Outline Of Therapies Available In The Drug Delivery Field

Drug delivery systems can take the form of microspheres,131718 nanospheres,19-22 hydrogels,23-25 capsules,26-28 transdermal membranes,23 29 and liposomes.47 30-33 Their use ranges from the release of growth hormones, anti-inflammatory agents, anticancer agents, and antibiotics, to gene therapy, diabetes, delivery of contraceptives, and respiratory sickness such as asthma,1 434-37 as well as many others. In this chapter, we will focus mainly on injectable or implantable drug delivery systems, such as micro- and nanoparticles and scaffolds that can present a dual function: to support tissue regeneration and to enhance it by itself or by loaded therapeutic agents. The tissue engineering applications of scaffolds as carriers for delivering bone and cartilage active agents will be covered later in this chapter.

15.2.1 Microparticles/Spheres

Polymer microspheres have attracted attention as carrier matrices in a wide variety of medical and biological applications, such as affinity chromatography, immobilization technologies, drug delivery systems, nuclear imaging, and cell culturing. Various parameters including particle size and size distribution, porosity and pore structure, and surface area are considered to describe the overall performance of polymer microspheres in these applications.38 Polymer spheres with sizes up to 2 mm are produced by various processes, including precipitation, spray drying, and suspension, emulsion, and dispersion polymerizations.3839 If the drug delivery systems are fabricated as microspheres, they can be injected with a syringe40 41 or administrated intranasally as a dry powder,41 thereby avoiding surgical implant. In the case of bone and cartilage, they can be injected or be combined with the scaffold used for implantation on the repair site.

15.2.2 Nanoparticles/Spheres

The development of intravenously administrated carriers with blood circulation times long enough to continuously deliver drugs (e.g., anti-inflammatory) and other bioactive compounds, imaging agents, or other entities to specific sites of action6 42-44 has been a major challenge. The desired features of such a carrier include3643 (1) that the agent to be encapsulated comprises a reasonably high weight fraction (loading) of the total carrier system (for example, more than 30%); (2) that the amount of agent used in the first step of the encapsulation process is incorporated into the final carrier (entrapment efficiency) at a reasonably high level (for example, more than 80%); (3) the ability to be freeze-dried and reconstituted in solution without aggregation; (4) biodegradability; (5) small size (between 10 to 5 mm); and (6) characteristics to prevent rapid clearance of the particles from the bloodstream.

Nanoparticles offer specific advantages over liposomes, because they increase the stability of drugs/proteins and possess useful controlled-release properties,36 which is of major concern when they are released in physiological fluids (e.g., blood) or organs (e.g., lungs), because these particles interact with other components of the environment.44 Some of the basic characteristics of nanoparticles stem to a large extent from their submicron size and, consequently, from their large surface-to-volume ratio.42 For liposomes and other soluble macromolecular drug carriers, nanoparticles have been shown to be effective in the treatment of certain experimental neoplasic diseases.6,42,45 This type of vector could be useful in ensuring better peptide delivery.42

Typically, the drug is dissolved, entrapped, encapsulated, or attached to a nanoparticle matrix, and depending on the method of preparation, nanoparticles, nanospheres, or nanocapsules can be obtained. Nanocapsules are vesicular systems in which the drug is confined to a cavity surrounded by a unique polymer membrane, while nanospheres are matrix systems in which the drug is physically and uniformly dispersed.36 There are several techniques for preparing nanoparticles, but two methods prevail: dispersion of the preformed polymers36 and polymerization of monomers.3646

Regarding the use of nanoparticles, the inclusion within the nanoparticles of magnetic particles to direct them to their target (e.g., tumor cells) through magnetic fields created around the tumor brings great advantages, such as the reduction of the dosage and side effects, and raises the therapeutic effect.

