Biologic scaffold for CNS repair - Future Medicine

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for dural mater repairs are of clinical interest as the dura provides barrier function ... regenerative medicine principles to the CNS tissues and dural mater repair.

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Biologic scaffold for CNS repair

Injury to the CNS typically results in significant morbidity and endogenous repair mechanisms are limited in their ability to restore fully functional CNS tissue. Biologic scaffolds composed of individual purified components have been shown to facilitate functional tissue reconstruction following CNS injury. Extracellular matrix scaffolds derived from mammalian tissues retain a number of bioactive molecules and their ability for CNS repair has recently been recognized. In addition, novel biomaterials for dural mater repairs are of clinical interest as the dura provides barrier function and maintains homeostasis to CNS. The present article describes the application of regenerative medicine principles to the CNS tissues and dural mater repair. While many approaches have been exploring the use of cells and/or therapeutic molecules, the strategies described herein focus upon the use of extracellular matrix scaffolds derived from mammalian tissues that are free of cells and exogenous factors. Keywords:  biologic scaffold • CNS • constructive remodeling • decellularization • ECM • regeneration

Approximately 1.5 million individuals in the USA suffer traumatic CNS injury annually, which includes spinal cord injury (SCI) and traumatic brain injury (TBI) [1,2] . An additional 300,000 cases of PNS trauma are reported each year. These injuries incur significant morbidity and a tremendous financial burden related to medical care and loss of income [3] . The extracellular matrix (ECM) constitutes approximately 20% of the total CNS tissue volume [4] . Unlike peripheral tissues such as the skin, urinary bladder and skeletal muscle are rich in collagen (Coll), fibronectin (FN) and laminin (LN), adult CNS ECM is enriched with a variety of proteoglycans, hyaluronic acids (HAs) and tenascins [5] . These negatively charged proteoglycans play an important role in retaining growth factors in the CNS. In addition, a specialized ECM network, the perineuronal net, is found surrounding many neuronal cells and may play a role in regulation of neuronal plasticity in the adult brain [5] .

10.2217/RME.14.9  © 2014 Future Medicine Ltd

Fanwei Meng1,2, Michel Modo1,3 & Stephen F Badylak*,1,2,4 McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, PA 15203, USA 2 Department of Surgery, University of Pittsburgh, Pittsburgh, PA 15203, USA 3 Department of Radiology, University of Pittsburgh, Pittsburgh, PA 15203, USA 4 Department of Bioengineering, University of Pittsburgh, Pittsburgh, PA 15203, USA *Author for correspondence: Tel.: +1 412 624 5253 Fax: +1 412 624 5256 [email protected] upmc.edu 1

Endogenous repair mechanisms occur spontaneously to mitigate CNS injury [6–8] , but their potential is limited [9] . However, recent studies have shown that the CNS is capable of a more robust regenerative ability than previously recognized when a permissive, proregenerative microenvironment is provided [10,11] . Moreover, endogenous resident cells and recruited inflammatory cells play a role in facilitating tissue remodeling [12–15] . It is now widely recognized that resident and circulating macrophages can assume phenotypes that range from proinflammatory (M1) to anti-inflammatory, ECM-depositing cells (M2) [12–14,16] . The presence of resident CNS stem cells further suggests that an as yet unidentified endogenous regenerative potential exists [17–19] . Regenerative medicine approaches to capitalize upon this constructive and functional CNS tissue remodeling potential have included, but are not limited to, cell-based approaches, scaffold-based approaches, the use of bioactive molecules (e.g., growth

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Review  Meng, Modo & Badylak factors and cytokines), or combinations thereof. The application of appropriate scaffolding materials, either synthetic or biologic, is an attractive approach in which the exogenous material serves as a temporary niche to support the survival of transplanted cells or recruited endogenous cells at the wound site to promote recovery. These scaffolds can also function as reservoirs for controlled therapeutic molecule delivery. Such novel biomaterials are designed for good biocompatibility, an adjustable degradation rate to match tissue regeneration and 3D architecture to closely mimic the native extracellular milieu. Collectively, these layers of tunable bioactivity contribute to maintaining appropriate cell phenotype and function. Recent studies particularly reveal the potential cellular and molecular mechanisms by which ECM biologic scaffolds facilitate constructive tissue remodeling. The present article describes the application of regenerative medicine principles to the CNS and dura mater repair with particular emphasis on the use of biologic ECM scaffolds derived from mammalian tissue sources. Current experimental strategies for CNS repair The seminal work of Aguayo and colleagues showed that injured CNS axons can regenerate over a lengthy distance in the presence of a suitable microenvironment [10] . Stated differently, the microenvironmental niche plays an important role in facilitating axonal growth. Advancements have been made in promoting axonal regeneration by modulating the hostile CNS microenvironment following injury. Such approaches include the use of bioactive molecules to suppress scar tissue formation, [11,20–24] , the use of therapeutic agents to enhance neuronal sprouting and regeneration [25,26] , cell transplantation strategies [27,28] , and the use of various scaffold materials to provide both molecular and structural signals [29–33] . Strategies designed to mitigate the repulsive effect of the glial scar tissue have been investigated including the use of bioactive molecules to degrade the chondroitin sulfate proteoglycan-rich scar matrix [21,22] , suppress Coll deposition [23,24] or neutralize myelinassociated molecules [11,20] . By contrast, rather than inhibition of adverse events, alternative approaches that facilitate neuronal survival and neuron extension have been proposed. Such approaches include the use of exogenous neurotrophins or growth factors essential for neuronal survival and growth [25,26,34] . Cell-based approaches have been investigated for several CNS pathologies. The typical cell-based approach involves direct injection of axonal growthpromoting cells into the injured tissue [27,28] . Such cell-based approaches may be supplemented with

