A novel composite type I collagen scaffold with micropatterned porosity regulates the entrance of phagocytes in a severe model of spinal cord injury
Corresponding Author
Silvia Snider
Division of Neurosurgery, San Raffaele Scientific Institute, Via Olgettina 60, 20132 Milan, Italy
Both authors contributed equally to this work.
Correspondence to: S. Snider (e-mail: [email protected])Search for more papers by this authorAndrea Cavalli
Division of Neurosurgery, San Raffaele Scientific Institute, Via Olgettina 60, 20132 Milan, Italy
Both authors contributed equally to this work.
Search for more papers by this authorFrancesca Colombo
Division of Neurosurgery, San Raffaele Scientific Institute, Via Olgettina 60, 20132 Milan, Italy
Search for more papers by this authorAlberto Luigi Gallotti
Division of Neurosurgery, San Raffaele Scientific Institute, Via Olgettina 60, 20132 Milan, Italy
Search for more papers by this authorAngelo Quattrini
Division of Neuroscience and INSPE, San Raffaele Scientific Institute, via Olgettina 60, 20132 Milan, Italy
Search for more papers by this authorLuca Salvatore
Department of Engineering for Innovation, University of Salento, Via per Monteroni, 73100 Lecce, Italy
Search for more papers by this authorMarta Madaghiele
Department of Engineering for Innovation, University of Salento, Via per Monteroni, 73100 Lecce, Italy
Search for more papers by this authorMaria Rosa Terreni
Division of Pathology, San Raffaele Scientific Institute, Via Olgettina 60, 20132 Milan, Italy
Search for more papers by this authorAlessandro Sannino
Department of Engineering for Innovation, University of Salento, Via per Monteroni, 73100 Lecce, Italy
Search for more papers by this authorPietro Mortini
Division of Neurosurgery, San Raffaele Scientific Institute, Via Olgettina 60, 20132 Milan, Italy
Search for more papers by this authorCorresponding Author
Silvia Snider
Division of Neurosurgery, San Raffaele Scientific Institute, Via Olgettina 60, 20132 Milan, Italy
Both authors contributed equally to this work.
Correspondence to: S. Snider (e-mail: [email protected])Search for more papers by this authorAndrea Cavalli
Division of Neurosurgery, San Raffaele Scientific Institute, Via Olgettina 60, 20132 Milan, Italy
Both authors contributed equally to this work.
Search for more papers by this authorFrancesca Colombo
Division of Neurosurgery, San Raffaele Scientific Institute, Via Olgettina 60, 20132 Milan, Italy
Search for more papers by this authorAlberto Luigi Gallotti
Division of Neurosurgery, San Raffaele Scientific Institute, Via Olgettina 60, 20132 Milan, Italy
Search for more papers by this authorAngelo Quattrini
Division of Neuroscience and INSPE, San Raffaele Scientific Institute, via Olgettina 60, 20132 Milan, Italy
Search for more papers by this authorLuca Salvatore
Department of Engineering for Innovation, University of Salento, Via per Monteroni, 73100 Lecce, Italy
Search for more papers by this authorMarta Madaghiele
Department of Engineering for Innovation, University of Salento, Via per Monteroni, 73100 Lecce, Italy
Search for more papers by this authorMaria Rosa Terreni
Division of Pathology, San Raffaele Scientific Institute, Via Olgettina 60, 20132 Milan, Italy
Search for more papers by this authorAlessandro Sannino
Department of Engineering for Innovation, University of Salento, Via per Monteroni, 73100 Lecce, Italy
Search for more papers by this authorPietro Mortini
Division of Neurosurgery, San Raffaele Scientific Institute, Via Olgettina 60, 20132 Milan, Italy
Search for more papers by this authorAbstract
Traumatic spinal cord injury (SCI) is a damage to the spinal cord that results in loss or impaired motor and/or sensory function. SCI is a sudden and unexpected event characterized by high morbidity and mortality rate during both acute and chronic stages, and it can be devastating in human, social and economical terms. Despite significant progresses in the clinical management of SCI, there remain no effective treatments to improve neurological outcomes. Among experimental strategies, bioengineered scaffolds have the potential to support and guide injured axons contributing to neural repair. The major aim of this study was to investigate a novel composite type I collagen scaffold with micropatterned porosity in a rodent model of severe spinal cord injury. After segment resection of the thoracic spinal cord we implanted the scaffold in female Sprague-Dawley rats. Controls were injured without receiving implantation. Behavioral analysis of the locomotor performance was monitored up to 55 days postinjury. Two months after injury histopathological analysis were performed to evaluate the extent of scar and demyelination, the presence of connective tissue and axonal regrowth through the scaffold and to evaluate inflammatory cell infiltration at the injured site. We provided evidence that the new collagen scaffold was well integrated with the host tissue, slightly ameliorated locomotor function, and limited the robust recruitment of the inflammatory cells at the injury site during both the acute and chronic stage in spinal cord injured rats. © 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 105B: 1040–1053, 2017.
REFERENCES
- 1 Chiu WT, Lin HC, Lam C, Chu SF, Chiang YH, Tsai SH. Epidemiology of traumatic spinal cord injury: Comparisons between developed and developing countries. Asia-Pacific J Public Health 2010; 22(1): 9–18.
- 2 Stokols S, Tuszynski MH. The fabrication and characterization of linearly oriented nerve guidance scaffolds for spinal cord injury. Biomaterials 2004; 25: 5839–5846.
- 3 Eccleston PA, Mirsky R, Jessen KR. Type I collagen preparations inhibit DNA synthesis in glial cells of the peripheral nervous system. Exp Cell Res 1989; 182: 173–185.
- 4 Chamberlain LJ, Yannas IV, Arrizabalaga A, Hsu HP, Norregaard TV, Spector M. Early peripheral nerve healing in collagen and silicone tube implants: Myofibroblasts and the cellular response. Biomaterials 1998; 19: 1393–1403.
- 5 Spilker MH, Yannas IV, Kostyk SK, Norregaard TV, Hsu HP, Spector M. The effects of tubulation on healing and scar formation after transection of the adult rat spinal cord. Restor Neurol Neurosci 2001; 18: 23–38.
- 6 Weadock KS, Miller EJ, Bellincampi LD, Zawadsky JP, Dunn MG. Physical crosslinking of collagen fibers: Comparison of ultraviolet irradiation and dehydrothermal treatment. J Biomed Mater Res 1995; 29: 1373–1379.
- 7 Haugh MG, Jaasma MJ, O'Brien FJ. The effect of dehydrothermal treatment on the mechanical and structural properties of collagen-GAG scaffolds. J Biomed Mater Res A 2009; 89: 363–369.
- 8 Charulatha V, Rajaram A. Influence of different crosslinking treatments on the physical properties of collagen membranes. Biomaterials 2003; 24: 759–767.
- 9 Harley BA, Hastings AZ, Yannas IV, Sannino A. Fabricating tubular scaffolds with a radial pore size gradient by a spinning technique. Biomaterials 2006; 27: 866–874.
- 10 Salvatore L, Madaghiele M, Parisi C, Gatti F, Sannino A. Crosslinking of micropatterned collagen-based nerve guides to modulate the expected half-life. J Biomed Mater Res A 2014; 102: 4406–4414.
- 11 Madaghiele M, Sannino A, Yannas IV, Spector M. Collagen-based matrices with axially oriented pores. J Biomed Mater Res A 2008; 85: 757–767.
- 12 Basso DM, Beattie MS, Bresnahan JC. A sensitive and reliable locomotor rating scale for open field testing in rats. J Neurotrauma 1995; 12: 1–21.
- 13 Altinova H, Mollers S, Fuhrmann T, Deumens R, Bozkurt A, Heschel I, Damink LH, Schugner F, Weis J, Brook GA. Functional improvement following implantation of a microstructured, type-I collagen scaffold into experimental injuries of the adult rat spinal cord. Brain Res 2014; 1585: 37–50.
- 14 Franklin RJ, Ffrench-Constant C. Remyelination in the CNS: From biology to therapy. Nat Rev Neurosci 2008; 9: 839–855.
- 15 Maier IC, Schwab ME. Sprouting, regeneration and circuit formation in the injured spinal cord: factors and activity. Philos Trans Roy Soc Lond B Biol Sci 2006; 361: 1611–1634.
- 16 Madigan NN, McMahon S, O'Brien T, Yaszemski MJ, Windebank AJ. Current tissue engineering and novel therapeutic approaches to axonal regeneration following spinal cord injury using polymer scaffolds. Respir Physiol Neurobiol 2009; 169: 183–199.
- 17 Wang M, Zhai P, Chen X, Schreyer DJ, Sun X, Cui F. Bioengineered scaffolds for spinal cord repair. Tissue Eng B Rev 2011; 17: 177–194.
- 18 Stokols S, Sakamoto J, Breckon C, Holt T, Weiss J, Tuszynski MH. Templated agarose scaffolds support linear axonal regeneration. Tissue Eng 2006; 12: 2777–2787.
- 19 Gros T, Sakamoto JS, Blesch A, Havton LA, Tuszynski MH. Regeneration of long-tract axons through sites of spinal cord injury using templated agarose scaffolds. Biomaterials 2010; 31: 6719–6729.
- 20 Prang P, Muller R, Eljaouhari A, Heckmann K, Kunz W, Weber T, Faber C, Vroemen M, Bogdahn U, Weidner N. The promotion of oriented axonal regrowth in the injured spinal cord by alginate-based anisotropic capillary hydrogels. Biomaterials 2006; 27: 3560–3569.
- 21 Yoshii S, Ito S, Shima M, Taniguchi A, Akagi M. Functional restoration of rabbit spinal cord using collagen-filament scaffold. J Tissue Eng Regen Med 2009; 3: 19–25.
- 22
Liu S,
Bodjarian N,
Langlois O,
Bonnard AS,
Boisset N,
Peulve P,
Said G,
Tadie M. Axonal regrowth through a collagen guidance channel bridging spinal cord to the avulsed C6 roots: Functional recovery in primates with brachial plexus injury. J Neurosci Res 1998; 51: 723–734.
10.1002/(SICI)1097-4547(19980315)51:6<723::AID-JNR6>3.0.CO;2-D CAS PubMed Web of Science® Google Scholar
- 23 Cholas R, Hsu HP, Spector M. Collagen scaffolds incorporating select therapeutic agents to facilitate a reparative response in a standardized hemiresection defect in the rat spinal cord. Tissue Eng A 2012; 18: 2158–2172.
- 24 Kassar-Duchossoy L, Duchossoy Y, Rhrich-Haddout F, Horvat JC. Reinnervation of a denervated skeletal muscle by spinal axons regenerating through a collagen channel directly implanted into the rat spinal cord. Brain Res 2001; 908: 25–34.
- 25 Cerri F, Salvatore L, Memon D, Martinelli Boneschi F, Madaghiele M, Brambilla P, Del Carro U, Taveggia C, Riva N, Trimarco A, Lopez ID, Comi G, Pluchino S, Martino G, Sannino A, Quattrini A. Peripheral nerve morphogenesis induced by scaffold micropatterning. Biomaterials 2014; 35: 4035–4045.
- 26 Chen BK, Knight AM, de Ruiter GC, Spinner RJ, Yaszemski MJ, Currier BL, Windebank AJ. Axon regeneration through scaffold into distal spinal cord after transection. J Neurotrauma 2009; 26: 1759–1771.
- 27 Chen BK, Knight AM, Madigan NN, Gross L, Dadsetan M, Nesbitt JJ, Rooney GE, Currier BL, Yaszemski MJ, Spinner RJ, Windebank AJ. Comparison of polymer scaffolds in rat spinal cord: A step toward quantitative assessment of combinatorial approaches to spinal cord repair. Biomaterials 2011; 32: 8077–8086.
- 28 Cholas RH, Hsu HP, Spector M. The reparative response to cross-linked collagen-based scaffolds in a rat spinal cord gap model. Biomaterials 2012; 33: 2050–2059.
- 29 Gao M, Lu P, Bednark B, Lynam D, Conner JM, Sakamoto J, Tuszynski MH. Templated agarose scaffolds for the support of motor axon regeneration into sites of complete spinal cord transection. Biomaterials 2013; 34: 1529–1536.
- 30 Joo NY, Knowles JC, Lee GS, Kim JW, Kim HW, Son YJ, Hyun JK. Effects of phosphate glass fiber-collagen scaffolds on functional recovery of completely transected rat spinal cords. Acta Biomater 2012; 8: 1802–1812.
- 31 Teng YD, Lavik EB, Qu X, Park KI, Ourednik J, Zurakowski D, Langer R, Snyder EY. Functional recovery following traumatic spinal cord injury mediated by a unique polymer scaffold seeded with neural stem cells. Proc Natl Acad Sci USA 2002; 99: 3024–3029.
