Biogelx-IKVAV is an innovative HPL-ADSC delivery strategy to improve peripheral nerve repair.

Adipose-derived stem cells (ADSC) are nowadays one of the most exploited cells in regenerative medicine. They are fast growing, capable of enhancing axonal elongation, support and locally stimulate Schwann cells (SC) and protect de-innervated muscles from atrophy after a peripheral nerve injury. With the aim of developing a bio-safe, clinically translatable cell-therapy, we assessed the effect of ADSC pre-expanded with human platelet lysate (hPL) in an in vivo rat model, delivering the cells into a 15 mm critical-size sciatic nerve defect embedded within a laminin-peptide-functionalised hydrogel (Biogelx-IKVAV) wrapped by a poly-"ℇ" -caprolactone (PCL) nerve conduit. ADSC retained their stemness, their immunophenotype and proliferative activity when tested in vitro. At six weeks post implantation, robust regeneration was observed across the critical-size gap as evaluated by both the axonal elongation (anti-NF 200) and SC proliferation (anti-S100) within the hADSC-IKVAV filled PCL conduit. All the other experimental groups manifested significantly lower levels of growth cone elongation. The histological gastrocnemius muscle analysis was comparable with no quantitative significant differences among the experimental groups. Taken together, these results suggest that ADSC encapsulated in Biogelx-IKVAV are a potential path to improve the efficacy of nerve regeneration. New perspectives can be pursued for the development of a fully synthetic bioengineered nerve graft for the treatment of peripheral nerve injury.

[1]  M. Riehle,et al.  Human Platelet Lysate Acts Synergistically With Laminin to Improve the Neurotrophic Effect of Human Adipose-Derived Stem Cells on Primary Neurons in vitro , 2021, Frontiers in Bioengineering and Biotechnology.

[2]  M. Riehle,et al.  Human platelet lysate to substitute fetal bovine serum in hMSC expansion for translational applications: a systematic review , 2020, Journal of translational medicine.

[3]  G. Christ,et al.  Adipose Stem Cells Enhance Nerve Regeneration and Muscle Function in a Peroneal Nerve Ablation Model. , 2019, Tissue engineering. Part A.

[4]  J. Rubin,et al.  Delivery of adipose‐derived stem cells in poloxamer hydrogel improves peripheral nerve regeneration , 2018, Muscle & nerve.

[5]  Shuyi Wu,et al.  Differentiated adipose‐derived stem cell cocultures for bone regeneration in RADA16‐I in vitro , 2018, Journal of cellular physiology.

[6]  M. Riehle,et al.  Microtopographical cues promote peripheral nerve regeneration via transient mTORC2 activation , 2017, Acta biomaterialia.

[7]  Jiang Peng,et al.  Prompt peripheral nerve regeneration induced by a hierarchically aligned fibrin nanofiber hydrogel. , 2017, Acta biomaterialia.

[8]  J. Kohn,et al.  Dual-Component Gelatinous Peptide/Reactive Oligomer Formulations as Conduit Material and Luminal Filler for Peripheral Nerve Regeneration , 2017, International journal of molecular sciences.

[9]  Abbygail A. Foster,et al.  The Diverse Roles of Hydrogel Mechanics in Injectable Stem Cell Transplantation. , 2017, Current opinion in chemical engineering.

[10]  S. Cartmell,et al.  Peptide hydrogel in vitro non‐inflammatory potential , 2016, Journal of peptide science : an official publication of the European Peptide Society.

[11]  S. Downes,et al.  Differentiated adipose‐derived stem cells act synergistically with RGD‐modified surfaces to improve neurite outgrowth in a co‐culture model , 2016, Journal of tissue engineering and regenerative medicine.

[12]  Wassim Raffoul,et al.  Extracellular matrix components in peripheral nerve repair: how to affect neural cellular response and nerve regeneration? , 2014, Neural regeneration research.

[13]  P. Bonaldo,et al.  Extracellular matrix: A dynamic microenvironment for stem cell niche , 2014, Biochimica et biophysica acta.

[14]  A. Reid,et al.  Adipose derived stem cells and nerve regeneration , 2014, Neural regeneration research.

[15]  G. Terenghi,et al.  Glial differentiation of human adipose-derived stem cells: Implications for cell-based transplantation therapy , 2013, Neuroscience.

[16]  M. Wiberg,et al.  Effect of Delayed Peripheral Nerve Repair on Nerve Regeneration, Schwann Cell Function and Target Muscle Recovery , 2013, PloS one.

[17]  N. Gadegaard,et al.  The development of a ε-polycaprolactone scaffold for central nervous system repair. , 2013, Tissue engineering. Part A.

[18]  Giorgio Terenghi,et al.  Differentiated adipose‐derived stem cells promote myelination and enhance functional recovery in a rat model of chronic denervation , 2012, Journal of neuroscience research.

[19]  R. Midha,et al.  Fate of stem cell transplants in peripheral nerves. , 2012, Stem cell research.

[20]  M. Wiberg,et al.  Nerve repair with adipose-derived stem cells protects dorsal root ganglia neurons from apoptosis , 2011, Neuroscience.

[21]  G. Pierer,et al.  Regeneration potential and survival of transplanted undifferentiated adipose tissue-derived stem cells in peripheral nerve conduits. , 2010, Journal of plastic, reconstructive & aesthetic surgery : JPRAS.

[22]  Jessica O. Winter,et al.  Adhesion Molecule-Modified Biomaterials for Neural Tissue Engineering , 2009, Front. Neuroeng..

[23]  D. Carey,et al.  Regulation of Schwann cell function by the extracellular matrix , 2008, Glia.

[24]  N. Gadegaard,et al.  3D polymer scaffolds for tissue engineering. , 2006, Nanomedicine.

[25]  Marcus Müller,et al.  Biofunctionalized peptide-based hydrogels provide permissive scaffolds to attract neurite outgrowth from spiral ganglion neurons. , 2017, Colloids and surfaces. B, Biointerfaces.