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the use of neurotrophic factors to promote axonal regeneration [35] . Scaffold-based approaches have used both surfacemodified polymers [29,30] and scaffolds seeded with growth-promoting cells [31,32] or incorporated with growth factors [33] . Such combination approaches that include cells, scaffolds and the use of trophic factors are complicated, not only from a scientific perspective, but represent approaches with significant regulatory and practical hurdles. On the other hand, biologic scaffolds such as those composed of ECM are US FDA approved and have been successfully used in millions of patients for non-CNS tissue repair. Successful experimental approaches utilizing biologic ECM scaffolds for CNS repair could lead to rapid clinical translation. Biologic ECM scaffolds for constructive tissue remodeling The therapeutic potential of biologic scaffolds composed of ECM has been extensively studied for regenerative medicine applications [36,37] . Such scaffolds are typically manufactured by the decellularization of a variety of sources of mammalian tissues [37,38] . The clinical application of ECM scaffolds, either of allogeneic or xenogeneic origin, has been shown to facilitate the functional reconstruction of injured tissues and lead to the formation of site-appropriate new tissues and reduced scar tissue deposition [39–41] . While a large body of literature has reported the promising results of utilizing ECM scaffolds for non-nervous system tissue repair, the therapeutic potential of ECM scaffolds for nervous system tissue repair is relatively unexplored [42–45] . Appropriate decellularization processes are required to remove the cellular components of the source tissue and thereby minimize the immunogenic and proinflammatory response to the ECM scaffolds, which makes allogeneic or xenogeneic transplantation feasible. A variety of decellularization approaches have been reported depending on the source tissues [38,46] . The resulting acellular ECM scaffolds are composed of a mixture of structural and functional molecules that influence cell behavior [47,48] . For example, the human breast epithelial cell phenotype has been shown to be dramatically affected by the microenvironmental niche provided by breast mammary gland ECM [49] . Stem cell differentiation has also been reported to be modulated by ECM [50] , and ECM has been shown to be critical during tissue development and regeneration [51] . ECM scaffolds prepared from different tissues or organs have a distinct composition of protein and nonprotein constituents [52] . These scaffolds are

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Biologic scaffold for CNS repair 

enriched with functional molecules, both soluble and insoluble, secreted by the resident cells of each tissue [53] and embedded within the ECM [54] . These factors are often found in association with another important family of ECM components, glycosaminoglycans (GAGs) [54] . The remaining complex ultrastructure of the tissue-derived ECM scaffold retains inductive cues. Such structural and compositional elegance represents a significant challenge faced by tissue engineers attempting to create biomimetic synthetic scaffolds. The ability of ECM scaffolds to facilitate constructive remodeling of injured tissues has been shown in many preclinical animal models and in clinical settings [39,40,55,56] . However, the underlying mechanism by which ECM scaffolds facilitate tissue reconstruction is only partially understood. Following ECM biologic scaffold implantation in different anatomic sites, an intense polymorphonuclear cell infiltration occurs, followed by rapid macrophage-mediated scaffold degradation [57] . Once degradation has initiated, host-derived and site-specific parenchymal cells appear at the implantation site, which is associated with deposition of neomatrix. In addition to the bioactive molecules embedded in the ECM scaffolds that are released during scaffold degradation, cryptic peptide fragments are created by cleavage of parent molecules such as Coll, FN and LN [58,59] . These cryptic peptide motifs influence cell proliferation [60,61] , direct cell migration [60,62] , increase vascular permeability [63,64] and induce angiogenesis [65] , and modulate the innate immune response [66] . Furthermore, the presentation of matricryptic sites has been suggested to contribute to provisional matrix assembly [67,68] . The release of bioactive growth factors and cytokines that occurs concurrently during ECM degradation likely plays a role in tissue remodeling processes [69,70] . These soluble factors appear to retain their bioactivity following ECM scaffold preparation and sterilization [71–73] , although further studies are required to validate this concept. A growing body of evidence suggests a positive correlation between ECM bioscaffold implantation and downstream M2 (e.g., anti-inflammatory/proregenerative) macrophage phenotype at the implantation site [66,74,75] . Studies have shown that processing and manufacturing methods of ECM bioscaffolds have a significant influence upon the phenotype of infiltrating macrophages, as well as the downstream remodeling events [66] . The M2 phenotype has been suggested to contribute to tissue repair through cytokine secretion that supports neomatrix deposition and tissue remodeling in the late wound healing stage [76] . Therefore, one potential mechanism by which bioactive ECM scaffolds facilitate tissue reconstruction is through modulation of the macrophage phenotype.

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Biologic scaffold for CNS repair Dural repair

The dura mater is the outermost layer of the meningeal tissue and is often injured as a result of trauma or surgical procedures [77,78] . The accepted surgical practice is to repair dural defects to restore tissue homeostasis and barrier functions. A variety of materials have been evaluated as dural substitutes and this article will only discuss dural substitutes composed of biologic materials. Coll-based dural substitutes