15.3 BONE AND CARTILAGE CARRIER SYSTEMS FOR tissue ENGINEERING

Bone and cartilage repair is the main goal for several bone and cartilage tissue engineering studies. Their particular properties make it extremely difficult to create in vitro a system that mimics in perfection these two tissues. The major challenge in developing an optimal delivery system continues to be the conflicting design elements desired in such a system.47 In cartilage, the limited regenerative capacity is one of the main challenges that researchers have to overcome. In bone, the combination of bone tissue with different properties, together with the balance between bone formation and resorption, signaling molecules, and recruitment of bone cells — and in cartilage the particular nature of the tissue together with the cell type — create several barriers to the development of a perfect substitute. Among the many tissues in the human body, bone has been considered as a powerful marker for regeneration, and its formation serves as a prototype for tissue engineering based on morphogenesis.48 There are many site-specific drug delivery strategies, but osseous tissues are still difficult to target because of the biological and mechanical properties of bone.49 Osseous tissues have a great amount of the inorganic compound hydroxylapatite (HA), and bones lack the efficient circulatory systems of other tissues, with blood flow rates in bone of 0.05 to 0.2 ml min.1 g.1.49 As far as scaffold designing and cellular studies are concerned, they are not the scope of this chapter, but they can be found in other chapters of this book. Within this chapter, we will deal with strategies to deliver bone and cartilage factors (from drugs to growth and differentiation factors) that may help or enhance the repair or regeneration of the target tissue for tissue engineering applications.

As it is now well accepted, a tissue-engineered implant is a biological/biomaterials combination in which some component of tissue has been combined with biomaterials to create a device for the restoration or modification of tissue or organ function.50 The tissue engineering approach is one ideal strategy to help combat serious problems (such as transplantation due to the short number of donor tissues and organs) and to enable the self-healing potential of the patient to regenerate body tissue and organs (in this case, bone remodeling). The development of this specific approach of tissue engineering is based on several observations:51-53 (1) most of the tissues undergo constant remodeling due to apoptosis and renewal of constituent cells; (2) isolated cells tend toward forming tissue structures in vitro if the conditions are favorable; and (3) although isolated cells have the capacity to remodel and form the proper tissue structures, they require a template to guide their organization into the proper architecture.51 So, according to these observations and in order to achieve a successful bone tissue engineering approach, there are three necessary key components:51-54 scaffolds, cells, and growth factors, the last one being the main focus of this chapter, although we will also discuss the technology of cell encapsulation as it can be included as a strategy of drug delivery.

For applications that require the creation of large volumes of bone, an optimal carrier would be both a controlled-release system and a scaffold.47 Additional crucial requirements for the carrier include the ease of manufacture (feasible scale-up of bench processes), cost-effectiveness, biocom-patibility, malleability (to fit in various defect sizes), and user-friendliness.47 In the ideal situation, good carrier selection leads to a synergistic effect with the growth factor.

For the first generation of carriers, researchers frequently turned to the primary constituents of bone matrix — hydroxylapatite (HA) and collagen — because they naturally bind and sequester endogenous BMPs.48 In addition to collagen and HA, researchers have explored biomaterials with demonstrated osteoconductive properties.47 In this chapter, biodegradable polymeric systems will be the main focus, with an emphasis on the more recent developments.

Natural materials have been the focus of interest for several groups, and particularly starch-based2,55-57 and chitosan-based materials58-60 have been developed in our research group. These materials have been shown to possess properties that can render them suitable for several applications, ranging from scaffolds for bone and cartilage tissue engineering61 to bone cements62 and drug delivery systems.2,63,64 This last point is of particular interest for this chapter, and so far the work from our group has ranged from the encapsulation of anti-inflammatory agents2 to antibiotics,63 retinoic acid,58 and steroids (prednisolone and dexamethasone).65,66 The materials used are starch-based and chitosan-based materials, both from natural origin.

