Stroke is the third leading cause of death in the world. Recently, randomized clinical trials (RCTs) confirmed that endovascular treatment improved the outcomes of stroke patients [1–5]. However, 30–50 % of patients experience disabilities or death even after receiving endovascular treatment [1–5]. RCTs restrict the patient inclusion criteria for endovascular treatment. Thus, more patients need access to promising treatment alternatives for acute ischemic stroke.

It is believed that both the adult peripheral nervous system (PNS) and central nervous system (CNS) do not have the ability to regenerate. However, specific adult nerve cells have the instinctive ability to regenerate after damage. Researchers have shown that there are stem cells in the CNS, and in under some conditions, the CNS can self-renew. However, this phenomenon is highly limited. Thus, the main focus of basic research or preclinical research for the purpose of restoration of the CNS is cell transplantation.

Aguayo et al. reported that retinal cells, part of the CNS, were able to regenerate when used within a peripheral nerve graft, but they did not migrate beyond the graft into the CNS tissue [6]. Post-injury physiological responses and associated glial cell function inhibit the CNS from readily regenerating. Neurotrophic factor has positive anti-apoptosis and anti-inflammatory effects, but the appropriate administration protocol to achieve a satisfactory effect is unknown. In theory, direct administration will result in the maximum effect on neural function improvement. However, this method may also lead to secondary injury after operation due to injection. When neurotrophic factors are administered via a peripheral route such as transvenous delivery, they may cross the blood-brain barrier or blood-spine barrier, and adverse effects may occur.

Cell therapy has been successfully used for the treatment of specific organs such as the skin, heart, and cartilage. Many studies have applied cell therapy to treat central neural dysfunction after stroke. Embryonic stem (ES) cells, induced pluripotent stem (iPS) cells, neuronal stem cells (NSCs), and bone marrow stromal cells (BMSCs) have been employed as donor cells in past research. It is well known that the use of these cells results in improvements in animal models of cerebral infarction, cerebral trauma, spinal injury, and Parkinson’s disease.

Multipotential cells like ES cells, iPS cells, and NSCs are promising candidates for cell therapy. These cells may be used to regenerate neurons and improve neuronal function. Very few studies have been performed using these multipotential cells. However, it was shown that adult NSCs derived from human wisdom teeth improved neurological function after implantation in a rat middle cerebral artery occlusion model.

BMSCs, adult stem cells, are the most extensively examined source for brain cell therapy to date. BMSCs are a promising cell source because of their ethical acceptability and low immune impact owing to the possibility of utilizing the patient’s own BMSCs. BMSCs exhibit neural differentiation and produce growth factors to restore the CNS. Research has shown that cell therapy with BMSCs improved the outcome and cognitive function in animal stroke models for middle cerebral artery occlusion (MCAO) [7] and transient common carotid artery occlusion [8]. Some studies have shown that BMSCs have the potential to aid in functional recovery regardless of the implantation route (intravenous or direct) [9]. However, the mechanism of functional recovery is unknown. Factors secreted by BMSCs are believed to promote neurological benefits [10–12]. However, the BMSC survival rate is low, and few differentiate into neural cells such as NeuN-positive cells. Thus, differentiation into neural cells is not believed to be the main factor aiding in neural function recovery.

While cell therapy is promising, satisfactory outcomes have not been achieved in more complex organs such as the brain. In addition, only 10–20 % of transplanted cells survive, and those that do may exhibit loss of cell function and uncontrolled cell differentiation. There are ethical issues associated with the use of embryonic cells, and optimal cell transplantation methods are yet to be unveiled.

The following approaches have been utilized for CNS BMSC transplantation: (1) direct transplantation, (2) transvenous transplantation, (3) the transventricle or transthecal approach, and (4) the transarterial approach. In direct transplantation, BMSCs are transplanted directly on or around the infarct lesions. These donor cells can migrate toward a damaged lesion from the peri-infarcted lesion in a couple weeks and remain there after administration [5–7]. The disadvantage of this method is the creation of new damage and the possibility of cell death before engraftment of donor cells.

Transvenous transplantation is a less invasive technique. Bang et al. applied transvenous administration in a clinical study on patients with cerebral infarction [8].

Studies on transthecal transplantation of BMSCs via the fourth ventricle or using lumbar puncture for rat spinal injury models have also been reported. BMSCs transplanted into the cerebrospinal fluid cavity remain in the damaged spine, and clinical studies on patients with spinal injury have been initiated. Moreover, transarterial transplantation via the cervical artery has been assessed by Shen [13], and clinical studies are underway. However, Lee used magnetic resonance imaging to show that multiple cerebral infarctions occurred after transplantation.

Based on the above articles, it is uncertain whether BMSC transplantation through the vein would be effective in a clinical setting. The optimal method of cell transplantation needs to be elucidated in order to achieve satisfactory outcomes after brain injury due to stroke.

Scaffold technology can be used to enhance the regeneration of both the PNS and CNS. Non-cell-carrying polymeric nerve guide conduits (NGCs) have been approved for promoting nerve regeneration in various countries [13, 14]. NGCs simulate the instinctual regeneration process by providing a proper environment for neuroregeneration and have achieved clinical success for PNS treatment (Wosnick, J.H.; Baumann, M.D.; Shoichet, M.S. 73 Tissue therapy: Central nervous system. In Principles of Regenerative Medicine; Atala, A., Lanza, R., Thomson, J.A., Nerem, R.M., Eds.; Academic Press: San Diego, CA, USA, 2008; pp. 1248–1269). NGCs were used to control glial scar formation, promote neuronal sprouting, and provide protection from the invading immune system in spinal cord injury [15]. These phenomena have been confirmed in scaffolds constructed of various materials and architectural features. However, scaffold technology is still less effective than autografting for long lesions.

