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  • Periodic Report Summary 2 - NEURIMP (Novel combination of biopolymers and manufacturing technologies for production of a peripheral nerve implant containing an internal aligned channels array)

NEURIMP Report Summary

Project ID: 604450
Funded under: FP7-NMP
Country: Spain

Periodic Report Summary 2 - NEURIMP (Novel combination of biopolymers and manufacturing technologies for production of a peripheral nerve implant containing an internal aligned channels array)

Project Context and Objectives:
*A summary description of project context and objectives

Peripheral nerves are basic communications structures guiding motor and sensitive information from Cord Nerve Surgery to effector or receptor units. Severe nerve injuries include axon bundles section and Schwann cells destruction, which results in loss of motion control and sensorial perception. After the lesion, cells present in damaged nerves activate spontaneously self-regeneration programs that might facilitate further treatment. Nerve autograft is the “gold-standard” surgical intervention that demands autologous tissue extraction and corresponding function loss. The goal of the project is the validation of biomaterials structural plasticity and those compatible manufacturing technologies that will enable the generation of a tubular structure containing an intraluminal microstructure based on an array of aligned channels or fibers. The intraluminar structure proposed in NEURIMP consists of a combination of stiffer and softer materials where the biological and physicochemical properties of each material will define the role that it will play into the scaffold and therefore, its location in it. Stiffer materials (material 1 and 2 in Figure 1) will be required to create the external suturable tube and the internal skeleton core of the scaffold that will confer structural stability to the device during the regeneration period. Softer hydrogels (material 3 in figure 1) will be incorporated into the lumen of the channels created in the axonal regenerative core. The device will contain a set of intraluminar structures (channels or aligned fibers) especially designed to optimize axon contact surface, improve guided axon growth and bridge nerve gaps larger that 3 cm.

NEURIMP will select candidate biomaterials according to their biocompatibility, mechanical properties, biotoxicity and biodegradability, evaluating their adequacy as a function of these parameters and nerve cell proliferation, axon growth facilitation and myelination in a 2D and 3D in vitro system. Optimization of biomaterial composition and configurations (blends) will be developed according to these in vitro tests. The regenerative properties of selected prototypes will be validated in vivo in a sciatic nerve section model.
(see image in the report).

Objective 1: Develop advanced synthetic-natural biohybrid materials with improved biocompatibility and biodegradability (18 – 24 months), regenerative capacity (nerve gaps > 3cm) and mechanical properties (Young Module ≈ 1 MPa) suitable for the generation of 3D micropatterned structures comprising with selective porosity and controlled degradation. Determine the optimal physical parameters required by biomimetical endoneural tubes to pave for an efficient regeneration of both sensory and motor axons. Scale – up biomaterial production to industrial levels.
Objective 2: Develop advanced manufacturing technologies for the generation of biomimetic endoneural tubes with precise morphologies and sizes (intraluminal microchannels or fibers with high aspect ratio). Scale – up manufacturing technologies to industrial levels.
Objective 3: Understand the interplay between scaffolds and the endothelial cells, the Schwann cells and neurons (via in vitro assays) to promote the generation of Bands of Büngner and revascularization inside the INGCs, and provide the trophic and tropic conditions for an optimal axonal regeneration and remyelination.
Objective 4: Design, fabricate and optimize a new generation of Neural Guides composed of two clearly differentiated parts: i) An outer wall with selective porosity for nutrient exchange and a slow-degrading degradation ratetax to reduce fibrosis, to protect the newly formed nerve cord, and to provide physical stability that avoids the INGC collapse while regeneration progresses; ii) An inner endoneural-like microstructure to provide a topographical axonal regeneration. This part will be composed of a biomaterial with a regulated degradation tax according to the repaired gap length, being replaced once the Bands of Büngner and the axons have regenerated across the INGC.
Objective 5: Characterize, in a clinically relevant animal model of sciatic nerve injury, the performance of the produced INGCs for key parameters such as the maximum gap length that can be repaired, their ability to promote the regeneration of both motor and sensory axons, and their ability to pave for precise target reinnervation with as resulting in improved functional recovery. Comparison to regenerative capacity of autografts.
Objective 6: Scaled up production of the new generation of INGCs taking into account standards, regulatory affair and economical issues.

