Ochsner Health System Neurosciences Symposium Biologic Therapies for Peripheral Nerve Pathology

Transcription

1 Ochsner Health System Neurosciences Symposium Biologic Therapies for Peripheral Nerve Pathology Nick Goyeneche, M.D. 1

2 Disclosure I have nothing to disclose 2

3 Objectives Biochemical basis for the use of biologic therapies Current research in platelet rich plasma Current research in stem cell therapies Future outlook 3

4 Biologic Invasion PRP Mesenchymal stem cells 4

5 Nerve Regrowth Axonal regeneration Re-myelination Restoration of synaptic connections Recover physiologic functions/skeletal muscle 5

6 Platelet-Rich Plasma (PRP) PRP is an autologous concentrate of platelets made from whole blood. Platelet concentration: Not defined. WBCs/RBCs present/absent or concentration: Not defined. 6

7 Platelet-Rich Plasma (PRP) Contents of platelets: Alpha granule: contains 30 bioactive proteins, including PDGF, TGF-beta, IGF, VEGF, EGF, platelet factor 4, IL-1, platelet derived endothelial growth factor, epithelial cell growth factor, osteocalcin, osteonectin, fibrinogen, vitronectin, fibronectin, thrombospondin. Delta granule: ADP (pro-coagulant), ATP, ionized calcium, histamine, serotonin, epinephrine. Lambda granule: Lysosomal enzymes. 7

8 Platelet-Rich Plasma (PRP) Platelets are vehicle for growth factor delivery IGF-1 required for axon myelination Trigger mitosis and induce angiogenesis VEGF can stimulate axonal outgrowth and enhance Schwann cell proliferation Provides matrix for migration of tissue forming cells. Chemotactic for fibroblasts, mesenchymal cells, monocytes, and neutrophils. Decreases infections 8

9 Zheng et al, 2013 Cultured rat Schwann cells with varying concentrations of PRP (40%, 20%, 10%, 5% and 2.5%) PRP significantly stimulated SC proliferation and migration compared to untreated controls in a dose-dependent manner Suppression seen with high PRP concentrations (40%) The expression and secretion of nerve growth factor and glial cell line-derived neurotrophic factor were significantly increased 9

10 Emel et al, 2011 Compared the effects of IGF-I and PRP on Sciatic Function Index (SFI), sensory function (SF), axon count, and myelin thickness/axon diameter ratio (G-ratio) in a rat model of crush-injured sciatic nerves 10

11 Emel et al,

12 Emel et al,

13 Küçük et al, 2014 Effects of PRP on a sciatic nerve injury model in rats (N=12/24 sciatic nerves) Angle of climb was 63.6 degrees in the PRP group, in the control group In the PRP group, CMAP amplitudes of the gastrocnemius and interdigital muscles were 14.01mV and 0.85mV, respectively. In the control group, CMAP amplitudes were 5.78mV and 0.24mV, respectively The average number of total axons in the control group was and 1, in the PRP group All differences were statistically significant 13

14 Malahias et al, 2015, Pilot study Effects of a single injection of PRP on the clinical symptoms of carpal tunnel syndrome N=14 (excluded pts with prior corticosteroid injections, prior surgery, etc) Injected 1-2cc of PRP under U/S guidance No complications Mean VAS reduced ~50% at 1 month post-injection Q-DASH score ~70% reduced at 3 months U/S cross sectional area of the median nerve was normalized or reduced in 10/14 3 underwent open CTR 14

15 Kuffler et al 2014 Refreshed both the central and distal nerve stumps of nerves causing neuropathic pain, inserting the nerve stumps into a collagen tube, and filling the tube with autologous PRP Induced the resected axons to regenerate across long gaps Some injuries 3.5 years later 94% of the patients, including one with excruciating neuropathic pain, had elimination of pain 15

16 Sánchez et al, 2015 Peripheral motor nerve injury treated with PRP Group 1 (N=3): No intervention, spontaneous recovery Group 2 (N=5): Saline injecitons Group 3 (N=6): PRP with scaffold Week 8, 70% of PRP group were CMAP-positive; no response in the other groups Histomorphometric analysis at 12 weeks: axonal density of groups 1 and 2 were significantly inferior to the control and the PRP group. No significant differences between the control and PRP groups Morphometry of the target muscles indicated that the PRP group had the lowest percentage volume reduction at 12 weeks 16

17 Sánchez et al, 2014 Application of PRP for the treatment of peroneal nerve palsy with drop foot secondary to multi-ligament knee injury 28 y/o M with severe axonotmesis; 11 months post-injury Serial ultrasound intraneural infiltraions of PRP Complete but partial useful recovery obtained at 21 months post-injection EMG with complete reinnervation of the peroneus longus and improved reinnervation of the tibialis anterior 17

18 Mesenchymal Stem Cells Easily expanded, multipotent stromal cells found in most tissue that can differentiate into a variety of cell types Can home in on injured tissue Non-immunogenic, paracrine function (secretome) Schwann cell collection causes new damage to nerve segments and prolonged doubling time reduce the practicality MSCs are capable of cross oligolineage boundaries between mesodermal to ectodermal lineages to form a comparable Schwann cell Wakao,

19 Mesenchymal Stem Cells Harvest sites: bone marrow, adipose, umbilical cord, dental pulp Source may differ in their differentiation propensity and secretory profiles Effects of MSCs on nerve injury models: Modulation of the inflammatory environment on the site; Modulation of the Wallerian degeneration stage; Increased thickness of the myelin sheaths; Accelerated fiber regeneration and in increased numbers; Improved fiber organization; Enhanced vascularization of the regenerating site; and Reduction of fibrotic scaring. 19

