple NIH awards (R01s, R25, R15s), NSF CAREER awards, and numerous other awards from federal, industry, state INBRE/EPSCOR, or internal competitions at Clemson University.

SC TRIMH has three types of one-year Pilot Project grants: Fast Forward grants, Discovery grants, and Mentored Investigator grants. Additional ad hoc Requests for Applications (RFAs) have been issued for a Joint Pilot Project Program with the MUSC College of Dental Medicine (2020) and to solicit SC TRIMH Phase II Targeted Project Lead candidates (2021). The Awardees for each grant are listed below along with results achieved from the sponsored work.

2021- Phase II Developmental Awards
These awards were given to develop preliminary data for potential Targeted Faculty Project Lead positions in the SC TRIMH Phase II application that was submitted in fall 2022. In addition to funding, awardees were provided dedicated mentoring support from the SC TRIMH Mentoring Team. The awardees of the $20,000 Developmental Pilot Project grant were:

2019-2021 - Fast Forward Grants generate critical preliminary data for a planned submission or resubmission of an extramural grant application within six months.
The awardees of the $10,000 Fast Forward grants were:

2019 Discovery Grants provide strategic support to explore the feasibility of projects that might become collaborative R01s, which are National Institute of Health Research Project Grants or center grants.
The $25,000 Discovery grant was awarded to:

2019 Mentored Investigator Grants provide mentored research experiences for investigators who may become candidates to replace current COBRE (Centers of Biological Research Excellence) research project lead investigators.
The $25,000 Mentored Investigator grant awardees are:

2020 SC TRIMH/MUSC CDM Pilot Projects were created as a joint initiative sponsored by SC TRIMH and the Medical University of South Carolina College of Dental Medicine to fund collaborative teams incorporating both Clemson University and Medical University of South Carolina faculty to work together on studies relevant to dental musculoskeletal health care.
The awardees for the $30,000 Joint SC TRIMH MUSC-CDM Pilot Projects were: