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Biomaterial Design Strategies for the Treatment of Spinal Cord Injuries

Biomaterial Design Strategies for the Treatment of Spinal Cord Injuries
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  See discussions, stats, and author profiles for this publication at: Biomaterial Design Strategies for the Treatmentof Spinal Cord Injuries  Article   in  Journal of neurotrauma · September 2009 DOI: 10.1089/neu.2009.0948 · Source: PubMed CITATIONS 128 READS 77 3 authors , including:Cheryl Wong Po FooBioCardia 30   PUBLICATIONS   1,910   CITATIONS   SEE PROFILE Sarah HeilshornStanford University 99   PUBLICATIONS   2,701   CITATIONS   SEE PROFILE All content following this page was uploaded by Cheryl Wong Po Foo on 07 January 2014. The user has requested enhancement of the downloaded file. All in-text references underlined in blue are added to the srcinal documentand are linked to publications on ResearchGate, letting you access and read them immediately.  Reviews Biomaterial Design Strategies for the Treatmentof Spinal Cord Injuries Karin S. Straley, 1 Cheryl Wong Po Foo, 2 and Sarah C. Heilshorn 3 Abstract The highly debilitating nature of spinal cord injuries has provided much inspiration for the design of novel biomaterialsthatcanstimulatecellularregenerationandfunctionalrecovery.Manyexpertsagreethatthegreatesthope for treatment of spinal cord injuries will involve a combinatorial approach that integrates biomaterialscaffolds, cell transplantation, and molecule delivery. This manuscript presents a comprehensive review of  biomaterial-scaffold designstrategiescurrentlybeing appliedtothedevelopmentofnerveguidancechannels andhydrogels that more effectively stimulate spinal cord tissue regeneration. To enhance the regenerative capacity of these two scaffold types, researchers are focusing on optimizing the mechanical properties, cell-adhesivity, bio-degradability, electrical activity, and topography of synthetic and natural materials, and are developing mecha-nisms to use these scaffolds to deliver cells and biomolecules. Developing scaffolds that address several of thesekey design parameters will lead to more successful therapies for the regeneration of spinal cord tissue. Keywords:  biomaterials; peripheral nerve injury; regeneration; spinal cord injury; therapeutic approaches for thetreatment of CNS injury Introduction I njuries to the spinal cord  pose a significant healthproblem; approximately 12,000 people sustain spinal cordinjuries annually in the United States (National Spinal CordInjury Statistical Center, 2009). Spinal cord injury symptomscan vary in severity and can often be highly debilitating.Despite early beliefs that damaged nerves in the central ner-vous system (CNS) lacked the intrinsic ability to regenerate,spinal cord nerves have been shown to partially regrow intoperipheralnervegrafts(Richardsonetal.,1980).Thisdiscoveryhas sparked much interest in the field of spinal cord repair, but to date no single repair strategy has been repeatedlysuccessful in promoting full functional recovery followingspinal cord injury. Therefore, clinical treatments are generallylimited to reduction of pain and swelling and the preventionof secondary injuries through the administration of anti-inflammatory drugs such as methylprednisolone (Brackenet al., 1990).In this review, we will discuss design strategies for nerveguidance channels and hydrogel scaffolds with implicationsfor spinal cord-injury repair. Many excellent review articlesexist that comprehensively detail the chemical and physicalproperties of the variety of materials currently being investi-gatedforCNSrepair(Nomuraetal.,2006;SchmidtandLeach,2003; Willerth and Sakiyama-Elbert, 2007; L.M.Y. Yu et al.,2008; Zhong and Bellamkonda, 2008). Here, we strive toprovideanoverviewofthegeneraldesignstrategiesthathave been used historically, to highlight especially promising ad-vancements in the development of new materials, and toidentify potential opportunities for improved materials forspinalcord-injurytreatment.Specifically,wewilldescribethecurrent benefits and challenges of common material designstrategies that have been used for the fabrication of nerveguidance channels and hydrogels, and identify the criticaldesigncriteriathatarehypothesizedtoaffecttheregenerativecapacity of these materials. Finally, some of the key scientificand technical hurdles currently limiting the development of materials for spinal cord therapy will be discussed. Historical perspective  The development of treatments for CNS injuries, includingspinalcordinjuries,isgreatlycomplicatedbytheexistenceofahighly complex injury environment. Spinal cord nerve injuryis normally caused by compression from displaced bone 1 Chemical Engineering Department, Stanford University, Stanford, California. 