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A Tissue-Engineered Conduit for Peripheral Nerve Repair

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A Tissue-Engineered Conduit for Peripheral Nerve Repair ORIGINAL ARTICLE A Tissue-Engineered Conduit for Peripheral Nerve Repair Tessa Hadlock, MD; Jennifer Elisseeff, BS; Robert Langer, ScD; Joseph Vacanti, MD; Mack Cheney, MD Background: Peripheral nerve repair using autograft ma- formed using a dip-molding technique. They were cre- terial has several shortcomings, including donor site mor- ated containing 1, 2, 4, or 5 sublumina, or “fascicular ana- bidity, inadequate return of function, and aberrant re- logs.” Populations of Schwann cells were isolated, ex- generation. Recently, peripheral nerve research has panded in culture, and plated onto these polymer films, focused on the generation of synthetic nerve guidance where they demonstrated excellent adherence to the poly- conduits that might overcome these phenomena to im- mer surfaces. Regeneration was demonstrated through prove regeneration. In our laboratory, we use the unique several constructs. chemical and physical properties of synthetic polymers in conjunction with the biological properties of Schwann Conclusions: A tubular nerve guidance conduit pos- cells to create a superior prosthesis for the repair of mul- sessing the macroarchitecture of a polyfascicular periph- tiply branched peripheral nerves, such as the facial nerve. eral nerve was created. The establishment of resident Schwann cells onto poly-L-lactic acid and polylactic–co- Objectives: To create a polymeric facial nerve analog glycolic acid surfaces was demonstrated, and the feasi- approximating the fascicular architecture of the extra- bility of in vivo regeneration through the conduit was temporal facial nerve, to introduce a population of shown. It is hypothesized that these tissue-engineered de- Schwann cells into the analog, and to implant the vices, composed of widely used biocompatible, biode- prosthesis into an animal model for assessment of gradable polymer materials and adherent Schwann cells, regeneration. will be useful in promoting both more robust and more precisely directed peripheral nerve regeneration. Results: Tubes of poly-L-lactic acid (molecular weight, 100 000) or polylactic–co-glycolic acid copolymer were Arch Otolaryngol Head Neck Surg. 1998;124:1081-1086 ERIPHERAL NERVE injuries sults are obtained.1,2 While this approach continue to be among the incurs some donor site morbidity and usu- most challenging problems ally involves a secondary surgical site, its faced by surgeons. Within main drawback is insufficient functional otolaryngology, it has been outcome. In the case of the facial nerve, Pparticularly difficult to develop appropri- autografted repairs rarely, if ever, result in ate strategies for the management of fa- a recovery that is better than House- From the Department of cial paralysis, recurrent laryngeal nerve in- Brackmann grade III.3 Otolaryngology, Massachusetts Eye and Ear Infirmary jury, and the morbidity associated with Attention has long been directed at al- (Drs Hadlock and Cheney), insensate oropharyngeal and esophageal ternatives to autografting. Researchers in and the Laboratory of flap reconstructions after ablative sur- the past have attempted to bridge severed Transplantation and Tissue gery for malignancy. The development of nerve endings with a wide variety of au- Engineering, Children’s a synthetic nerve guidance conduit would tologous biological tubular structures, in- Hospital (Drs Hadlock and be of enormous utility in the manage- cluding artery, vein, inside-out vein con- Vacanti), Boston, Mass, and the ment of these and other nerve-related duits, and decalcified bone channels.4-8 Department of Chemical problems in otolaryngology. Some have used cadaveric nerve allografts Engineering and the The standard approach to repair a pe- or xenografts to bridge long nerve de- Harvard–Massachusetts ripheral nerve when a gap is present is to fects.9 Others have used skeletal muscle Institute of Technology Division 10-12 of Health Sciences and bridge the severed ends with a segment of grafts for this purpose. While investi- Technology, Massachusetts autologous donor nerve. When the cali- gators have achieved promising results us- Institute of Technology, ber of the donor autograft matches that of ing many of these techniques, to our knowl- Cambridge (Ms Elisseeff the recipient nerve, in both total diam- edge none has matched or surpassed those and Dr Langer). eter and average axon density, superior re- achieved by autograft repair. ARCH OTOLARYNGOL HEAD NECK SURG/ VOL 124, OCT 1998 1081 ©1998 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/26/2021 MATERIALS AND METHODS collagenase and dispase, the crude cell suspension was plated in Dulbecco modified Eagle medium, enriched with 10% POLYMER PREPARATION heat-inactivated fetal bovine serum and antibiotics. The cells were treated for the ensuing 2 to 3 days with cytosine ara- Poly-L-lactic acid with a molecular weight (MW) of 100 000 binoside for the elimination of fibroblasts. On day 5, a thy1.1 and a copolymer of PLGA with a lactide-glycolide ratio of 85:15 antibody