Project Results:
The consortium has synthetized natural and synthetic polymers with predefined physicochemical properties for novel nerve conduit manufacture. Three main types of polymers have been analized: highly hydrophilic soft hyaluronic acid polymers, and polyesters natural (poly(hydroxyalkanoates)) or synthetic (polylactides, polycaprolactone). These matarials have been also combined in the form of blends and copolymers to create novel materials with suitable properties. Based on mechanical and biological properties, selection of materials has been conducted by the consortium. Some of the selected materials support neuronal cell attachment, spreading, proliferation and neurite extension in vitro. Also the selection includes materials with good processability enabling fabrication of porous materials. Biocompatibility of these materials according to ISO10993 has been studied and cytotoxicity under the presence of different porogens has been analysed.
Different manufacturing processes such as Photopatterning-based 3D Micromoulding, Microextrusion, Microstereolithography, Microinjection and Cast Micromoulding have been developed for all materials synthetized. Aligned channels have been successfully produced by a wire casting UV system with external tube manufacture via Microstereolithography being successful. (figure 3).
(see image in the report)
The combination of biomaterials along with its manufacturability and its physicochemical properties such as mechanical properties, neuroregeneration, cytotoxicity and biodegradability has allowed the consortium to shortlist a few biomaterials as candidates to the NEURIMP’s implant. In-vitro and ex-vivo evaluation of 3D nerve regeneration model will allow the consortium to choose the final implants that will be up-scaled and validated in-vivo during the second part of the NEURIMP’s project.

Potential Impact:
The NEURIMP project is concerned to peripheral nerve injury, which affects 1/1000 children and adults. Currently, microsurgical repair is the mainstay of treatment for acute lesion without tension on nerve ending after coaptations and nerve autograft is used to bridge gaps greater than 1-2cm. Motor recovery is possible and acceptable after simple injuries although not complete and the restoration of normal sensation is very rare in children and never occurs in adults. When conventional microsurgical connection of nerve stumps fails or is not possible due to tissue loss, there is a limiting nerve gap that requires a tissue engineering approach. Significant prolonged disability, plus socio-economic dependency upon family and social services is inevitable. Of patients with injuries in the forearm less than two-thirds return to useful employment. Patients with brachial plexus injury rarely return to work, and such injuries are comparable with spinal injury on these terms.

The disappointing outcome largely reflects the failure of microsurgical approaches to adequately address nerve regeneration at the cellular level. Autograft dissection is limited for major reconstructions, and brings donor-site morbidity. To date, tubulizations are the selected intervention for these gaps but the existing devices have a basic architecture consisting in empty hollow tubes. The future therefore lies with bioengineered constructs. Current nerve guides can be used for defects of up to 20–25 mm, eliminating the need to graft tissue, and 3-cm nerve defects have been corroborated in independent studies as the maximum limit allowable for successful recovery. Even though, the number of commercially available nerve guides is still relatively small, a number of products have recently become Food and Drug Administration (FDA) approved.
Existing conduits facilitate repair, but don’t activate cells sufficiently. Further, although nerve guides show clinical efficacy, their use presently is not widespread. Both naturally derived and biodegradable synthetic devices give reasonable results for short gap injury repair. But an ongoing challenge is the limit of 20–25mm for transection injuries. New technologies are being addressed which can be grouped in to cell-free and cell-containing approaches, however cell-free approaches are attractive as off-the-shelf products, and are more straightforward and cost effective compared to cell-therapy approaches. The next generation of cell-free nerve guides is therefore being designed in NEURIMP.
During this period, the NEURIMP consortium met with the External Advisor Committee, which is integrated by three prestigious clinicians in the field of peripheral nerve. The experts attended a face to face meeting, in which questions related to the device’s intended use, the medical practise and the device’s design were presented by the experts and discussed in detail with all the consortium’s members.

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