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Principal Investigator: Ngan F. Huang
Organization: PALO ALTO VETERANS INSTIT FOR RESEARCH
Fiscal Year: 2024
Award: $556,684
Funding agency: National Cancer Institute
ABSTRACT: Lymphedema affects approximately 200 million patients globally, and it is characterized by the
accumulation of lymph fluid in soft tissues due to obstructions in the lymphatic system. In Western countries, it
most commonly occurs as a direct outcome of the cancer treatment itself, most frequently in survivors of breast
and gynecological cancers. Lymphedema is a chronic and progressive disease that has no cure. Current
treatment approaches mainly address the symptoms of tissue swelling and discomfort by physiotherapy and
compression. We recently developed an aligned-braided nanofibrillar collagen conduit that is implanted to bridge
the region of lymphatic obstruction as a new surgical treatment strategy. Our preliminary preclinical and clinical
studies demonstrate that implantation of the conduit reduces symptoms associated with lymphedema. We
propose to advance translational research and application of this novel resorbable conduit to deliver a much-
needed surgical preventative treatment for lymphedema. Based on technology developed by Fibralign Corp. and
a previous version of the conduit that showed promising preclinical and clinical results in lymphedema treatment,
the objective is to optimize the structural and mechanical properties of the conduit for targeting lymphedema
prevention in well-established mouse and rat lymphedema models. Accordingly, in Specific Aim 1, we
hypothesize that aligned nanofibrillar conduits with optimally engineered structural and mechanical properties
will promote capillary flow and lymphatic endothelial cell (LEC) function. We will determine the optimal properties
(stiffness, nanofibril diameter, degradation rate, and capillarity) of the conduit that maximize LEC phenotype and
lymphatic sprouting. In Specific Aim 2, we will test the hypothesis that optimally engineered aligned nanofibrillar
conduits will accelerate lymphatic regeneration and normalize lymphatic flow in a murine tail model of secondary
lymphedema. We will first test the therapeutic efficacy in a mouse model of lymphedema, in which conduit
formulations will be implanted into the mouse tail immediately after induction of lymphedema. Output measures
will consist of tail volume and lymph drainage pattern, based on indocyanine green (ICG) imaging. ICG imaging
will enable non-invasive tracking of perfusion over time to track for the ability of the conduits to promote
lymphangiogenesis. The conduit whose properties maximize lymphatic regeneration and lymph drainage will
undergo further analysis in a more clinically relevant rat model of lymphedema induced by lymph node resection
and irradiation in Aim 3. Here, conduits will be implanted immediately after lymphedema induction surgery as a
preventative intervention. Treatment groups will consist of optimally engineered conduit compared to the no
treatment control group or to reference conduit formulations. Over 3 months, we will quantify edema
accumulation by micro computed tomography, lymph drainage pattern by ICG imaging, and lymphatic
regeneration will be confirmed by histological quantification of lymphatic density. Through this industry-academia
partnership, we anticipate these studies will advance the surgical prevention of lymphedema.