Coll-based materials have been well studied as dural substitutes. Such scaffolds are generally considered to be minimally immunogenic, while supporting cell migration, proliferation and stimulation of new connective tissue deposition during the process of scaffold degradation. These acellular Coll materials avoid potential disease transmission, which has been reported in association with cellularized animal tissues and cadaveric dura [79,80] . Kline, and Jannetta and Whayne studied the potential of using processed Coll films and laminates as dural substitutes [81,82] . While both types of Coll structure degraded following implantation, the Coll laminate was shown to have a slower degradation rate and induced a more intense fibrosis and meningocerebral adhesions than the film structure. Studies have also reported the formation of a foreign body response when Coll laminates were used as dural substitutes [83,84] . Coll sponges as dural grafts have been comprehensively studied by Narotam and colleagues [85,86] . The authors reported blood cells and early fibroblastic infiltration into the sponge, with neomembrane formation during the first 2 weeks. The fibroblast activity and neovascularization were well established by 30 days, followed by Coll sponge resorption and incorporation of the material with surrounding tissue by 6 months. Dura-guard® (Synovis, IL, USA), Duragen® (Integra, NJ, USA) and Durepair ® (Medtronic, MN, USA) are three commercially available Coll-based dural substitutes of bovine origin [87] . Depending upon the source tissues and processing methods, these materials have different interstitial pore sizes. When tested in dogs, the interstitial pore size was found to play an important role in affecting degradation where Duragen degraded the fastest (i.e., largest pore size, 1 month). Dura-guard and Durepair similarly remained largely intact even after 6 months. Duraguard was associated with strong fibrotic encapsulation, which in turn was suggested to cause compression of the brain tissue [88] . Tissudura® (Baxter, IL, USA) is a transparent, type-1 Coll dural substitute of equine origin that

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Review  Meng, Modo & Badylak has been utilized both in experimental animals and human subjects [89–91] . In sheep, Tissudura has been shown to induce an intense acute inflammatory response, followed by graft degradation and full incorporation with native tissue after 8 weeks [89] . When applied clinically, Parlato and colleagues reported no complications during a 1-year follow-up [91] , whereas several cases of cerebrospinal fluid leakage were reported by Gazzeri and colleagues as early as 7 days postsurgery [90] . Dural substitutes derived from decellularized tissues

Dermal grafts composed of acellular human cadaveric skin have been conducted as dural substitutes [92–94] . Acellular dermal grafts have a faster degradation rate compared with autologous pericranium grafts in minipigs [92] . Histologically, acellular dermal grafts resulted in deposition of organized, fibrous structure similar to the native dura, whereas autologous pericranial tissue was associated with disorganized Coll deposition. Small intestinal submucosa (SIS) has also been investigated as a dural substitute based on the successful application of SIS in repairing soft tissues [95,96] . SIS has been found to enhance vascularization at the defect area and support spindle-shaped mesenchymal cells infiltrating the graft area following SIS resorption [95] . CNS repair

As stated earlier, traumatic CNS injury often leads to irreversible, devastating results as CNS tissues have limited ability to regenerate. The primary mechanical injury combined with the secondary events closely associated with sustained inflammation contribute to tissue loss and necrotic cavity formation. To avoid further damage to adjacent neural tissues and their complex neuronal circuits, biomaterials that can be delivered to the injury site to facilitate tissue repair through minimally invasive routes are desirable. Biologic scaffolds derived from purified ECM components have been extensively studied for CNS repair in either solid or hydrogel forms. Recently, the therapeutic potential of biologic scaffolds derived from decellularized tissues for CNS repair applications has been investigated. While the intact biologic ECM scaffolds retain the complex biochemical and structural cues that mimic the native extracellular milieu, the hydrogel form of the ECM scaffolds are advantageous because of their potential for minimally invasive delivery. Studies that highlight the therapeutic potential of biologic scaffolds composed of purified ECM components and biologic ECM scaffolds for CNS and dural repair are summarized in Tables 1 & 2.

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Biologic scaffolds composed of purified ECM components Hyaluronan or hyaluronic acid

HA is a negatively charged GAG and is one of the major ECM components in the CNS [127] . HA is a commonly used biomaterial for CNS injury repair because of its minimal immunogenicity, tunable mechanical properties and beneficial role in wound healing [128,129] . Highmolecular-weight HA (HMW-HA) has been shown to exert an anti-inflammatory effect on microglial cells in vitro [130,131] . One report has suggested that HMWHA modulates the inflammatory response by inhibiting NF-κB activation via interacting with the TLR-4 receptor [132] . When applied in vivo, HMW-HA was found to decrease inflammatory cell infiltration and reduce chondroitin sulfate proteoglycan production at the early SCI stage [97] , and reduce glial scar formation by decreasing the participation of GFAP+ cells [97,98] . Similar observations were also found when other bioactive ligands were incorporated with HA gel [133,134] . Additionally, HA has been associated with both the fetal and adult stem cell niche [135,136] . The ability of HA to influence stem cell phenotype and differentiation has been extensively studied in vitro [129,137] . HA hydrogel, with stiffness similar to neonatal brain tissue, induced the majority of neural precursor cells to differentiate into β-III tubulin+ neurons, whereas HA hydrogels with mechanical properties, which approximate those of the adult brain-induced neural precursor cells to differentiate into an astrocytic lineage [129] . HA gels have been shown to support lengthy dorsal root ganglion neurite outgrowth in vitro; however, when applied in vivo for a transected SCI model, animals treated wtih thiolated HA hydrogel showed no differences from untreated animals [100,133] . One potential drawback of HA is that it is generally not cell adhesive, and must be incorporated with or modified with other ECM proteins to improve its adhesive property [99,101,134] . LN-incorporated HA gels were reported to enhance neurite infiltration into the matrices following brain injury [102] . In addition to intact ECM proteins, HA hydrogels have been complemented with adhesive or bioactive peptide sequences, such as RGD and IKVAV, and have shown the ability to induce neuronal process invasion [99,101] . Good biocompatibility of HA/gelatin scaffolds was also shown in the lesioned brain cortex [138] . The ability of HA hydrogel to serve as carriers for cell transplantation [139] or delivery of bioactive molecules [134,140] has also been explored. Fibronectin

FN is a prominent glycoprotein within mammalian ECM. FN is involved in many important cellular functions, including adhesion, guidance and differentiation

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Table 1. Summary of biologic scaffolds derived from purified extracellular matrix components for regenerative medicine applications in CNS and dural repair. Purified ECM component

Application

Longest time point

Reconstruction outcome

Ref.

High-molecular-weight HA

Spinal cord repair in rat

9 weeks

Reduced infiltrating inflammatory cells and CSPG deposition at the acute time points, decreased astrocytic response

[97]

HA

Spinal cord repair in rat

12 weeks

Reduced GFAP+ cells and astrogliosis

[98]

HA with RGD peptide

TBI in rat

12 weeks

Increased axonal infiltration, reduced glial scar formation

[99]

Thiolated HA

Spinal cord repair in rat

8 weeks

No difference in motor function recovery observed between groups

[100]

HA with IKVAV peptide

TBI in rat

6 weeks

Support endogeoous glial cell and axonal invasion

[101]

HA with laminin

TBI in rat

12 weeks

Support glial cell, axonal infiltration and angiogenesis, reduced glial scar formation

[102]

FN hydrogel

Spinal cord repair in rat

4 weeks

Increased axonal invasion, cavities seen between hydrogel and spinal cord tissue

[103]

FN mat

Spinal cord repair in rat

4 weeks, 2 months Decreased apoptosis at early time points, reduced lesion size, enhanced locomotor performance

Shear aggregated FN fiber

Spinal cord repair in rat

4 weeks

Increased axonal invasion, FN fibers induced axonal alignment

[107]

Coll tubulation device

Spinal cord repair in rat

30 days

Reduced scar invasion, promoted astrocyte migration, oriented neuronal processes

[108]

Coll channel

Spinal cord repair in rat

9 months

Axonal regeneration through the channel, Coll channel as effective as Coll channel with nerve graft

[109]

Coll tube

Spinal cord repair in rat

9 months

Rostral spinal axons regrow, reconnect ventral root through the tube and reinnervate target tissue

Nanofibrous Coll conduits

Spinal cord repair in rat

30 days

Axonal infiltration into the conduits

[112]

Coll filament

Spinal cord repair in rat

12 weeks

Somatosensory envoked potential found in rat that were treated with Coll filament

[113]

Coll filament

Spinal cord repair in rabbit

24 weeks

Improved motor function recovery

[114]

Coll sponge

Spinal cord repair in rat

10 weeks

Functional motor-evoked potential recovery observed

[115]

Coll hydrogel (injectable or solid)

Spinal cord repair in rat

4 weeks

Reduced astrogliosis, axonal invasion only seen in animals that were treated with injectable Coll hydrogel

[116]

HA

FN

[104–106]

Coll

[110,111]

Coll: Collagen; CSPG: Chondroitin sulfate proteoglycan; ECM: Extracellular matrix; FN: Fibronectin; GFAP: Glial fibrillary acidic protein; HA: Hyaluronic acid; TBI: Traumatic brain injury.

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Table 1. Summary of biologic scaffolds derived from purified extracellular matrix components for regenerative medicine applications in CNS and dural repair (cont.). Purified ECM component

Application

Longest time point

Reconstruction outcome

Ref.

Equine Coll

Dural repair in sheep

24 weeks

Graft remodeled to assume the connective tissue appearance of surrounding dura

[89]

Equine Coll

Dural repair in patient Median 4.3 months of follow-up

1 patient needed reoperation by 40 days

[90]

Equine Coll

Dural repair in patient 1 year

2 patients needed reoperation by 1 year

[91]

Coll: Collagen; CSPG: Chondroitin sulfate proteoglycan; ECM: Extracellular matrix; FN: Fibronectin; GFAP: Glial fibrillary acidic protein; HA: Hyaluronic acid; TBI: Traumatic brain injury.

through interactions between its binding sites and cell surface receptors, as well as other ECM components [141,142] . A number of studies have suggested a protective role of FN following CNS injury, including facilitating debris removal [143–145] , antiapoptosis [146,147] and reduction in infarct size following cerebral ischemia [148,149] . In light of the potential neuroprotective role, FN in the form of a mat or injectable hydrogel were investigated for CNS repair [103–107] . King et al. first reported the application of FN mats in SCI repair [106] . Although FN mats incubated with neurotrophins induced more regeneration of axons that express high-affinity neurotrophin receptors, FN mats incubated with saline induced a similar level of axonal outgrowth of protein gene product 9.5+ axons, suggesting the FN mats themselves provide a permissive substrate for axonal growth. Early vascularization and Schwann cell infiltration into FN mats were observed [105] . The ability of FN mats to support Schwann cell-mediated LN deposition and organization was suggested to play a role in facilitating axonal ingrowth. FN mats exerted neuroprotective roles, which reduced apoptosis in the surrounding healthy spinal cord tissue, decreased lesion size and improved functional recovery [104] . This protective effect may be mediated by the degradation products of FN mats [104] . One disadvantage of preformed, solid biomaterials for CNS repair is that host tissues must typically be excised for device implantation. The surgical procedure itself increases the risks of damaging spared neural tissues. An injectable form of FN-based material has been developed such that it can be delivered through minimally invasive approaches for SCI repair [103] . While both FN based materials (i.e., FN hydrogel and FN/fibrin [FB]-blended hydrogel) supported axonal ingrowth, FN/FB-blended hydrogels showed superior results. The increased NeuN+ neurons adjacent to the injection site were also observed in animals that received a FN/FB injection when compared

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with a FN injection alone. When applied as a cell transplantation carrier, FN-based scaffolds generated a more uniform neural stem cell (NSC) distribution in the lesion site when compared with cells delivered in media alone. Moreover, cell survival was improved at 8 weeks postimplantation in animals that received FN-based scaffolds [150] . Collagen

