Lymphatic regeneration after implantation of aligned nanofibrillar collagen scaffolds: Preliminary preclinical and clinical results

Abstract

Background: We tested our hypothesis that implantation of aligned nanofibrillar collagen scaffolds (BioBridge™) can both prevent and reduce established lymphedema in the rat lymphedema model. Our authors report clinical cases that demonstrate new lymphatic formation guided by BioBridge™ as seen by near-infrared (NIR) fluoroscopy and magnetic resonance (MR) lymphography. Methods: A rat lymphedema model was utilized. A prevention group received implantation of BioBridge™ immediately after lymphadenectomy. A lymphedema group received implantation of BioBridge™ with autologous adipose-derived stem cells (ADSC; treatment group) or remained untreated (control group). All subjects were observed for 4 months after lymphadenectomy. The hindlimb change was evaluated using computed tomography-based volumetric analysis. Lymphagiogenesis was assessed by indocyanine green (ICG) lymphography. Results: Animals in the treatment group showed a reduction in affected limb volume. Animals in the prevention group showed no increase in the affected limb volume. ICG fluoroscopy demonstrated lymph flow and formation of lymphatics toward healthy lymphatics. Conclusions: In the rat lymphedema model, implantation of BioBridge™ at the time of lymph node removal prevents the development of lymphedema. Treatment of established lymphedema with the BioBridge™ and ADSC reduces lymphedema. New lymphatic vessels are demonstrated by NIR fluoroscopy and MR lymphography. These findings have implications for the treatment of lymphedema in human subjects.

Enhancing lymphangiogenesis and lymphatic drainage to vascularized lymph nodes with nanofibrillar collagen scaffolds

“…The rat hind limb lymphedema with radical excision of the groin, popliteal lymph nodes, and lymphatic vessels followed by a 20 G radiation was developed by Yang et al 28 in 2014 with a success rate of extremity lymphedema of 80%. Several articles used the rat hind lymphedema model for further investigations 27,29 . We used the micro‐CT to measure the volumetric difference and ICG lymphography to measure the dermal backflow and lymphangiogensis of the hind limbs.…”

“…23,25 The nanofibrillar collagen scaffolds (BioBridge) were first reported to be effective in treating the rat and pig lymphedema models. 26 Nguyen et al 27 reported preclinical and clinical results of two patients using BioBridge. One patient underwent VLNT initially and received the BioBridge scaffold as a second procedure, and the other patient underwent LVA first and followed by secondary implantation of BioBridge.…”

Emerging Anti-Inflammatory Pharmacotherapy and Cell-Based Therapy for Lymphedema

“…Recent studies have focused on paracrine functions that exert anti- inflammatory, anti-fibrosis, and immunomodulatory effects. In animal studies, the therapeutic effects of MSCs increased the lymphatic vessel density (by secreting lymphangiogenic factors such as VEGF-C) [ 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 ], restored lymphatic vessel function (by promoting the regeneration of lymphatic collecting vessels and lymphatic pumping) [ 35 , 41 , 42 , 45 ], promoted wound healing [ 39 , 42 ], and improved the tissue microenvironment (by anti-fibrotic and anti-inflammatory effects) [ 38 , 39 , 44 ].…”

“…MSC-based therapies combined with biomaterial scaffolds such as Matrigel ® [ 42 ] and BioBridge ® [ 45 ] or surgical therapy (VLNT) [ 41 ] exhibit efficient regeneration of the functional lymphatic system. These combinational therapies are expected to have a more synergistic effect on lymphedema than individual therapy.…”

“…Several studies focus on the migration and accumulation of CD4+ T cells in the edematous region as a new target to treat lymphedema [ 23 , 24 , 25 , 26 , 27 , 28 ]. Mesenchymal stem/stromal cells (MSCs) exert anti-inflammatory, anti-fibrosis, antioxidant stress, and immunomodulatory effects and are hence used in studies to establish cell-based therapy to treat wounds [ 29 ], inflammatory bowel diseases [ 30 ], diabetes mellitus [ 31 ], psoriasis [ 32 , 33 ], and graft-versus-host disease [ 34 ]; they are useful since they promote lymphangiogenesis in lymphedema animal models [ 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 ]. In this review, we focused on the inflammatory cells involved in the pathogenesis of lymphedema and discuss the efficacy and challenges of pharmacotherapy and cell-based therapies for lymphedema.…”