purification was used to remove residual fibro- were purchased commercially (Polysciences, Worthington, blasts, and the purified Schwann cell population was ex- Pa). Stock solutions of 2.5% to 5% (wt/vol) of the polymers panded on polylysine-coated dishes over a period of 6 weeks were generated by dissolution in either chloroform (CHCl3) using mitogenic media enriched with a cyclic AMP activa- or methylene chloride (CH2Cl2). Tubes were prepared by a tor (Forskolin, Sigma Chemical Co, St Louis, Mo) and glial modification of a standard dip-molding technique. Briefly, growth factor (Biomedical Technologies, Wilmington, for the single lumen conduits, a thin-walled polytef sheath Mass). Cultures were assessed for purity using an immu- (outer diameter, 1.8 mm) was passed over a glass capillary nocytochemical stain against S100 protein, a glial-specific tube. Inside the fume hood, the tube was secured to a dip- marker. ping apparatus and systematically dipped into the polymer For adult Schwann cell isolation a previously de- suspension every 15 seconds, for a total of 20 dips. The tubes scribed explant technique was used.32 Lewis rats (weigh- were placed into and removed from the solution at a con- ing 200-250 g) were killed, and the sciatic were nerves re- stant rate and were suspended for a total of 10 seconds be- moved. The epineurial tissue was microscopically peeled tween each subsequent dip for solvent evaporation. After the away, and the remaining tissue was cut into 1-mm seg- dipping procedure, the tubes remained in the fume hood over- ments. These segments were placed on tissue culture plas- night for evaporation of solvent at atmospheric pressure, fol- tic in Dulbecco modified Eagle medium and explanted on lowed by an additional 24-hour period under low vacuum a weekly basis. After 6 weeks, the explants were enzymati- for the removal of residual solvent, and then stored in a des- cally digested, purified, and expanded as described above. sicator for later characterization. Yields from these explants were much lower, as expected, A similar approach was taken for the creation of tubes and Schwann cells for the majority of the ensuing studies with multiple sublumina. Smaller polytef sheaths (OD, 600 were performed using the neonatal preparations. µm) were passed over stainless steel wires rather than glass For the adherence studies, polymer films prepared and capillary tubes. Each sublumen was made separately, as de- sterilized as described above were placed onto tissue cul- scribed above, and then bundled together for creation of ture plates. A Schwann cell suspension was then plated onto the final multiluminal channel. For example, to create a the films, and the cultures were examined using light mi- 5-lumen conduit, 5 tubes were prepared separately. The croscopy on a daily basis for observations of adherence, sur- group of tubes was then bound together with a suture at vival, and proliferation behavior. either end and dipped as a bundle for a total of 20 addi- tional dips to achieve a single prosthesis with 5 separate IN VIVO STUDIES compartments. The bundled conduits were redried and stored as described above. The polymer conduits, with or without inhabitant synge- Polymer films for the plating of Schwann cells were neic Schwann cell populations, were implanted into 20-mm prepared from the same polymer stock solutions as the con- gaps in the left sciatic nerve of 10 adult Lewis rats. After duits. They were formed by a standard solvent casting tech- induction of anesthesia with inhalational methoxyfluor- nique. Several milliliters of the polymer suspension was ane, the animal was shaved and prepped. An incision was placed into a 100-mm glass Petri dish in the fume hood, made over the left hind limb, and the gluteal muscles were and the solvent was allowed to slowly evaporate. The re- divided to expose the sciatic nerve. Under the operating sultant films were gas sterilized with ethylene oxide and microscope, a 20-mm segment of nerve was removed, and used for the plating of Schwann cells. the proximal and distal stumps were secured to either end of the polymer conduit using several 9-0 nylon microsu- POLYMER CHARACTERIZATION tures. The muscle and skin were closed in layers, and the animals recovered in a controlled environment. They were The tubes were examined grossly for mechanical strength given food and water ad libitum and examined for signs of and pliability. Scanning electron microscopy using an en- autotomy. Institutional guidelines regarding animal ex- vironmental scanning electron microscope (Jeol USA Inc, perimentation were followed. After 3 months, the animals Peabody, Mass) was used to examine luminal surfaces and were evaluated for functional sensory recovery using stan- porosity. Gel permeation chromatography using a peristal- dard pinch testing and perfused with 3% glutaraldehyde, tic pump (Hewlett-Packard Co, Palo Alto, Calif) and com- and the implants were harvested. Observations were made mercially purchased columns (Polymers Inc, Burlington, regarding tubular continuity both along the length and at Vt) was carried out to determine the MW of the processed the anastomoses.
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