Coll is the major component in most connective tissues and more than 20 different types of Coll have been identified. Coll is commonly used as a surgical mesh material and is manufactured into various configurations, dependent upon the intended clinical application. The therapeutic potential of Coll scaffolds for CNS repair has been evaluated extensively. Traumatic SCIs are typically associated with either transected spinal cord or the formation of lesion gaps. In vitro studies have demonstrated that guidance cues facilitate axonal regeneration in the direction of interest [141,151] . Bridging devices that can guide the trajectories of regenerating/sprouting axons are utilized to reconstruct the organized fiber pathway and facilitate the regenerative process. Coll-based biomaterials have been fabricated into both a filamentous structure and a tubular device in an attempt to reconnect the lesion stumps and direct regenerating/sprouting axonal trajectories [108–114] . When tested in a transection SCI model in rats, Coll tubes were found to reduce the scar tissue deposition within the lesion gap and promote astrocyte invasion [108] . While similar axonal density was observed between tubulated and control animals, myelinated axons in animals that received Coll tubes were found to follow a more restricted axial path, suggesting that Coll tubes direct axonal outgrowth between stumps. Tubular Coll grafts were also studied as a bridging device to reconnect the CNS–PNS interface, support axonal regeneration across the lesion site [109,110] and make functional connections [110] . Interestingly, it was

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found that a hollow Coll entubulization device supported axonal regeneration across small CNS–PNS gaps comparable to that of Coll tubes filled with different nerve grafts [109] . Similarly, Coll guidance scaffolds performed comparably to autologous nerve grafts in a primate brachial plexus injury model [111] . Coll filaments (aligned or randomly oriented) [112–114] were also

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implanted in transected spinal cords and reestablished the continuity of the spinal cord tissues within 4 weeks following implantation. Partial recovery of both motor and sensory function was seen within 12 weeks [113] . Similar results were reported by Yoshii et al. [114] , where animals that received a Coll filament scaffold implantation demonstrated significantly improved motor

Table 2. Summary of biologic extracellular matrix scaffolds for regenerative medicine applications in CNS and dural repair. ECM scaffold and tissue source

Application

Longest time point

Reconstruction outcome

Acellular human dermis

Dural repair in minipigs

6 months

Graft remodeled to assume the connective tissue appearance of surrounding dura

[92]

Acellular human dermis

Dural repair in patient

Minimal 1 year

3.5% of patients developed complications

[93]

Acellular human dermis

Dural repair in canine 3 months

Good dural regeneration

[94]

Porcine SIS

Dural repair in rat

Mononuclear cell infiltration, deposition of connective tissue, neovascularity

[95]

Dural repair in canine

Dural repair in canine 120 days

Complete resorption of SIS by 60 days, no evidence of graft rejection and no adverse effect on cortical tissue

[96]

Acellular rat peripheral nerve

Optic nerve repair in rat

30 days

Regenerating axons reach the juctional [117–119] zone between graft and native tissue, no axons invading the acellular peripheral nerve graft

Acellular rat peripheral nerve

Spinal cord repair in rat

8 weeks

Enhanced axonal regeneration and improved electrophysiological testing outcome

[120]

Acellular rat spinal Subcutanous cord biocompatibility test

4 weeks

N/A

[121]

Acellular rat spinal Spinal cord repair cord in rat

8 weeks

Improved motor function score

[122]

Acellular rat muscle

Spinal cord repair in rat

28 days

Well integrated with host tissue, increased axonal invasion, no glial cell activation

[123]

Acellular rat muscle and epithelial cell

Spinal cord repair in rat

4 weeks

Improved motor function and electrophysiology score comparing to acellular muscle-only group

[124]

28 days

Ref.

Solubilized B-ECM In vitro neuronal culture and in vivo gelation test

14 days Support neurite outgrowth and gelled in vitro and in vivo 20 mins in vivo

Solubilized porcine U-ECM

TBI in rat

21 days

Reduced lesion volume and attenuated myelin disruption

[125]

Solubilized porcine U-ECM

Stroke in rat

2 weeks

Increase uniform cell distribution within lesion cavity and support neural stem cell creating de novo tissue

[126]

[42]

B-ECM: Brain extracellular matrix; ECM: Extracellular matrix; N/A: No repair data available; SIS: Small intestinal submucosa; TBI: Traumatic brain injury; U-ECM: Urinary bladder extracellular matrix.

