Enhancement of Cell-Based Therapeutic Angiogenesis Using a Novel Type of Injectable Scaffolds of Hydroxyapatite-Polymer Nanocomposite Microspheres

Abstract

BackgroundClinical trials demonstrate the effectiveness of cell-based therapeutic angiogenesis in patients with severe ischemic diseases; however, their success remains limited. Maintaining transplanted cells in place are expected to augment the cell-based therapeutic angiogenesis. We have reported that nano-hydroxyapatite (HAp) coating on medical devices shows marked cell adhesiveness. Using this nanotechnology, HAp-coated poly(l-lactic acid) (PLLA) microspheres, named nano-scaffold (NS), were generated as a non-biological, biodegradable and injectable cell scaffold. We investigate the effectiveness of NS on cell-based therapeutic angiogenesis.Methods and ResultsBone marrow mononuclear cells (BMNC) and NS or control PLLA microspheres (LA) were intramuscularly co-implanted into mice ischemic hindlimbs. When BMNC derived from enhanced green fluorescent protein (EGFP)-transgenic mice were injected into ischemic muscle, the muscle GFP level in NS+BMNC group was approximate fivefold higher than that in BMNC or LA+BMNC groups seven days after operation. Kaplan-Meier analysis demonstrated that NS+BMNC markedly prevented hindlimb necrosis (P<0.05 vs. BMNC or LA+BMNC). NS+BMNC revealed much higher induction of angiogenesis in ischemic tissues and collateral blood flow confirmed by three-dimensional computed tomography angiography than those of BMNC or LA+BMNC groups. NS-enhanced therapeutic angiogenesis and arteriogenesis showed good correlations with increased intramuscular levels of vascular endothelial growth factor and fibroblast growth factor-2. NS co-implantation also prevented apoptotic cell death of transplanted cells, resulting in prolonged cell retention.ConclusionA novel and feasible injectable cell scaffold potentiates cell-based therapeutic angiogenesis, which could be extremely useful for the treatment of severe ischemic disorders.

Primed 3D injectable microniches enabling low-dosage cell therapy for critical limb ischemia

“…In particular, previous studies revealed the efficacy of cell therapy for CLI is dosage dependent, which usually required at least 1 × 10 6 ∼ 1 × 10 7 cells to exert significant therapeutic functions, and 1 × 10 5 cells could not effectively induce therapeutic angiogenesis in mouse models (11,20). To improve the efficacy of cell therapy for CLI, we developed a cell delivery strategy based on primed 3D injectable microniches to achieve superior therapeutic effects for CLI with cell dosage (1 × 10 5 cells) 10 times less than the lowest dosage (1 × 10 6 cells) used in all previously reported CLI therapy.…”

Hydroxylapatite nanoparticles: fabrication methods and medical applications

“…The HAp-nanoparticle-coated microspheres showed improved cell adhesion and spreading compared with bare biodegradable microspheres [285]. Recently, Mima et al [368] showed the effectiveness of HAp-coated biodegradable polymer microspheres as an injectable cell scaffold for cell-based therapeutic angiogenesis. a challenging task.…”

Adipose-derived stem cells combined with Neuregulin-1 delivery systems for heart tissue engineering

“…Moreover, MP possess many features that make them suitable for use as cardiac scaffolds. In particular, they are biodegradable, biocompatible, non-toxic and, importantly, they can provide structural support for cell survival and differentiation [18][19][20][21][22][23][24].…”