Cell inductive molecules (growth, differentiation and migration factors and therapeutics) play an important role in controlling cell function in tissue engineering and regenerative medicine. The use of appropriate delivery strategies to locally deliver these important molecules in a controlled manner for a desired time frame is prerequisite. All these cell inductive molecules are nothing but powerful drugs and act in a concentration and time dependent manner. Therefore, the release of these drugs in minute quantities (even in nano or pico grams) can elicit the required biological response. So the chosen controlled delivery vehicle should be able to maintain the drug’s biological activity for relatively longer duration. Furthermore, the release profile of these drugs from the delivery device should be precisely controlled and can be delivered based on the demand. Temporal control over concentration and spatial localization control the extent and pattern of tissue formation (for regeneration) and healing (for drug therapy). In view to fulfil the described design criterion, a variety of polymeric delivery systems are designed for drug delivery in tissue engineering. Polymeric systems are of key interest because of their easy processiablity and control over their degradation in order to achieve desired controlled release profile of the encapsulated

   
drug. One of the simplest delivery techniques could be the direct incorporation of the drugs into the porous polymeric matrices or scaffolds during the fabrication process. In such a case, drug release depends on the physicochemical properties of the polymer that are used to construct the porous scaffolds. Two fundamental release mechanisms such as diffusion and degradation-induced release play an important role in release of the entrapped drugs from the porous scaffolds. In in vivo implantation of such scaffolds, hydrolytic and enzymatic degradation of polymer matrix lead to the detachment of drugs from the porous intricate polymeric networks.  

Biodegradable polymeric drug delivery systems encapsulating the drugs (e.g. drug loaded microspheres) could be incorporated in hydrogels or prefabricated porous scaffolds for spatio-temporal delivery of desired drug. In this method, either a single or multiple (a combination of drugs) can be used for delivery from a single material platform or porous scaffold. Polymer matrices that incorporate uniformly distributed protein drugs are commonly used for protein drug delivery in tissue engineering. Biodegradable microspheres made from synthetic polymers such as PLGA encapsulating protein drugs were used to hybridize with porous scaffolds of collagen and gelatin. 

The release of drugs from these porous matrices is dependent on the diffusion and behavior of the material. The degradation process of these materials involves hydrolysis of polymer backbones into non-toxic monomers. The drug release rate could be controlled by changing the degradation rate of polymers which can be achieved by tailor made properties of the polymer material. Microencapsulation technique provides a powerful mean to protect the bioactive molecule or drug from in-vivo biodegradation as well as to achieve the sustain release for longer time frame. As discussed, the polymer PLGA has already been demonstrated its success in microencapsulation of a number of drugs and also approved from food and drug administration (FDA) for various biomedical applications. PLGA microspheres can be prepared by a number of techniques which has been explained in many literatures. The most popular method for preparing drug-incorporated microspheres is the emulsion-based method. To microencapsulate hydrophilic protein drugs, water-in-oil-in-water (w/o/w) or double emulsion technique is often used. Double emulsion technique is often considered as the most appropriate method to microencapsulate hydrophilic drugs or protein based biopharmaceuticals. High drug loading in microsphere formulations is most important to sustain the release of an encapsulated drug for a relatively longer time and is extremely important in context of tissue engineering and drug therapy. The drug release mechanism from these microspheres depends on polymer degradation, diffusion of drug, and complexation between drug and polymer matrices. Therefore, the rate of drug release could be regulated by chemically and physically by engineering the polymer degradation rate, the permeability of the microspheres, the internal structure of microspheres matrices (porous and compact), and the interaction between drug and polymer matrix. To obtain the desired drug release profile, the nature of polymer, compositions, chemistry of cross linking, properties of drug, size of microspheres, and the surface and core properties of microspheres matrices should be well considered in designing appropriate drug releasing microspheres for incorporation into the porous scaffolds.

The third common scaffold based drug delivery method could be the drug loaded hydrogels. Hydrogels behave as a scaffolds and have been used for variety of tissue regeneration studies. A hydrogel can be fabricated into many geometrical configurations such as. cylinders, slabs, disks, or spheres. Hydrogel are often referred to as macro-gels and prepared from synthetic (poly ethylene glycol, poly vinyl alcohol and so on) and natural (gelatin, collagen and so on) polymers and usually have a porous surface and a complex internal network. The swelling property of hydrogels in water allows free movement of drugs throughout the cavities in hydrogels to release the drugs.

The last and least common method could be the prefabricated porous polymeric scaffolds soaked in drug solution. In this method, the drug release from the porous scaffold is exclusively governed by the process of diffusion. This method has the major drawback of higher initial burst release and poor sustain release of the drugs from the scaffolding materials and therefore considered as the least preferred method for scaffold based drug delivery.

In conclusion, the suitable integration of porous scaffold design and drug delivery technologies can generate innovative functional materials that can truly mimic an extracellular matrix (ECM) for regeneration of neo tissues and can functionally be capable of releasing the drugs for various therapeutic applications.

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4. Himansu Sekhar Nanda, Nokamoto Tomoko, Shangwu Chen, Naoki Kawazoe, Guoping Chen, et al (2014) Controlled release of bioactive dexamethasone from collagen micro-gel functionalized PLLA scaffold of controlled pore structure for Osteogenic differentiation of h-MSCs ” Journal of Biomaterial Science: Polymer Edition 25, no. 13:1374-1386 

5. Himansu Sekhar Nanda, Naoki Kawazoe, Qin Zhang, Shangwu Chen, Guoping Chen, et al (2014) Preparation of collagen porous scaffold for controlled and sustained release of bioactive insulin” Journal of Bioactive and Compatible Polymers: Biomedical Applications March 29: 95-109 

6. Himansu Sekhar Nanda, Shangwu Chen, Qin Zhang, Naoki Kawazoe, Guoping Chen, et al, (2014) “Collagen Scaffolds with Controlled Insulin Release and Controlled Pore Structure for Cartilage Tissue Engineering,” Biomed Research International