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Review  Meng, Modo & Badylak functions 24 weeks postoperatively. Oriented Coll filament conduits have been associated with a slow degradation rate in vivo [112] , probably as a result of dense packing of aligned fibers. Functional recovery following transected SCI was reported following honeycomb Coll sponge implantation [115] . Coll scaffolds have also been evaluated for TBI repair [152] . In vitro, electrospun Coll filaments were shown to support proliferation of C17.2 NSC cell lines and induce neurite-like projections from cell bodies [153] . Oriented Coll fibers were engineered by applying shear flow deposition [154] and when cocultured with stem cell-derived neurons, oriented Coll fibers directed neuronal trajectories, but had similar effects on NSC survival and differentiation when compared with randomly organized Coll fibers. Wang et al. found that spinal cord-derived NSCs had the highest proliferation rate on oriented Coll fibers, followed by randomly organized fibers and smooth surfaces [155] . In particular, the authors found that the β1 integrin and the MAPK pathway are associated with increased proliferation induced by oriented fibers. Möllers et al. engineered longitudinally aligned channels into Coll scaffolds [156] and similar to Coll filaments, oriented channels guided the elongation of the invading glial cell population and the nerve fibers from the human SH-SY5Y cell line. Hydrogel forms of Coll provide the advantage of minimally invasive delivery methods. Marchand and Woerly first delivered Coll hydrogels into transected rat spinal cords [157] and a loose fibrillar network was established between stumps following gelation. The Coll hydrogel also supported cell infiltration and deposition of new a Coll and GAG matrix. Regenerating/sprouting axons were observed passing stumps and penetrating into the Coll matrix. This study demonstrated the potential of using Coll hydrogel either directly or indirectly for CNS repair. Interestingly, it was shown that the method of Coll scaffold application plays a role in SCI repair [116] . Joosten et al. applied both injectable and preformed Coll gels to study regeneration of corticospinal tract fibers [116] . Although, reduced astrogliosis around the lesion site was observed in animals treated with either injectable or solid preformed Coll hydrogels, axonal ingrowth only occurred when the injectable Coll hydrogel was applied. The in situ gelation property of Coll also makes it a promising carrier for cell transplantation studies as the hydrogel form helps retain the transplanted cells in the lesion cavity. Watanabe et al. found that, using an in vitro assay, the highest viability of neural stem/progenitor cells (NSPCs) was achieved when NSPCs were incorporated into Coll hydrogels with a concentration between 0.5 and 0.75 mg/ml and at a cell density between 1 × 107 and 5 × 107 cells/ml [158] .

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Ma et al. elegantly showed that rat NSPCs not only differentiated into glial cell lineages in the 3D Coll hydrogels, but also into different neuronal cell types [159] . Moreover, these neurons generated spontaneous synaptic currents and expressed functional receptors for neurotransmitters. Coll hydrogels also protected rat cortical neurons from apoptosis and enhanced neurite outgrowth when compared with agarose gel after 3 weeks in vitro [160] . The mechanical properties of the scaffold have been shown to affect neuronal behavior [161] . Elias et al. found that a 1% Coll hydrogel has similar stiffness to the rat brain and proposed that it is a potential candidate for brain repair applications [162] . The mechanical properties and the degradation rate of gels were also shown to be tunable when treated with different concentrations of chemical crosslinker [163] . While high genipin concentration showed cytotoxicity to encapsulated stem cells, low genipin concentration (0.25 mM) promoted stem cell proliferation. Laminin

LN is the most abundant glycoprotein found in basement membranes and has been shown to play a critical role during neural development [164,165] . LN has been suggested to be protective to neurons in mature brains [166] . Similar to FN, the presentation of LN is upregulated at the acute stage following TBI [167,168] . As LN plays a role in the vascular integrity, it is hypothesized that LN upregulation might contribute to the blood–brain barrier repair. In vitro, LN has been shown to promote adhesion and migration of NSCs [169] . LN also regulates NSC survival and proliferation through a β1 integrin-mediated mechanism [170] . Based on this evidence, rather than being applied directly for CNS repair, LN and LN-derived peptides have been incorporated with other biomaterials to increase the material’s ability to support cell adhesion and cell survival [150,171] . When incorporated within Coll hydrogels, increased NSC survival was noted following implantation after 8 weeks [150] . Similar results were also reported with LN-derived peptide sequence both in vitro and in vivo [171,172] . LN-modified scaffolds increased neuronal process infiltration [102,173] and supported neural cell and vasculature penetration into the matrices following implantation [101] . When presented in a gradient, LN peptide-supplemented Coll scaffolds directed neuronal trajectories [174] . Collectively, these studies suggest the LN component of ECM as a potent mediator of cellular behavior with great therapeutic potential. Limitations of biologic scaffolds composed of individual ECM components

While significant advances have been made in CNS tissue repair with biologic scaffolds composed of

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Biologic scaffold for CNS repair 

purified ECM components, there are limitations associated with these materials. Notably, as these purified materials do not fully represent the complexity of the native tissues, combinational strategies that involves mutiple ECM components is likely required for optimal therapeutic benefits. For example, the incorporation of FB into FN hydrogels was shown to support superior axonal ingrowth than the pure FN hydrogel [103] . While FN hydrogel has been shown to induce axonal ingrowth, FN deposition has also been shown to induce microglia activation during demyelinating diseases [175] . Addition of HMW-HA into FN hydrogel might provide a way to modulate the microglial response while facilitating axonal outgrowth. As stated earlier, HA is intrinsically nonadhesive to cells and the introduction of other adhesive ligands or ECM components is required to increase its adhesiveness. Intact biologic ECM scaffolds derived from decellularized tissue/organ

Several studies have evaluated the potential of acellular peripheral nerve (PNS) scaffolds for optic nerve repair following injury [117–119] as its cellularized counterparts have been demonstrated to facilitate long distance CNS axonal regeneration [10] . However, while regenerating or sprouting axons were observed at the scaffold–native tissue interface, no axonal ingrowth into acellular PNS grafts was observed. It was found that the presence of viable Schwann cells is essential for sprouting optic nerve axons to penetrate into acellular PNS grafts, suggesting Schwann cell-mediated trophic factor secretion and/or cell membrane ligand expression are essential for PNS graft-mediated axonal regeneration of the optic nerve [91–93] . Although significant improvement in sensory-evoked potential was observed in animals receiving acellular sciatic nerve grafts following spinal cord repair [120] , animals treated with brain-derived neurotrophic factor-laden acellular sciatic nerve grafts had significantly more fluorogold-labeled regenerating axons/neurons in the sensorimotor cortex and neurofilament-200 positive axons rostral to the spinal cord lesion site compared with control animals. Given the promising results of ECM scaffolds in facilitating non-CNS soft tissue reconstruction, it is plausible that similar constructive remodeling events could occur in the CNS. Guo et al. studied the biocompatibility of acellular spinal cord ECM scaffolds prepared via chemical extraction [121] . The resultant spinal cord scaffolds were free of cells, myelin sheath and nerve fibers, but preserved major ECM proteins including LN, FN and Coll. When implanted subcutaneously, less CD4 + and CD8 + T-cell infiltration was observed in the acellular spinal cord implant compared with the spinal cord allograft, suggesting that