- 32 Loy DN, Magnuson DS, Zhang YP, Onifer SM, Mills MD, Cao QL, Darnall JB, Fajardo LC, Burke DA, Whittemore SR. Functional redundancy of ventral spinal locomotor pathways. J Neurosci 2002; 22: 315–323.
- 33 Ramsey JB, Ramer LM, Inskip JA, Alan N, Ramer MS, Krassioukov AV. Care of rats with complete high-thoracic spinal cord injury. J Neurotrauma 2010; 27: 1709–22.
- 34 Wang F, Huang SL, He XJ, Li XH. Determination of the ideal rat model for spinal cord injury by diffusion tensor imaging. Neuroreport 2014; 25: 1386–1392.
- 35 Yoshii S, Oka M, Shima M, Taniguchi A, Taki Y, Akagi M. Restoration of function after spinal cord transection using a collagen bridge. J Biomed Mater Res A 2004; 70: 569–575.
- 36 Hakim JS, Esmaeili Rad M, Grahn PJ, Chen BK, Knight AM, Schmeichel AM, Isaq NA, Dadsetan M, Yaszemski MJ, Windebank AJ. Positively charged oligo[poly(ethylene glycol) fumarate] scaffold implantation results in a permissive lesion environment after spinal cord injury in rat. Tissue Eng A 2015; 21: 2099–2114.
- 37 Sugai K, Nishimura S, Kato-Negishi M, Onoe H, Iwanaga S, Toyama Y, Matsumoto M, Takeuchi S, Okano H, Nakamura M. Neural stem/progenitor cell-laden microfibers promote transplant survival in a mouse transected spinal cord injury model. J Neurosci Res 2015; 93: 1826–1838.
- 38 Norenberg MD, Smith J, Marcillo A. The pathology of human spinal cord injury: Defining the problems. J Neurotrauma 2004; 21: 429–440.
- 39 Carlson SL, Parrish ME, Springer JE, Doty K, Dossett L. Acute inflammatory response in spinal cord following impact injury. Exp Neurol 1998; 151: 77–88.
- 40
Popovich PG,
Wei P,
Stokes BT. Cellular inflammatory response after spinal cord injury in Sprague-Dawley and Lewis rats. J Comp Neurol 1997; 377: 443–464.
10.1002/(SICI)1096-9861(19970120)377:3<443::AID-CNE10>3.0.CO;2-S CAS PubMed Web of Science® Google Scholar
- 41 Shechter R, London A, Varol C, Raposo C, Cusimano M, Yovel G, Rolls A, Mack M, Pluchino S, Martino G, Jung S, Schwartz M. Infiltrating blood-derived macrophages are vital cells playing an anti-inflammatory role in recovery from spinal cord injury in mice. PLoS Med 2009; 6: e1000113.
- 42 Kigerl KA, Gensel JC, Ankeny DP, Alexander JK, Donnelly DJ, Popovich PG. Identification of two distinct macrophage subsets with divergent effects causing either neurotoxicity or regeneration in the injured mouse spinal cord. J Neurosci 2009; 29: 13435–13444.
- 43 Cusimano M, Biziato D, Brambilla E, Donega M, Alfaro-Cervello C, Snider S, Salani G, Pucci F, Comi G, Garcia-Verdugo JM, De Palma M, Martino G, Pluchino S. Transplanted neural stem/precursor cells instruct phagocytes and reduce secondary tissue damage in the injured spinal cord. Brain 2012; 135: 447–460.
- 44 Arnold L, Henry A, Poron F, Baba-Amer Y, van Rooijen N, Plonquet A, Gherardi RK, Chazaud B. Inflammatory monocytes recruited after skeletal muscle injury switch into antiinflammatory macrophages to support myogenesis. J Exp Med 2007; 204: 1057–1069.
- 45 Nahrendorf M, Swirski FK, Aikawa E, Stangenberg L, Wurdinger T, Figueiredo JL, Libby P, Weissleder R, Pittet MJ. The healing myocardium sequentially mobilizes two monocyte subsets with divergent and complementary functions. J Exp Med 2007; 204: 3037–3047.
- 46 Macaya D, Spector M. Injectable hydrogel materials for spinal cord regeneration: A review. Biomed Mater 2012; 7: 012001.
- 47 O'Brien FJ, Harley BA, Yannas IV, Gibson LJ. The effect of pore size on cell adhesion in collagen–GAG scaffolds. Biomaterials 2005; 26: 433–441.