Terms: <Abscission><Academia><Acceleration><Address><Affect><Animal Model><Animal Models and Related Studies><Armpit><Automobile Driving><Axilla><Axillary><Axillary Lymph Node Dissection><Biocompatible Materials><Biomaterials><Biomedical Engineering><Blood><Blood Reticuloendothelial System><Blood capillaries><Body Tissues><Breast Cancer><Breast Cancer survivor><Bypass><Cancer Intervention><Cancer Patient><Cancer Treatment><Cancers><Capillarity><Cell Function><Cell Physiology><Cell Process><Cell-Extracellular Matrix><Cellular Function><Cellular Immune Function><Cellular Physiology><Cellular Process><Chronic><Chronic Disease><Chronic Illness><Clinical><Clinical Research><Clinical Study><Collaborations><Collagen><Common Rat Strains><Control Groups><Country><Data><Deep Vein Thrombosis><Deep-Venous Thrombosis><Development><Devices><Diameter><Disease><Disorder><Doctor of Philosophy><Drainage><Drainage procedure><Dropsy><ECM><Edema><Engineering><Excision><Extirpation><Extracellular Matrix><Female Reproductive Cancer><Fibrillar Collagen><Formulation><Generations><Gynecologic Cancer><Gynecological Cancer><Healthcare><Histologic><Histologically><Human><Hydrops><Image><Implant><In Vitro><Incidence><Indocyanine Green><Industry><Intercellular Fluid><Interstitial Fluids><Intervention><Intervention Strategies><Length of Stay><Liquid substance><Lymph><Lymph Node Reticuloendothelial System><Lymph System><Lymph node proper><Lymphangiogeneses><Lymphangiogenesis><Lymphatic><Lymphatic Endothelial Cells><Lymphatic Network><Lymphatic Obstruction><Lymphatic System><Lymphatic System Reticuloendothelial System><Lymphatic nodes><Lymphedema><Malignant Breast Neoplasm><Malignant Female Reproductive System Neoplasm><Malignant Gynecologic Neoplasm><Malignant Gynecologic Tumor><Malignant Neoplasm Therapy><Malignant Neoplasm Treatment><Malignant Neoplasms><Malignant Tumor><Malignant Tumor of the Female Reproductive System><Measures><Mice><Mice Mammals><Microsurgery><Modeling><Modern Man><Murine><Mus><Nanostructures><Natural regeneration><Number of Days in Hospital><Obstruction><Operative Procedures><Operative Surgical Procedures><Outcome><Output><Patients><Pattern><Perfusion><Ph.D.><PhD><Phenotype><Physiatric Procedure><Physical Medicine Procedure><Physical Therapeutics><Physical therapy><Physiotherapy><Preventative intervention><Preventative treatment><Prevention><Preventive><Preventive treatment><Progressive Disease><Property><Rat><Rats Mammals><Rattus><Regeneration><Removal><Reporting><Risk><Rodent Model><Secondary Prevention><Structure><Subcellular Process><Surgical><Surgical Interventions><Surgical Procedure><Surgical Removal><Swelling><Symptoms><Tail><Technology><Testing><Therapeutic><Time><Tissues><Translating><Translational Research><Translational Science><Treatment Efficacy><Ujoveridin><Underarm><Universities><Veins><Visualization><Wofaverdin><X-ray microtomography><Xray microtomography><alleviate symptom><ameliorating symptom><anti-cancer therapy><associated symptom><axillary dissection><bio-engineered><bio-engineers><bioengineering><biological engineering><biological material><biophysical characteristics><biophysical characterization><biophysical measurement><biophysical parameters><biophysical properties><cancer surgery><cancer therapy><cancer-directed therapy><capillary><chemical property><chronic disorder><clinical relevance><clinical translation><clinically relevant><clinically translatable><co-morbid symptom><co-occuring symptom><comorbid symptom><concurrent symptom><cooccuring symptom><decrease symptom><density><developmental><driving><fewer symptoms><fluid><gynecologic malignancy><gynecological malignancy><healing><health care><high risk><high risk group><high risk individual><high risk people><high risk population><hospital days><hospital length of stay><hospital stay><imaging><immune function><implantation><improved><in vivo><interest><intervention efficacy><intervention for prevention><interventional strategy><irradiation><liquid><lymph channel><lymph edema><lymph flow><lymph gland><lymph nodes><lymph vessel><lymphatic channel><lymphatic edema><lymphatic flow><lymphatic fluid><lymphatic vessel><lymphnodes><macromolecule><malignancy><malignant breast tumor><mechanical properties><micro CT><micro computed tomography><microCT><microtomography><model of animal><mouse model><murine model><nano fibrillar><nano fibrils><nano meter scale><nano meter sized><nano-sized structures><nano-structures><nanofibrillar><nanofibrils><nanometer scale><nanometer sized><nanoscale><neoplasm/cancer><novel><pre-clinical><pre-clinical study><preclinical><preclinical study><prevention intervention><preventional intervention strategy><preventive intervention><psychosocial><reduce symptoms><regenerate><relieves symptoms><resection><secondary lymphedema><soft tissue><surgery><symptom alleviation><symptom association><symptom comorbidity><symptom reduction><symptom relief><therapeutic efficacy><therapeutic evaluation><therapeutic testing><therapy efficacy><translation research><translational applications><translational investigation><treatment group><treatment strategy>