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acellular spinal cord implant was less immunoreactive. Jiang et al. found that while having similar mechanical properties, genipin-crosslinked acellular spinal cord ECM scaffolds showed superior biocompatibility than their glutaraldehyde-crosslinked counterparts [122] . Genipin-crosslinked spinal cord ECM scaffolds also supported mesenchymal stem cell infiltration. Interestingly, acellular spinal cord scaffolds were able to induce similar levels of functional recovery compared with acellular spinal cord scaffolds seeded with mesenchymal stem cells [123] . Zhang et al. reported the use of biologic ECM scaffolds derived from acellular muscle for treating hemisection SCI in rats [124] . After 4 weeks, the muscle scaffolds were well integrated with surrounding tissues and sprouting axons were found to grow the full length of the scaffolds in a parallel fashion. These results suggest that the native architecture of acellular muscle scaffolds directed axonal trajectories. Moreover, acellular muscle grafts did not upregulate glial cell activation when compared with the lesion-only group. When acellular muscle scaffolds were further seeded with amniotic epithelial cells, the combination approach further promoted re-myelination and functional recovery [176] . Crapo et al. prepared three different porcine CNS ECM scaffolds, including whole-brain ECM (B-ECM), spinal cord (S-ECM) and optic nerve ECM [45] . Detectable levels of bioactive molecules such as VEGF, bFGF and NGF were found to be retained in the ECM scaffolds following decellularization. When tested in vitro, all three CNS ECM scaffolds were cyto-compatible to PC12 cells and were found to influence PC12 cell proliferation, migration and differentiation. In summary, application of ECM scaffolds in the CNS show promising findings and appear to promote constructive remodeling events following injury. Solubilized ECM biologic scaffolds

The therapeutic potential of ECM scaffolds and their delivery to a defect site by minimally invasive routes is facilitated by the development of a hydrogel form [42,44] . DeQuach et al. developed B-ECM scaffolds by decellularizing porcine brains [42] . The resultant B-ECM scaffolds were rich in different forms of Coll, GAGs and LN. When the B-ECM scaffolds were solubilized and used as cell culture-coating materials, B-ECM coating promoted neuronal differentiation from induced pluripotent stem cells when compared with Matrigel. After 14 days, neurons cultured on either Matrigel or B-ECM coating showed increased synapsin expression, but no significant difference was found between the two materials. When injected into mice, the B-ECM digest was able to gel at the injection site, suggesting the material has the potential to

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Review  Meng, Modo & Badylak be used as a cell or drug-delivery vehicle. Medberry et al. converted porcine S-ECM and B-ECM scaffolds into the hydrogel form and found that different CNS ECM hydrogels showed distinct rheologic properties [44] . S-ECM hydrogel had the highest rheologic modulus, suggesting unique ECM composition of different tissue types [44] . Both B-ECM and S-ECM hydrogels supported N1E-115 cell neurite extension. When N1E-115 cells were cultured in an ECM digest solution, both pregel solutions showed a dosedependent increase in the number of cells with neurite extension. However, only the B-ECM pregel solution showed a dose-dependent increase in neurite length, with increasing concentrations of ECM, suggesting a possible tissue-specific effect. Urinary bladder matrix (U-ECM) has been shown to facilitate functional tissue reconstruction in nonCNS anatomic sites [66,74] and to support neuronal outgrowth and induce Schwann cell migration in vitro [177] . Crapo et al. showed that solubilized ECM bioscaffolds composed of UBM, B-ECM, S-ECM increase human perivascular stem cell proliferation and migration in vitro [178] . In particular, B-ECM and S-ECM increase the differentiation of human cortical neuroepithelial stem cell into β-III tubulin-positive neurons when compared with U-ECM, probably a CNS tissue ECM-specific effect [178] . When evaluated in a rat TBI model, a hydrogel form of UBM was associated with a constructive cellular response and was neuroprotective to injured brain tissues [125] . UBM treatment did not induce microglia accumulation, astrocyte activation or neuronal degeneration when injected into healthy brains. Moreover, UBM treatment effectively reduced the lesion volume, as well as myelin disruption in TBI rats and improved vestibulomotor function. However, no improvement in cognitive recovery was seen between UBM and vehicle-treated groups. Recently, Wang et al. reported similar results and that UBM decreased the loss of sensorimotor skills in rats following TBI [43] . Memory and cognitive improvement were only observed in rats that received transplantation of U-ECM-containing NSCs. Achieving a uniform distribution of transplanted cells in the defect area to interact with surrounding tissues is a significant challenge to cell-based therapy. Bible et al. utilized UBM-derived hydrogels as a delivery vehicle for NSC transplantation in a rat middle cerebral artery occlusion model and showed that the U-ECM hydrogel provided structural support and retained a uniform distribution of cells within the lesion cavity, which was associated with primitive tissue formation [126] . The combined therapeutic effects of the ECM hydrogels and the delivered cells may be an attractive strategy.

