Elsevier

Biomaterials

Volume 33, Issue 7, March 2012, Pages 2067-2075
Biomaterials

Functional improvement and neurogenesis after collagen-GAG matrix implantation into surgical brain trauma

https://doi.org/10.1016/j.biomaterials.2011.11.040Get rights and content

Abstract

Surgical or traumatic brain injury often leads to loss of cerebral parenchyma but there is as yet no clinically effective strategy for neural regeneration. Collagen glycosaminoglycan (collagen-GAG, CG) scaffolds have previously been used in many tissues in vivo but have never been utilized in the brain. Using an animal model, we investigated the effects of the implantation of CG scaffold matrix following surgical brain trauma. Results indicated that implantation of CG scaffold could significantly promote functional recovery following surgical brain trauma. The CG scaffold was found to facilitate proliferation, differentiation and migration of endogenous neural precursor cells (NPCs) both in the intra-matrix zone (IMZ) and lesion boundary zone (LBZ). The tissue concentration of brain-derived neurotrophic factor (BDNF) and glia-derived neurotrophic factor (GDNF) in the cortex demonstrated a sustained increase after implantation of CG scaffold following surgical brain trauma. These results suggest that the utilization of CG scaffolds can be considered as a potential clinical strategy for tissue regeneration and functional recovery after brain injury.

Introduction

Surgical or traumatic brain injury may cause serious long term neurological deficits [1]. The brain is fragile, but unlike other tissues has a limited capacity to regenerate upon being damaged. Current management strategies for brain injury are mainly focused on neuroprotection such as preventing tissue loss with pharmacological agents, but these still demonstrate poor long term outcomes [2], [3]. To date, there is no clinical intervention to promote tissue regeneration after brain injury [4], [5], [6]. But recent reports regarding progress of brain injury repair disclose some newly developed strategies based on the concept of neurogenesis in the adult brain [7]. It is known that the lack of regeneration in the brain might arise from the complex cellular and molecular environment in the damaged area and the lack of structural continuity, which makes cellular adhesion impossible. Implanting a scaffold into the lesion cavity to provide supporting substrates contributes to cell infiltration and axon outgrowth and may also be used for delivery of growth factors to promote axon regeneration [8].

Tissue engineering scaffolds, as analogs of the extracellular matrix (ECM), are used extensively in the body and were initially thought to only provide physical support structure for tissues [9]. Under normal conditions,the ECM makes up about one-fifth of the normal brain [10], and has a unique composition in the CNS as it contains relatively small amounts of fibrous proteins (collagens, laminins and fibronectin) with high amounts of linear polysaccharides (glycosaminoglycans (GAGs) such as hyaluronan, chondroitin sulfate and heparan sulfate) [11], [12], [13]. In addition, CNS resident cells including endothelial cells, astrocytes, neurons, microglia and others can synthesize and secrete ECM proteins [14]. It is known that in adults the ECM not only provides physical support for CNS resident cells, but also regulates ionic and nutritional homeostasis [12]. At present, scaffolds constructed from type I collagen and GAG (CG) have already been used for a variety of regenerative processes in vivo and cell migration in vitro. In addition, CG scaffolds were previously used to induce regeneration of the skin, conjunctiva, cartilage, bone and peripheral nerves in vivo [15], [16], [17], [18]. However, the use of CG scaffolds in the brain has not yet been well studied. The structural characteristics of the biomaterial and its speed of degradation are both critical factors in determining the successful outcome of wound repair when using tissue engineering scaffolds. A three-dimensional (3-D) scaffold can provide a microenvironment for cell migration and so facilitate the wound healing process.

In this study, we cross-linked collagen-GAG by immersing it in a glutaraldehyde solution for 24 h to maintain its 3-D structure until post-operative day 28, when it degraded completely. We hypothesized that the implantation of the ECM analog at the site of the cortical lesion would promote cell migration and differentiation and thus facilitate functional recovery. To test this hypothesis, our study was designed to evaluate the effects of the CG scaffold implantation following surgical brain trauma.

Section snippets

Preparation of scaffold (Synthesis of CG copolymer matrix)

The biodegradable collagen matrix of 1% collagen/0.02% GAG copolymer matrices were produced as previously described [16], [19], [20]. Briefly, a coprecipitate of type I porcine tendon (SPF, Animal Technology Institute Taiwan) and chondroitin 6-sulfate (Sigma Chemical Company, St. Louis, MO) in 0.05 m acetic acid was freeze-dried to yield a highly porous sheet 4 mm in thickness. The freeze-drying process yielded a network of CG copolymer with approximately 95% pore volume fraction and average

Cell migration into CG matrix

Fig. 1 shows the appearance of brains on day 0 and day 7 following surgery from animals with experimental surgical traumatic brain lesion (L) and with L then followed by implantation of CG matrix (L + CG) (Fig. 1A). Cross-sectional slicing revealed lesion areas in the L + CG animal were smaller than that in L animal (Fig. 1C). Hematoxylin and eosin (H&E)-stained coronal sections indicated cavity formation and deformation of the cerebral cortex with ipsilateral lateral ventricle dilation in an L

Discussion

Employing an animal model of surgical brain trauma, we have demonstrated that CG matrix implantation into a traumatic cavity can promote lesion repair and functional improvement. We also show histological evidence of cell migration into the IMZ in the L + CG group of animals. Significant increases in cell density within the LBZ of L + CG group was noted as compared to sham or L group. Astrocytes were found only in the LBZ and the proliferative cells are not astrocytes. In the LBZ and the IMZ,

Conclusions

Our results demonstrate that CG matrix by itself improves functional recovery, increases cell proliferation and also promotes differentiation and migration of endogenous neural precursor cells and increases tissue concentration of BDNF and GDNF after surgical brain trauma in rats. Consequently, the study suggests a potential clinical role for the CG matrix in promoting CNS regeneration after surgical brain trauma.

Acknowledgments

This study was supported in part by a grant from the National Science Council (NSC 99-2320-B-038-006-MY3 to JY Wang) and from the Buddhist Tzu-Chi General Hospital Taipei branch (TCRD-TPE-100-35 to KF Huang) at Taipei, Taiwan, without conflict of interest. We would like to thank Ms. Jia-Hsun Lee and Dr. Shun-Yuan Jiang for data collection and analysis.

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