Tissue engineering involves implantation of a scaffold made with biomaterials and seeded with transplanted cells. Nutrients and other bioactive elements may also be embedded within the scaffold. Surgical materials such as surgical sutures or artificial dura mater made from polymers, ceramics, and titanium are used widely in daily clinical work. Unlike the materials used for surgical procedures, the biomaterials used in regenerative medicine must be biodegradable, porous, and cytophilic. Such biomaterials have been used for adult cell therapy in the bone, cartilage, vessel, heart, and skin. However, these organs are less complex than the CNS. Adult cell therapy using scaffolds for the CNS has many limitations.

According to a previous study, scaffolds for the CNS have had various properties, compositions, and shapes [16]. Size is the most important factor for CNS applications because of the narrow space within the bone structure. Additionally, the CNS has small, sensitive tissues such as nuclei that are adjacent to each other. Therefore, scaffolds have to be small enough to not affect neighboring tissue. Small scaffolds have other advantages in regard to the CNS. Recently, advances in nanotechnology have enabled scaffolds to become finer and smaller [17]. Menei et al. reported that repeated implantations were possible without open surgery when using poly(lactide-co-glycolide) microspheres [18]. In addition, nanomaterials can have several advantageous properties, such as higher surface area and high porosity required for cell adhesion [19].

Another important consideration is biocompatibility. For a substance to be considered biocompatible, it must support the appropriate cellular behaviors without being toxic to living tissue. Scaffolds must elicit minimal adverse cell responses, such as glial scarring, inflammation, hemolysis, coagulation, thrombus formation, and immune cell invasion, including foreign body reaction [20, 21].

The biocompatibility of neural scaffolds can be evaluated based on three aspects: blood compatibility, histocompatibility, and mechanical compatibility [20]. Blood compatibility means that scaffolds do not induce hemolysis, destroy blood components, or promote coagulation and thrombus formation after coming into contact with blood. Histocompatibility is defined as compatibility between tissues of different individuals so that one may accept a graft from the other without having an immune reaction. For example, poly(lactic-co-glycolic acid) (PLGA) microspheres do not induce a specific astrocytic reaction.

Mechanical compatibility between the scaffolds and host tissues requires that the scaffold have the appropriate compressive and tensile properties. Mechanical properties are one of the most important parameters for successful implantation [22].

Biodegradability or degradation after implantation is also critical. Whether or not a biodegradable scaffold is required depends on the specific application [23]. If scaffolds are non-biodegradable or biodegrade slowly, they act as a barrier to protect transplanted cells from the host immune system and provide a proper environment for cells to survive for long periods. Moreover, it is easy to retrieve non-biodegradable scaffolds after prescribed treatment periods. Some clinical trials have shown that cells survived in non-biodegradable scaffolds and there was no evidence of immune cell infiltration [24, 25]. However, it is believed that non-degrading scaffolds often cause long-term complications that often require revision surgery for removal because they may become harmful and constrict nerve remodeling [26]. As a result, biodegradable scaffolds have become the main focus for neuronal regeneration applications. Biodegradable scaffolds allow for cells to differentiate into neuronal cells at the site while also replacing lost or injured tissues. The degradation products must also be tolerated by the transplanted cells and host and ideally be metabolized completely without toxic effects or adverse immune reaction [16]. The biodegradation rate is an important factor to control. If the degradation rate is too slow, chronic compression, foreign body reactions, and mild inflammatory reactions may occur [13, 20]. On the other hand, rapid degradation may result in failure to protect the regenerated axon. Keilhoff reported that neuroregeneration may be hampered by inadequate protection of transplanted cells from invading fibrous tissue or insufficient time for nerve fibers to mature [27]. Biodegradability depends on a number of factors, such as temperature, PH, ionic strength, hydrolysis (swelling), the presence of enzymes, and engulfing cells. In vitro degradability tests can be performed in water or phosphate-buffered saline (PBS).

The ways in which scaffolds affect transplanted cells and damaged tissue in the CNS have been described. The mechanisms by which scaffolds improve neurological function are unclear, but several have been proposed. First, placing a biomaterial scaffold into the damaged area or cavity may provide support for the surrounding brain tissue. The tissue around the cavity is damaged by secondary injury; thus, the biomaterial protects the peri-cavity tissue from consequent impairment. In addition, scaffolds act as supportive cells like astrocytes. These mechanisms are thought to improve neurological function after implantation of a biomaterial. The scaffold can also be used to deliver various promoting factors for the growth of cells such as drugs.

Scaffolds are known to improve the cell survival rate in vivo owing to the 3D environment as well as mechanical signal cues [16]. Scaffolds help to direct the enlargement of axial cells, function as a substrate for cells, promote neurite formation, and enable cell infiltration. Scaffolds also restrict astrocytosis, which has a deleterious effect on healthy tissue. Scaffolds should allow for graft integration while also promoting cellular differentiation and migration.

Finally, scaffolds aid in the development of extracellular matrix that controls the structure of tissues and helps regulate cell nutrition, humoral factors, and metabolites. Hence, scaffold technology is promising for clinical use to help improve cell replacement and tissue repair, and investigators are focused on further enhancing scaffold properties.