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Limitations of biologic ECM scaffolds

Despite a plethora of bioactive molecules retained by biologic ECM scaffolds, currently there are no decellularization protocols that selectively remove growthinhibiting molecules, but retain growth-promoting molecules. Moreover, due to the complexity of different tissue sources, a harsh decellularization process may be needed to effectively remove all the cellular components, which might elicit negative side effects to the host tissues. This variability in decellularization may limit the overall therapeutic potential of these materials. In addition, as ECM scaffolds are prepared from mammalian tissue sources, animal to animal (i.e., biologic) variability may influence the remodeling outcome. Age differences in the source animals from which ECM is derived have been shown to affect the host response mediated by a biologic ECM scaffold. [179] . Finally, as stated earlier, the mechanical properties of ECM materials are difficult to control, unlike synthetic counterparts. Conclusion Biologic scaffolds composed of individual ECM protein components, fabricated into different configurations, have been evaluated for CNS injury repair. While positive results have been reported, only limited functional improvement has been achieved. The recent development of biologic ECM scaffolds from CNS and non-CNS tissue sources provides exciting new opportunities for regenerative medicine applications. Biologic ECM scaffolds derived from mammalian tissues, both soluble and insoluble, retain a plethora of bioactive molecules and can facilitate tissue reconstruction for a wide range of non-CNS tissues. Although the cellular and molecular mechanisms by which ECM bioscaffolds facilitate tissue reconstruction are only partially understood, a body of literature has suggested that the release of matricryptic peptides during scaffold degradation, and the ability to recruit stem/progenitor cells and modulate inflammatory cell phenotype may contribute to the improved remodeling outcome. The therapeutic potential of these biologic ECM scaffolds for CNS repair has only recently been recognized. Biologic ECM scaffolds derived from non-CNS tissue sources (e.g., U-ECM and muscle ECM) have been shown to exert beneficial effects when administered in traumatic CNS injury models. These results highlight the therapeutic potential of biologic ECM scaffolds and suggest the existence of other (probably superior) non-CNS derived biologic ECM scaffolds for CNS injury repair. However, further work is required to evaluate the response of neural cells to biologic ECM scaffold materials in different CNS injury/disease models.

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Biologic scaffold for CNS repair 

Future perspective While the application of biologic scaffolds for CNS repair leads to promising results, it is likely that combination strategies that involve the use of cells, therapeutic molecules and implantation of scaffolding materials is required to achieve optimal therapeutic benefits. For example, the addition of scaffolding material for cell transplantation and therapeutic molecule delivery may increase donor cell survival and maintain the bioactivity of therapeutic molecules to be released in a controlled manner. Furthermore, a combinational strategy that incorporates multiple ECM protein components (e.g., FN/FB and FN/HMW-HA) may be important to develop smart biomaterials that have matching mechanical properties to nervous tissues of different anatomical areas, appropriate ligand presentation for transplantation of different cell types, ideal growth factor sequestering ability or the ability to promote tissue reconstruction and modulate immune response at the same time. The development of ECM scaffolds from decellularized mammalian tissue sources offer an exciting set of novel biomaterials. These ECM scaffolds retain a plethora of bioactive molecules, which better mimics the complexity of native extracellular milieu. While promising results have been reported, future studies will investigate whether the application of the ECM scaffolds leads to superior clinical outcome than biologic scaffolds

Review

composed of individual or a mixture of ECM components. Similarly, combinational strategies that involve cell transplantation, therapeutic molecule delivery and the application of ECM bioscaffolds for CNS repair applications will be explored A variety of decellularization protocols have been established to develop ECM scaffolds from different tissue sources. The availability of these biologic materials provides an opportunity to investigate the effect of tissue source specificity (e.g., urinary bladder, muscle and liver) upon the remodeling outcome in various CNS injury models (e.g., TBI, SCI and stroke, among others). A better understanding of matrix biology will be required to optimize current decellularization protocols such that the therapeutic effects of ECM scaffolds can be maximized by retaining the growth-promoting molecules, while removing the growth-inhibitory cellular components. Financial & competing interests disclosure The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. No writing assistance was utilized in the production of this manuscript.

Executive summary Regenerative medicine to facilitate CNS & dural reconstruction • CNS injuries lead to significant morbidity and a tremendous financial burden related to medical care and loss of income. • The CNS has limited endogenous ability to repair injured tissues and the application of biologic scaffolds can provide a temporary template that support the survival of transplanted cells or host the recruited endogenous cells to facilitate regeneration. Biologic scaffold materials can also serve as a vehicle for therapeutic molecule delivery.

Biologic extracellular matrix scaffold facilitate constructive tissue remodeling • Biologic extracellular matrix (ECM) scaffolds can facilitate non-CNS tissue reconstruction. • The potential mechanisms by which biologic ECM scaffolds facilitate tissue remodeling may include the release of matricryptic peptides during scaffold degradation, recruitment of stem/progenitor cells, and modulation of infiltrating inflammatory cells.

Reconstruction outcomes & limitations • Biologic scaffolds derived from purified ECM components can partially facilitate CNS repair; however, more work is needed to optimize this process. • A combinational approach that involves the use of cells, delivery of therapeutic molecules and the application of scaffolding materials may be desirable for CNS regenerative medicine applications. • Biologic ECM scaffolds derived from non-CNS tissue sources can facilitate CNS injury repair. • Solubilized ECM scaffold hydrogels can be delivered through a minimally invasive route to the injury site. • Biologic ECM scaffolds may have intrinsic tissue-to-tissue variation in bioactivity.

Future perspective • A combinational strategy that incorporates different ECM protein components may be important to develop smart biomaterials. • Optimization of decellularization protocols is required to maximize the beneficial effects of ECM scaffolds. • Future studies are required to evaluate if ECM scaffolds are superior to biologic scaffolds derived from individual or a mixture of purified ECM components.

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Review  Meng, Modo & Badylak and patterns of gene expression. J. Immunol. 177(10), 7303–7311 (2006).

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