Document text
Principal Investigator: HARRY K.W. KIM
Organization: UT SOUTHWESTERN MEDICAL CENTER
Fiscal Year: 2024
Award: $551,739
Funding agency: National Institute of Arthritis and Musculoskeletal and Skin Diseases
Project Summary
Legg-Calvé-Perthes disease is a childhood ischemic osteonecrosis of the femoral head (ONFH) that affects 1 in
1200 children between the ages of 2 to 14. It is one of the most serious conditions affecting the pediatric hip as
50% of patients will develop debilitating osteoarthritis, some in their teenage years. A disruption of blood flow
produces extensive ischemic cell death, abundance of necrotic cell debris, and damage-associated molecular
patterns (DAMPs) in the femoral head. We discovered that the necrotic microenvironment incites a chronic
inflammatory response, which impairs bone regeneration and produces femoral head deformity. Macrophages
are the central innate immune cells that coordinate the repair process based on local environmental stimuli. In
juvenile ONFH, macrophages exhibit chronic inflammatory response due to DAMPs and necrotic debris which
leads to further tissue damage and fibrosis. Current treatments do not address the negative pathologic role
played by macrophages in the necrotic bone repair. Here, we propose a new concept of reconditioning the
necrotic bone using minimally invasive tissue engineering methods, thereby, converting a necrotic inflammatory
microenvironment to a regenerative microenvironment. Our long-term goal is to establish these treatment
methods to overcome the substantial inflammatory roadblock and to rapidly recondition the necrotic bone in
order to jump start bone regeneration in patients with juvenile ONFH. Our central hypothesis is that the necrotic
bone microenvironment triggers chronic inflammatory macrophage response, and that tissue engineering of the
necrotic environment by local bone wash (i.e. clearance of DAMPs and necrotic debris) and application of
macrophage-directional modulators (such as bone morphogenetic protein-2 and interleukin-4) will increase pro-
healing macrophages and accelerate bone regeneration. We will attain our goal through three highly related but
independent specific aims. We will 1) determine the therapeutic effects of washing out DAMPs and necrotic cell
debris on macrophage response; 2) determine the effects of macrophage response to local controlled-release
bone morphogenetic protein-2 (BMP2) therapy using a hydrogel delivery system on bone regeneration; and 3)
determine the role of interleukin 4-induced macrophage modulation on bone regeneration, using the piglet model
of ischemic ONFH and in vitro experiments in each Aim. We will determine the macrophage and bone repair
responses to the immunomodulatory therapies using tissue, cell, and RNA analytic methods. Successful
completion of this project will have immediate clinical impact by providing a proof-of-concept for the minimally
invasive, yet potentially highly effective, tissue engineering strategies to overcome current barriers to successful
treatment of ONFH. The outcome of this work will lay the groundwork for clinical trials and will greatly advance
our ability to treat ONFH using immunomodulatory strategies.
Terms: <0-11 years old><Acceleration><Adolescent><Adolescent Youth><Affect><Age><Anatomic Abnormality><Anatomical Abnormality><B cell growth factor><B-Cell Differentiation Factor-1><B-Cell Growth Factor-1><B-Cell Growth Factor-I><B-Cell Proliferating Factor><B-Cell Stimulating Factor><B-Cell Stimulating Factor-1><B-Cell Stimulation Factor-1><B-Cell Stimulatory Factor 1 Gene><B-Cell Stimulatory Factor-1><BCDF-1><BCGF><BCGF-1><BCSF 1><BMP-2><BMP-2A><BMP2><BMP2 gene><BMP2A Gene><BSF-1><BSF-1 Gene><BSF1><BSF1 Gene><Binetrakin><Biocompatible Materials><Biological Agent><Biological Products><Biology><Biomaterials><Blood flow><Body Tissues><Bone Formation><Bone Morphogenetic Protein 2 Gene><Bone Morphogenetic Protein 2A Gene><Bone Regeneration><Bone necrosis><Cell Body><Cell Death><Cell Differentiation><Cell Differentiation process><Cells><Child><Child Youth><Childhood><Children (0-21)><Chronic><Clinical><Clinical Trials><Coxa><Coxa Plana><Cues><Deformity><Degenerative Arthritis><Degenerative polyarthritis><Disease><Disorder><Environment><Exhibits><Fibrosis><Goals><Hip><Hip region structure><Hydrogels><IL-4><IL-4 Gene><IL4><IL4 Protein><IL4 gene><Immune><Immune Modulation Therapy><Immunes><Immunomodulation><Impairment><In Vitro><Inflammatory><Inflammatory Response><Injectable><Injury><Interleukin-4><Interleukin-4 Gene><Interleukin-4 Precursor><Interleukin-4 Precursor Gene><Ischemia><Legg Calve Perthes disease><Legg-Perthes Disease><Length of Life><Liquid substance><Longevity><Lymphocyte Stimulatory Factor 1><MCGF-2><Macrophage><Mast Cell Growth Factor-2><Methods><Microbeads><Microspheres><Molecular><Mφ><Necrosis><Necrotic><Non-Polyadenylated RNA><Osteoarthritis><Osteoarthrosis><Osteogenesis><Osteonecrosis><Osteotomy><Outcome><Pathologic><Patients><Pattern><Perthes Disease><Phenotype><Play><Process><RNA><RNA Gene Products><Rat model of diabetes><Ribonucleic Acid><Role><Stimulus><System><T-Cell Growth Factor 2><Teen><Teenagers><Testing><Therapeutic Effect><Tissue Engineering><Tissues><Total Hip Replacement><Work><ages><analytical method><bioengineered tissue><biological material><biologics><biopharmaceutical><biotherapeutic agent><bone><bone morphogenetic protein 2><bone repair><bone tissue formation><cellular differentiation><clinical applicability><clinical application><conditioning><controlled release><degenerative joint disease><diabetic rat><diabetic rat model><effective therapy><effective treatment><engineered tissue><experiment><experimental research><experimental study><experiments><femur head><fluid><healing><hypertrophic arthritis><immune modulating strategy><immune modulating therapies><immune modulation><immune modulatory strategy><immune modulatory therapies><immune regulation><immune-modulation treatment><immunologic reactivity control><immunomodulation therapy><immunomodulation treatment><immunomodulator therapies><immunomodulator treatment><immunomodulator-based therapies><immunomodulatory><immunomodulatory strategy><immunomodulatory therapies><immunomodulatory therapy><immunomodulatory treatment><immunoregulation><immunoregulatory><in vivo><injuries><insight><juvenile><juvenile human><kids><liquid><mesenchymal stromal cell><minimally invasive><necrocytosis><novel><optimal therapies><optimal treatments><osteoarthritic><pediatric><pig model><piglet model><porcine model><prevent><preventing><pseudocoxalgia><recruit><regenerate bone><regenerative><repair><repaired><response><social role><swine model><teen years><teenage><youngster>