Aligned nanofibrillar collagen scaffolds – Guiding lymphangiogenesis for treatment of acquired lymphedema

Abstract

Secondary lymphedema is a common disorder associated with acquired functional impairment of the lymphatic system. The goal of this study was to evaluate the therapeutic efficacy of aligned nanofibrillar collagen scaffolds (BioBridge) positioned across the area of lymphatic obstruction in guiding lymphatic regeneration. In a porcine model of acquired lymphedema, animals were treated with BioBridge scaffolds, alone or in conjunction with autologous lymph node transfer as a source of endogenous lymphatic growth factor. They were compared with a surgical control group and a second control group in which the implanted BioBridge was supplemented with exogenous vascular endothelial growth factor-C (VEGF-C). Three months after implantation, immunofluorescence staining of lymphatic vessels demonstrated a significant increase in lymphatic collectors within close proximity to the scaffolds. To quantify the functional impact of scaffold implantation, bioimpedance was used as an early indicator of extracellular fluid accumulation. In comparison to the levels prior to implantation, the bioimpedance ratio was significantly improved only in the experimental BioBridge recipients with or without lymph node transfer, suggesting restoration of functional lymphatic drainage. These results further correlated with quantifiable lymphatic collectors, as visualized by contrast-enhanced computed tomography. They demonstrate the therapeutic potential of BioBridge scaffolds in secondary lymphedema.

New and Emerging Treatments for Lymphedema

“…[58][59][60] Using aligned nanofibrillar collagen scaffolds positioned across the area of lymphatic obstruction, in a porcine model of acquired LE, a study compared outcomes using the scaffolds either alone, in conjunction with autologous lymph node transfer, or supplemented with exogenous VEGF-C, with a control group. 61 At 3 months post implantation, immunofluorescence staining demonstrated a significant increase in lymphatic collectors within close proximity to the scaffolds, and bioimpedance spectroscopy demonstrated a significant reduction in extracellular fluid, as well as quantifiable lymphatic collectors visualized by contrast-enhanced computed tomography, in the groups with the scaffolds, and groups with scaffolds and lymph node transfer. Following the encouraging results of this study, a clinical trial of using the scaffold in conjunction with vascularized lymph node transfer surgery is currently underway.…”

“…Tissue-engineered solutions for LE, therefore, represent a very interesting future direction for LE treatment. [61][62][63][64][65]…”

Biomaterial Based Strategies for Engineering New Lymphatic Vasculature

“…For instance, parallel aligned collagen fibrils were found to preserve endothelial cell phenotype, provide LEC alignment and promote LEC migration along the fibrils. [171] These parallel aligned collagen fibers significantly increased both blood and lymphatic vasculature density, led to an increase in lymphatic collector vessels around the scaffold and reduced bioimpedance in a porcine model of secondary lymphedema. [171] Another polymer with applications for directing LEC migration is PLGA.…”

“…[171] These parallel aligned collagen fibers significantly increased both blood and lymphatic vasculature density, led to an increase in lymphatic collector vessels around the scaffold and reduced bioimpedance in a porcine model of secondary lymphedema. [171] Another polymer with applications for directing LEC migration is PLGA. PLGA hydrogels support a wide range of mechanical properties via varying the ratio and molecular weight of glycolic and lactic acid.…”

“…Targeted cells Predicted biomaterial mechanism Intended purpose Reference Collagen LECs Supports sprout ingrowth Biological studies/therapeutic screening [160][161][162][163] LECs Supports 3D microscale lymphatic vessels Biological studies/therapeutic screening [164,165] ECs Interstitial flow through hydrogels Biological studies [166] LECsCaco-2 Supports coculture and interactions between both cell types Biological studies/therapeutic screening of intestinal lymphatics [167] LECs PLGA nanofibers directed LEC migration Directed lymphangiogenesis [168] LECs Promotes tissue regeneration and prevents scar formation Topical dressing to promote lymphatic revascularization [169,170] LECs Aligned nanofibers promotes LEC alignment/migration Stimulate lymphatic regeneration [171] Fibrin LECs Supporting Sprout Ingrowth Therapeutic screening [134,162,172] ECs Incorporates matrix bound VEGF and interstitial flow Biological studies/Therapeutic screening [173,174] ECs Varying hydrogel mechanical properties effect sprouting Designing in vitro vascularized tissue [175] ECs Developing hydrogel channels to replicate lymphatic drainage Designing engineered tissues [176] PLGA LECs Aligning polymers to direct LEC behavior Repairing severed lymphatic vessels [177] using PLGA scaffolds loaded with SDF-1 were implanted into the subcutaneous cavity of mice and substantially increased the number of mesenchymal stem cells (MSCs) at the implantation site. [132] This homing strategy was also able to recruit hematopoietic stem cells and endothelial progenitor cells (EPCs) when an osmotic pump delivered continuous SDF-1 , which promoted lymphangiogenesis and increased local proinflammatory cytokines associated with lymphatic vascularization.…”