**2. Selective permeability of the basal lamina** *in vivo*

In the human body, the basal lamina always supports a cell layer of either endothelial or epithelial cells (**Figure 2**). Together, these two layers form a complex barrier which selectively regulates the entrance and distribution of molecules from or into the connective tissue. Molecules which are selectively transported across the basal lamina include growth factors, nutrients, and hormones. Examples for such basal lamina/cell barriers are found in the skin, the kidney, the blood–brain barrier, and the vascular system [10, 30–34].

**Figure 2.** Illustration of complex barriers consisting of a cell layer and an adjacent basal lamina layer. The inner layer of blood vessels is constituted by endothelial cells with a basal lamina layer located on the outer side of the blood vessel. Also epithelial cells are supported with a thin layer of basal lamina. In both examples, selective permeability of the complex cell/biopolymer barrier toward molecules is observed, that is, some molecules can penetrate the barrier whereas others are rejected.

The skin poses one of the largest and, in most cases, the first barrier for foreign compounds. In addition to this protective function, the skin also regulates the uptake of oxygen and prevents the loss of water from the underlying tissue [32]. In kidney tissue, the basal lamina is, in combination with the epithelial cells, responsible for filtering [10], and defects in the basal lamina can result in kidney malfunction [34]. The blood–brain barrier [30] protects the brain tissue from pathogens and neurotoxic molecules, whereas it allows the passage of regulatory molecules such as hormones from the blood stream into the cerebrospinal fluid [35]. A similar structure is present in the vascular system. Here, the first barrier is established by endothelial cells which rest on a thin layer of basal lamina on their basolateral side [10]. Nutrients, growth factors, proteins, hormones, and polysaccharides are prevented from leaking from the blood stream into the connective tissue by tight junctions between the endothelial cells [31, 35–37]. If the integrity of these tight junctions is impaired, the basal lamina becomes directly accessible for blood compounds. Moreover, if the basal lamina layer is damaged, the translocation of solutes from the blood stream into the connective tissue is increased, even if the tight junctions are intact [20]. Of course, for molecules which need to traverse from the connective tissue into the blood stream, the basal lamina is encountered first before the endothelial cells are reached. In this scenario, the basal lamina layer constitutes the primary barrier.

linking function entailed strong alteration of those tissues during embryonal development and ultimately led to death immediately after birth [28]. Of course, alterations in basal lamina properties can also have less severe consequences. For instance, long-term diabetes patients not only often suffer from retinopathies but also show an increased thickness and stiffness in the ocular basal lamina. Here, however, the higher amount of basal lamina proteins is due to the expression of diabetes-specific proteins whereas the production of the normal basal lamina

In the human body, the basal lamina always supports a cell layer of either endothelial or epithelial cells (**Figure 2**). Together, these two layers form a complex barrier which selectively regulates the entrance and distribution of molecules from or into the connective tissue. Molecules which are selectively transported across the basal lamina include growth factors, nutrients, and hormones. Examples for such basal lamina/cell barriers are found in the skin,

**Figure 2.** Illustration of complex barriers consisting of a cell layer and an adjacent basal lamina layer. The inner layer of blood vessels is constituted by endothelial cells with a basal lamina layer located on the outer side of the blood vessel. Also epithelial cells are supported with a thin layer of basal lamina. In both examples, selective permeability of the complex cell/biopolymer barrier toward molecules is observed, that is, some molecules can penetrate the barrier

The skin poses one of the largest and, in most cases, the first barrier for foreign compounds. In addition to this protective function, the skin also regulates the uptake of oxygen and

components is not increased [29].

whereas others are rejected.

**2. Selective permeability of the basal lamina** *in vivo*

206 Composition and Function of the Extracellular Matrix in the Human Body

the kidney, the blood–brain barrier, and the vascular system [10, 30–34].

A detailed knowledge of the molecular interactions which determine the selective filtering properties of the basal lamina is especially interesting for the design of new drug carrier vehicles for targeted drug delivery applications. One example for such an application is the specific targeting of tumors. In tumor tissue, the influence of the basal lamina barrier becomes even more important since tumors usually show an increased production of ECM [38]. Drug carriers are often injected intravenously; thus, the vascular system poses the critical barrier which the drug carriers have to pass. Here, the passage of drugs/drug carrier vehicles from the blood stream into the adjoining tissue is primarily regulated by the endothelial cells. However, in most cases, the endothelium around tumors is leaky. This is also known as an "enhanced permeability and retention effect" (EPR). Since the barrier function of the endo‐ thelium is impaired by the tumor, the basal lamina becomes directly accessible for compounds from the blood stream. In such a situation, the passage of drug carrier systems and their incorporated drugs is mainly regulated by the basal lamina.

In all of these examples, the selective barrier properties of the basal lamina are key for regulating complex biological processes. To possess such a high selectivity toward molecules or drug carrier particles, that is, deciding which of them are allowed to pass and which are rejected, an advanced molecular filter system based on various interactions is needed. Understanding the physical interactions between drug carriers and the complex multicom‐ ponent, basal lamina is crucial to efficiently adjust the surface parameters of drug carriers in such a way either that they are able to easily penetrate the basal lamina barrier or that they accumulate at the basal lamina interface. Studying the mechanistic principles which govern the selective permeability properties of the basal lamina layer *in vivo* is, however, very difficult: On the one hand, the basal lamina has a thickness of only a few hundred nanometers which would require optical experiments with a supreme spatial resolution such as PALM/STORM or STED microscopy [39]. On the other hand, the presence of a plethora of molecules, dynamic alterations in the basal lamina composition by enzymatic processes, or generation of new basal lamina components by the adjacent cell layer further complicates the interpretation of *in vivo* permeability studies and the correlation of the experimental results with physicochemical principles. Thus, a detailed investigation of the selective permeability properties of a complex biopolymer barrier such as the basal lamina requires a reliable *in vitro* model system, which is available in quantities large enough to conduct systematic tests while reproducing the behavior of the *in vivo* basal lamina layer*.*
