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Principal Investigator: Jason A Burdick
Organization: UNIVERSITY OF PENNSYLVANIA
Fiscal Year: 2024
Award: $516,327
Funding agency: National Institute of Arthritis and Musculoskeletal and Skin Diseases
Abstract
Fibrous tissues of the musculoskeletal system (e.g., the knee meniscus) are plagued by their poor intrinsic
healing capacity. In the previous funding cycles, we developed enabling technologies including multi-fiber
scaffolds to introduce various temporal and structural signals towards the repair of meniscal tissue. We used
these scaffolds to engineer constructs with properties and organization similar to native tissues (1st cycle) and
then developed scaffolds to enhance endogenous tissue repair through the delivery of factors to recruit local
cells (2nd cycle). The overall objective of this renewal is to further improve endogenous meniscus repair with
engineered scaffolds through the appropriate temporal and spatial orchestration of factor delivery, to first (i)
soften nuclei in cells (via a temporary reduction in heterochromatin content) near the injury site and then (ii)
recruit and stabilize the phenotype of these cells within the repair scaffolds. We hypothesize that the delivery of
these factors will permit recruitment of viable endogenous cells from the meniscus to the scaffolds and that the
spatial control of these factors will improve scaffold colonization, even with thick scaffolds. We will employ
composite scaffolds (developed during the previous funding cycles) that provide a stable fiber fraction
(polycaprolactone (PCL), to provide an instructional pattern and mechanical stability), a sacrificial fiber fraction
(polyethylene oxide (PEO), to define initial scaffold porosity and provide early release of factors into the
environment), and an engineered hyaluronic acid (HA) fiber fraction (that degrades over weeks and releases
factors in a sustained fashion). To address our hypotheses, the first Aim will utilize in vitro microfluidic-
platforms to investigate the timing and dosing of nuclear-softening (Trichostatin A), chemotactic (platelet-
derived growth factor), and fibro-chondrogenic factors (transforming growth factor-β3) to alter nuclear
mechanics, cell recruitment, and promote resumption of the cellular phenotype of cells migrating into fibrous
scaffolds from meniscal tissue. In the second Aim, we will control release from either the entire scaffold (as
before) or from an internal layer (newly proposed) across a variety of scaffold thicknesses and release rates to
promote population of thick scaffolds. This Aim will be conducted using our recently developed subcutaneous
model of meniscus tissue repair. In the third Aim, scaffolds will be implanted into meniscal defects in Yucatan
minipigs to evaluate their efficacy in a clinically relevant defect model. If successful, these studies and
technologies will advance our understanding of the use of engineered scaffolds for endogenous meniscus
repair and provide a step towards clinical translation.
Terms: <21+ years old><Abscission><Acceleration><Address><Adult><Adult Human><Animal Model><Animal Models and Related Studies><Animals><Biocompatible Materials><Biomaterials><Body Tissues><Bone-Derived Transforming Growth Factor><Cartilage><Cartilaginous Tissue><Cell Body><Cell Communication and Signaling><Cell Culture Techniques><Cell Locomotion><Cell Migration><Cell Movement><Cell Nucleus><Cell Signaling><Cells><Cellular Migration><Cellular Motility><Chemoattractants><Chemotactic Factors><Chemotaxins><Clinical><Cultured Cells><Data><Defect><Dense Connective Tissue><Development><Devices><Dose><Drug Delivery><Drug Delivery Systems><Enabling Factors><Engineering><Ensure><Environment><Excision><Exposure to><Extirpation><Fiber><Formulation><Funding><HDAC Agent><HDAC inhibitor><Health><Heterochromatin><Histone Deacetylase Inhibitor><Histone deacetylase inhibition><Hyaluronic Acid><Implant><In Vitro><Injury><Instruction><Intracellular Communication and Signaling><Invaded><Joints><Knee><Macrogols><Mechanics><Meniscus><Meniscus structure of joint><Methods><Microfluidics><Milk Growth Factor><Miniature Swine><Minipigs><Modeling><Musculoskeletal System><Nuclear><Nucleus><PDGF><Patients><Pattern><Phenotype><Platelet Transforming Growth Factor><Platelet-Derived Growth Factor><Polyethylene Glycols><Polyethylene Oxide><Polyethyleneoxide><Polyoxyethylenes><Population><Porosity><Production><Property><Removal><Role><Signal Transduction><Signal Transduction Systems><Signaling><Site><Surgical Removal><Surgical sutures><Sutures><TGF B><TGF-Beta-3><TGF-beta><TGF-beta3><TGF-β><TGF-β3><TGFbeta><TGFβ><TSA antibioitc><Technology><Testing><Thick><Thickness><Time><Tissue Differentiation><Tissues><Transforming Growth Factor Beta 3><Transforming Growth Factor beta><Transforming Growth Factor-Beta Family Gene><Trichostatin A><Work><adulthood><alleviate symptom><ameliorating symptom><biological material><biological signal transduction><cell culture><cell cultures><cell motility><clinical relevance><clinical translation><clinically relevant><clinically translatable><complement chemotactic factor><cost><customized therapy><customized treatment><decrease symptom><design><designing><developmental><directed differentiation><fewer symptoms><functional restoration><healing><implantation><improved><in vivo><individualized medicine><individualized patient treatment><individualized therapeutic strategy><individualized therapy><individualized treatment><injured><injuries><injury to meniscus><locomotor system><mechanic><mechanical><meniscal tear><meniscus injury><migration><mini pig><mini-swine><miniswine><model of animal><new drug treatments><new drugs><new pharmacological therapeutic><new therapeutics><new therapy><next generation therapeutics><novel drug treatments><novel drugs><novel pharmaco-therapeutic><novel pharmacological therapeutic><novel therapeutics><novel therapy><patient specific therapies><patient specific treatment><polycaprolactone><pre-clinical><preclinical><preservation><recruit><reduce symptoms><regenerate new tissue><regenerate tissue><regenerating damaged tissue><regenerating tissue><release factor><relieves symptoms><repair><repair function><repaired><reparative function><resection><restore function><restore functionality><restore lost function><scaffold><scaffolding><social role><subcutaneous><subdermal><symptom alleviation><symptom reduction><symptom relief><synergism><tailored medical treatment><tailored therapy><tailored treatment><tissue regeneration><tissue regrowth><tissue renewal><tissue repair><tissue specific regeneration><tissue wound><transforming growth factor beta3><transforming growth factor β3><tricostatin A><unique treatment><wound><wounding><wounds><µfluidic>