20 Mesenchymal Stem Cells May use conduits: Polyglycolic Acid (PGA), Polycarprolactone (PCL), Collagen, Polyvinyl alcohol 20

21 Zarbakhsh et al, 2016 Effects of bone marrow and umbilical cord stromal cell transplantation in regenerating rat peripheral nerves 10 mm segment of the left sciatic nerve in rats was removed and replaced with a silicone tube Bone marrow stromal cells (BMSCs) and human umbilical cord stromal cells (HUCSCs) were respectively obtained from rat and human Cells cultured and placed into the silicone tube 21

22 Zarbakhsh et al,

23 Zarbakhsh et al,

24 Ke et al, 2015 Effect of transplanting BMSCs that produce netrin-1 in a rat model of sciatic nerve crush injury Netrins are a family of secreted proteins that direct the migration of neuronal cells and axon growth cones during neural development, are angiogenic, and induce proliferation of Schwann cells 24

25 Unanswered Questions Optimal PRP concentrations/preparations Best source of harvesting stem cells Use of differentiated vs undifferentiated cells Optimal number of injections Unknown side effects Combination products 25

26 References Caseiro AR, Pereira T, Ivanova G, Luís AL, Maurício AC. Neuromuscular Regeneration: Perspective on the Application of Mesenchymal Stem Cells and Their Secretion Products. Stem Cells Int Emel E, Ergün SS, Kotan D, Gürsoy EB, Parman Y, Zengin A, Nurten A. Effects of insulin-like growth factor-i and platelet-rich plasma on sciatic nerve crush injury in a rat model. J Neurosurg Feb;114(2) Giannessi E, Coli A, Stornelli MR, Miragliotta V, Pirone A, Lenzi C, Burchielli S, Vozzi G, De Maria C, Giorgetti M. An autologously generated platelet-rich plasma suturable membrane may enhance peripheral nerve regeneration after neurorraphy in an acute injury model of sciatic nerve neurotmesis. J Reconstr Microsurg Nov;30(9): Ke X, Li Q, Xu L, Zhang Y, Li D, Ma J, Mao X. Netrin-1 overexpression in bone marrow mesenchymal stem cells promotes functional recovery in a rat model of peripheral nerve injury. J Biomed Res Sep;29(5): Küçük L, Günay H, Erbaş O, Küçük Ü, Atamaz F, Coşkunol E. Effects of platelet-rich plasma on nerve regeneration in a rat model. Acta Orthop Traumatol Turc. 2014;48(4): Kuffler DP. Platelet-rich plasma and the elimination of neuropathic pain. Mol Neurobiol Oct;48(2): Lichtenfels M, Colomé L, Sebben AD, Braga-Silva J. Effect of Platelet Rich Plasma and Platelet Rich Fibrin on sciatic nerve regeneration in a rat model. Microsurgery Jul;33(5): Malahias MA, Johnson EO, Babis GC, Nikolaou VS. Single injection of platelet-rich plasma as a novel treatment of carpal tunnel syndrome. Neural Regen Res Nov;10(11): Sánchez M, Anitua E, Delgado D, Prado R, Sánchez P, Fiz N, Guadilla J, Azofra J, Pompei O, Orive G, Ortega M, Yoshioka T, Padilla S. Ultrasound-guided plasma rich in growth factors injections and scaffolds hasten motor nerve functional recovery in an ovine model of nerve crush injury. J Tissue Eng Regen Med Sep 7. 26

27 References Sánchez M, Yoshioka T, Ortega M, Delgado D, Anitua E. Ultrasound-guided platelet-rich plasma injections for the treatment of common peroneal nerve palsy associated with multiple ligament injuries of the knee. Knee Surg Sports Traumatol Arthrosc May;22(5): Wakao S, Matsuse D, Dezawa M. Mesenchymal stem cells as a source of Schwann cells: their anticipated use in peripheral nerve regeneration. Cells Tissues Organs. 2014;200(1): Yang CC, Wang J, Chen SC, Jan YM, Hsieh YL. Enhanced functional recovery from sciatic nerve crush injury through a combined treatment of cold-water swimming and mesenchymal stem cell transplantation. Neurol Res Sep;37(9): Yu W, Wang J, Yin J. Platelet-rich plasma: a promising product for treatment of peripheral nerve regeneration after nerve injury. Int J Neurosci Apr;121(4): Zack-Williams SD, Butler PE, Kalaskar DM. Current progress in use of adipose derived stem cells in peripheral nerve regeneration. World J Stem Cells Jan 26;7(1): Zarbakhsh S, Goudarzi N, Shirmohammadi M, Safari M. Histological Study of Bone Marrow and Umbilical Cord Stromal Cell Transplantation in Regenerating Rat Peripheral Nerve. Cell J Winter;17(4): Zheng C, Zhu Q, Liu X, Huang X, He C, Jiang L, Quan D. Improved peripheral nerve regeneration using acellular nerve allografts loaded with platelet-rich plasma. Tissue Eng Part A Dec;20(23-24): Zheng C, Zhu Q, Liu X, Huang X, He C, Jiang L, Quan D, Zhou X, Zhu Z. Effect of platelet-rich plasma (PRP) concentration on proliferation, neurotrophic function and migration of Schwann cells in vitro. J Tissue Eng Regen Med May

28 THANK YOU 28