2 Materials Science and Engineering Department, Stanford University, Stanford, California. 3 Materials Science and Engineering Department, Stanford University, Stanford, California. JOURNAL OF NEUROTRAUMA 27:1–19 (January 2010) ª  Mary Ann Liebert, Inc.DOI: 10.1089 = neu.2009.0948 1  fragments, disc material, or ligaments. The resultant injurysite rarely involves a complete transection, and is often ir-regularly shaped. Upon spinal cord injury, the native fibro- blasts, neuroglia, and endothelial cells create an inhibitoryrepair environment by contributing to the formation of a glialscar that acts as both a mechanical and chemical barrier toregenerating axons. The presence of a blood–spinal barrieraids in the formation and permanence of the glial scar byslowing the infiltration of macrophages – cells that clear de- bris (Avellino et al., 1995). In addition to scarring, spinal cordnerves are also highly susceptible to secondary injuries thatoccur when damaged nerves and blood vessels release bio-chemicals that inhibit healthy neurons and oligodendrocytes.In contrast to the CNS, much success has been achieved inrepairinginjuriestotheperipheralnervoussystem(PNS).ThePNS and the CNS possess very distinct cellular environmentsthat respond differently to trauma; the PNS possesses a muchmore permissive atmosphere for repair than the CNS. This islargely due to the presence of Schwann cells, which secretegrowth-promoting cytokines (Bhatheja and Field, 2006; Fro-stick et al., 1998). For short nerve gaps (less than * 5mm), thesevered ends can be sutured back together as long as notension is created at the injury site (Berger and Mailander,1991; Ijkema-Paassen et al., 2004). For longer gaps, nerve au-tografts, or the transplantation of donor sensory nerves, areconsidered the ‘‘gold standard’’ for repair (Millesi et al., 1972;Pollard and Fitzpatrick, 1973; Seddon, 1963). Autograftscontain Schwann cells and neurotrophic factors, and providemechanical guidance for axons to grow toward their severeddistalstumps.However,theyareplaguedbyalimitedsupplyof donor tissue, the necessity of conducting a second surgery,and highly variable results (Mackinnon and Hudson, 1992;Millesi,1981; Ortiguelaet al., 1987).Someof theseissues have been addressed by the use of acellular grafts made from bothanimal and cadaver sources (Hudson et al., 2004; Marmor,1964). Much focus has been directed to the development of synthetic nerve guidance channels as an alternative to usinggrafts for repair. Nerve guidance channels bridge nerve gapsand provide directional guidance, a surface for nerve regen-eration, and protection from the surrounding environment.Based on the success of nerve guidance channels in thePNS, researchers have considered using nerve guides to re-pair spinal cord injuries. However, the physiological differ-encesandincreasedcomplexityoftheCNSrelativetothePNSplaces different demands on the design of CNS guidancechannels. As a result, the optimal design of CNS guidancechannels is expected to be quite different from the optimalPNSguidancechannels.Furthermore,guidancechannelsmaynot even be the most advantageous strategy for spinal cordrepair.Duetothecomplexgeometriesandpartialtransectionsoften encountered at spinal cord injury sites, the implantationof a nerve guidance channel may be surgically complicated.Therefore,hydrogelmaterialsthatcanexpandtofilltheentirewound site have also been considered for spinal cord-injurytreatment (see recent review articles: Nomura et al., 2006;Willerth and Sakiyama-Elbert, 2007; Zhong and Bellamkonda,2008). Hydrogels can be easily cast into various shapes orinjected directly into the wound site for  in situ  gelation and,once implanted, can provide a scaffold through which nervescan regenerate. The general consensus is that a combinatorialapproach involving channels, scaffolds, neurotrophic growthfactors, or cells must be taken in order to effectively repairspinal cord injuries (Bamber et al., 2001; Fouad et al., 2005;Nomura et al., 2008b; Taylor and Sakiyama-Elbert, 2006; To- bias et al., 2005; X.M. Xu et al., 1995b; and recent review ar-ticles: Benowitz and Yin, 2008;Busch and Silver, 2007;Lu andTuszynski, 2008). Current approaches for the design andcomposition of CNS nerve guidance channels and hydrogelswill be discussed separately in the following sections. Nerve Guidance Channels Nerve guidance channels have been synthesized from awide assortment of natural and synthetic polymers (Table 1).The channel serves to prevent the ingrowth of fibrous scartissue, to concentrate neurotrophic molecules released fromthe injured nerve stumps, and to direct growth from theproximal to the distal nerve stump (Danielsen et al., 1993;Longoetal.,1983;Lundborgetal.,1982;Williamsetal.,1983). The dimensions, material of construction, and luminal com-ponents all affect the