With regards to cartilage tissue, joint pain as a result of cartilage degeneration due to osteoar-thritis is an extremely prevalent age-related disease that causes considerable morbidity,67 and meniscus lesions are among the most frequent injuries in orthopedic practice.68 Both cases involve damage at a cartilage level. Since Hunter's observation in 1743 that cartilage once "destroyed, is not repaired," there are a number of therapies possible for articular cartilage repair (for a detailed review, please see Hunziker69), but none have had complete success. The most promising one that will be focused on in this chapter is tissue engineering, specifically the strategies of controlled delivery that can be applied in this therapy (for a review of the tissue engineering approach for articular cartilage, please see Temenoff and Mikos,70 Barron and Pandit,71 and van der Kraan et al.72). The same combinatorial approaches applied for bone tissue engineering are valid for cartilage tissue engineering, meaning that three necessary components are needed: cells for the generation of tissue, a scaffold to support growth and that degrades as the extracellular matrix is generated, and a bioactive factor to stimulate the correct biological signals in vivo for tissue growth and integration with native cartilage. The regulatory effects of growth factors and cytokines in cartilage are well documented.70 Interesting alternatives seem to be bilayer transplants consisting of periosteal cells for the reconstruction of subchondral bone and chondrocytes for reconstitution of the superficial cartilage layer, or the directed application of growth factors69 with or within the scaffolds.

The bilayer approach leads us to the discussion of another challenge to be solved involving bone and cartilage. The artificial cartilage prepared from tissue engineering approaches seems to offer promising treatments for cartilage defects.73-75 The same can be said of the bone tissue engineering approaches that are being developed worldwide.76-80 However, connecting the soft tissue to bone is difficult, meaning that it is rather complex to develop an osteochondral approach. The natural interface between cartilage and bone contains a zone of calcified cartilage.73,81,82 Mimicking this calcified interface may be a key issue for adhering an artificial cartilage to bone. One approach is to develop a substrate that supports the growth and attachment of cartilage and encourages a calcified zone. In addition, this substrate should also bond to bone on implantation in order to create an engineered interface between cartilage and bone. Several strategies for treating osteochondral defects are being investigated, such as biphasic transplants,83 porous polymer-ceramic compos-ites,81,82,84 anatomically shaped tissue constructs (bilayer),85 and two-phase composite materials.86

As an outline, for bone and cartilage tissue engineering approaches, the scaffold materials and procedures should allow both cartilage and bone regeneration and absorption of the biomaterials over time, so the approach to be used is the application of biodegradable polymers and when necessary, bioabsorbable ceramics to produce the desired scaffolds for this applications. But before the ideal tissue-engineered constructs for bone and cartilage applications are available, many questions remain to be answered — for example, the optimal cell type, the source of the cells, the need for growth factors, and another very important issue, the type of scaffold. From our point of view, the optimal scaffold must be used for stimulation of the cells into the desired tissue, meaning it must be able to differentiate and proliferate the desired cells with the help of the controlled release of relevant growth factor and be able to support the tissue regeneration when implanted and gradually fade out, ideally up to the complete regeneration of the new tissue.54,87 At this point, we have defined the main factors necessary to achieve this tissue engineering approach: (1) cells, (2) growth factors, and (3) their scaffolds. In other words, it is necessary to increase the number of cells that constitute the tissue as well as reconstruct the structure to support the cells. In addition, growth factors are required to promote cell differentiation and proliferation and then achieve tissue regeneration.52 The controlled-release concepts can be inherent and be a potential assistant in the three main factors. The "traditional" drug delivery approach can be applied to encapsulate living cells for incorporation within the scaffolds. In turn, scaffolds can be designed as "traditional" drug delivery carriers to control a site- and time-specific release profile and also to protect the growth factor.87 These strategies will be discussed in the coming sections, together with other potential approaches.

15.3.1 Bone and Cartilage Biologically Active Factors and Strategies for Delivery

Ideally, the combination of an adequate scaffold with proliferating cells and growth factors is the strategy to follow. The steps in between are the most difficult. Several factors are known to act in

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