regenerative capacity of a given nerveguidance channel design; see Figure 1 for a depiction of crit-ical design parameters integral for nerve guidance channelfunction. Several materials have already been approved bythe FDA for use in the repair of short gaps in human pe-ripheral nerves (Table 2) (Schlosshauer et al., 2006). To date,most research involving nerve guidance channels has in-volved PNS applications. However, encouraging resultsdemonstrating partial CNS nerve regeneration in PNS guid-ance channels have led to increased interest in their use forspinal cord repair.Since no material has currently established itself as a clearor dominant choice for either PNS or CNS repair, there is stilla large demand for new materials. The choice of material foruseinnerveguidancechannelshaslargelybeeninfluencedbythe underlying regeneration strategy. Central to the choice of regeneration strategy is the distinction between using non-degradable (and generally ‘‘bioinert’’) grafts versus biode-gradable (and generally ‘‘biointeractive’’) grafts. Material design strategies  Nondegradable materials.  Nondegradable channels aremade of synthetic materials that offer uniform and controlledsynthesis techniques. They also require a less complex designdue to the lack of issues such as degradation rate control andtoxicity of degradation products. However, the permanentimplantationofanondegradablechannelcreatesahigherriskof inflammation and may result in nerve compression overtime, which often necessitates a second surgery to remove thematerial (Belkas et al., 2005; Mackinnon et al., 1984; Merle etal.,1989).Furthermore,nondegradablematerialsarealmostalwaysinherentlynon-celladhesive,limitingtheirapplicationin more advanced channel designs involving cell transplan-tation. Despite these inherent limitations, the simplified de-sign and construction of nondegradable channels have madethem particularly useful in preliminary studies of CNS nerverepair and have sped up experimental progress through theiruse both  in vitro  and  in vivo .Common nondegradable materials that have been used tofabricate nerve guidance channels include silicone, polyac-rylonitrile = polyvinylchloride (PAN = PVC), poly(tetrafluoro-ethylene) (PTFE), and poly(2-hydroxyethyl methacrylate)(PHEMA). Despite several experiments demonstrating theability of silicone channels to support peripheral nerve re- 2 STRALEY ET AL.  generation  in vivo , silicone is not widely considered the ma-terialofchoicefornerverepairduetoitsnonporousstructure,questions about its toxicity, and the tendency of siliconechannels to compress regenerating axons after long-termimplantation (Merle et al., 1989). Alternatively, channelsconstructed from PAN = PVC are semipermeable and areconsidered structurally stable  in vivo  (Moon et al., 2006; X.M.Xu et al., 1999). This has made PAN = PVC a potential choicefor more advanced channel designs, often including the de-livery of Schwann cells or olfactory ensheathing glia (Moonet al., 2006; X.M. Xu et al., 1999). In spite of its biocompati-  bility, PAN = PVC is not inherently cell adhesive, and mostapplications have used a Matrigel coating to encourage celladhesion. Matrigel’s srcin as a mixture of proteins secretedfrom mouse tumor cells makes it problematic for use in hu-mans (see description in the section ‘‘Hydrogels,’’ subsection‘‘Physically Crosslinked Materials’’).PTFEwaschosen asapotential material forchannel designdue to its approval for use in humans and its previous usein a variety of medical devices (Pogrel et al., 1998; Stanecand Stanec, 1998a). PTFE channels possess a pronouncedhydrophobicitymakingthemhighlyanti-adhesive.Theiranti-adhesive nature both minimizes the resultant immune re-sponse upon implantationand limits their applicationto act asonly simple scar barrier systems. PTFE channels have shownmixedresults invivo fortheimprovementofPNSinjuries(Pittaet al., 2001; Pogrel et al., 1998; Stanec and Stanec, 1998 b), and are not being widely considered for CNS therapies.PHEMA is currently the most actively researched nonde-gradable material for use in nerve guidance channels. It pos-sesses soft, tunable mechanical properties and can be easilymolded into a tubular shape with controlled dimensions,morphology, and permeability (Dalton et al., 2002). Also,PHEMA synthesis is carried out at low temperatures andwithout toxic solvents, thus allowing for the incorporation of  bioactive compounds into the polymer scaffold (Tsai et al.,2004). Despite these benefits, PHEMA channels have dem-onstrated variable results in studies evaluating toxicity andmechanical strength (Belkas et al., 2005; Smetana et al., 1987). Progress has been made to address the mechanical strengthissues through copolymerization with hydrophobic methac-rylate monomers and increasing tube wall thickness (Daltonet al., 2002). Through inclusion of an internal matrix, PHEMAguidance channels have been shown to support axonal re-generation in injured rat spinal cords (Tsai et al., 2006). Eventhough some positive results have been seen with nonde-gradable channels such as those constructed with PHEMA,the simple designs of these channels are generally consideredless suitable for the more demanding regeneration environ-ments encountered in the CNS, as well as longer gaps in thePNS. As a result, nondegradable channels are not the focus of most current research efforts. Degradable materials.  Degradable channels circumventthe need to either permanently implant a nondegradable ma-terial or remove a nondegradable material with a second sur-gery. They also present a smaller risk of nerve compression,since they degrade as the nerve regenerates. Degradablechannels can be composed of either natural or synthetic mate-rials, but the majority of degradable channels come from nat-ural sources. 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Furthermore,many naturally harvested materials are difficult to purify, andincompletepurificationcanresultinimmune-systemactivation by the implant. Degradable channels also require more com-plex designs, since their degradation products must be non-toxic and their degradation rates must be tuned to match theregeneration rate. Natural materials are often more inherentlyadhesive to neurons and glial cells, making them candidatesfor more ‘‘biointeractive’’ designs. Some common degradablematerials that have been studied for use in nerve guidancechannels include the polymer family of poly( a -hydroxyacids),collagen, chitosan, and poly( b -hydroxybutyrate) (PHB).The family of poly( a -hydroxyacids) include syntheticpolymers and copolymers such as poly(glycolic acid) (PGA),poly(lactic acid) (PLA), poly(lactic acid-co-glycolic acid)(PLGA), and poly(lactide-co-caprolactone) (PLCL). Severalmechanisms have been identified for controlling the degra-dationandmechanicalpropertiesofthesepolymersincludingvaryingtheratioofmonomerunits,thestereochemistryofthemonomer units (either  d - or  l -form), and the molecularweight distribution of chains. Since poly( a -hydroxyacids)degrade in vivo  byhydrolysisandproduceacidicdegradationproducts that result in a transient pH decline, only a limitedamount of the polymer can be implanted (Park et al., 1995).Both PGA and PLCL have been approved by the FDA for usein the repair of human peripheral nerves, and this success hasinspiredinvestigationoftheiruseinCNSrepair(Gautieretal.,1998; Oudega et al., 2001).Collagen’s natural abundance in the connective tissue of animals makes it an attractive material for the construction of nerve guidance channels. It is typically formed into guidancechannels through the addition of chemical crosslinkingagents, which allows direct control over the strength of thechannel and the degradation rate, but also introduces issueswith toxicity of the crosslinking agent (Itoh et al., 2002). Col-lagen has been shown  in vitro  to enhance the growth anddifferentiation of many cell types. The main drawback to us-ing collagen is that it is difficult to harvest and cleanly purifyin an inexpensive and reproducible manner. If purifiedcleanly, collagen from mature bovine sources is nonimmuno-genic in humans; however, collagen from nonhuman sourcescan cause an immune response when purified using lessstringent protocols (Wahl and Czernuszka, 2006). The studyof collagen in nerve repair has resulted in the FDA approvalof two collagen peripheral nerve guidance channel designsand their investigation for use in CNS therapies (Kassar-Duchossoy et al., 2001; Liu et al., 1998).Chitosan is a natural polysaccharide produced from the N  -deacetylation of chitin, one of the most abundant natural biopolymers. Interest in chitosan for channel design largelystems from its capacity to exhibit tunable properties throughvariation in the acetyl group content. Specifically, the rate of degradation, compressive strength, and cell adhesivity of thematerial have been shown to be controlled by the amount of acetylation (Freier et al., 2005b). Furthermore, the cationicnature of chitosan polymers is believed to contribute to en-hanced neuronal adhesion and interaction with anionicgrowth factors and compounds present in the extracellularmatrix (ECM) (Freier et al., 2005a). Some drawbacks to usingchitosan are that it has shown issues with low mechanicalstrength and it is insoluble in many common solvents, whichprevents easy processing into channels (Freier et al., 2005a;Yamaguchi et al., 2003b). However, novel fabrication tech-niques have been developed recently to address these pro- FIG. 1.  Key design elements in the construction of nerve guidance channels (adapted from Huang and Huang, 2006). 4 STRALEY ET AL.
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