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Therapeutic Delivery

Importance of controlled delivery systems for regenerative therapeutics “

Optimistic hope is the key to a successful scientific invention and modern therapeutics is having an optimistic hope from advances in stem cell research for regenerative therapy.



Keywords:  controlled delivery systems • differentiation • regenerative medicine • stem cell technology • tissue engineering

Stem cells technology can result in a paradigm shift in medicine therapeutic armamentarium In the recent past, researches on tissue engineering and regenerative medicine (TERM) have gained momentum as the next generation technology for transplantation of whole organ and tissue for diseased/malfunctioned organs, although the notion of regeneration ability of a lost tissue is already revealed to mankind for several years [1] . Each year, millions of patients suffer from end-stage organ disease or tissue loss, resulting in high mortality rate due to lack of adequate donors and clinical limitations of surgical therapies [2] . Addressing such formidable challenges, the growing interest in regenerative medicine coupled with extraordinary advances on stem cells science can likely result in a paradigm shift in medicine therapeutic armamentarium [3,4] . This will ultimately lead to considerable biological solutions to surmount typical/simple medical shortcomings. Very recently, three stem cell products approved from Korea Food and Drug Administration (KFDA), were launched in the Korean market in 2012, which includes world’s first-time reported autologous bone marrow derived stem cells (BMSC), autologous adipose derived stem cell (ADSC) and allogenic umbilical cord derived stem cell (UBMSC) for the treatment of myocardial infarction, Chron’s disease and chondyle defect, respectively [1] . Additionally, over one – two hundred clinical trial Phase I, II, III with a wide arena of scientific field is under development throughout the world.

10.4155/TDE.14.80 © 2014 Future Science Ltd

This may be a burgeoning step towards the advancement of regenerative medicine compared with that of conventional medication therapy however, their impressions will provide a platform for future advances in stem cell technology applications. The basic concept of TERM is to manipulate the extracellular environment for cells inherently present in the body to enhance their biological potentials for tissue generation [5] . To realize a successful therapy using regenerative medicinal technique, triad ingredients are fundamentals, that is: (i) specific/desired cells as harvested and dissociated primary cells, adult stem cell, embryonic stem cell (ESC) and induced pluripotent cell (iPS); (ii) natural or artificial extracellular matrix (ECM) known as scaffolds, provides a favorable environment for cells adhesion, growth resulting in desired number of healthy cells with specific functions; (iii) biomolecules including growth factors, cytokines and phospholipids which furnishes the nourishment for cell proliferation and/or differentiation by up-regulation or down-regulation of specific proteins, receptors, etc. [1,6]

Gilson Khang Author for correspondence: Dept of PolymerNano Sci & Tech, Dept of BIN Fusion Tech & Polymer BIN Fusion Research Center, Chonbuk National University, 567 Beakje-dearo, Deokjin-gu, Jeonju 561–756, Republic of Korea Tel.: +82632702355 Fax: +82632702341 gskhang@ jbnu.ac.kr

Nirmalya Tripathy

Adult stem cells differentiate into specialized cell types Smart selection of the cells source is highly crucial for application of tissue engineering technology. Basically, three types of stem cells were considered for these technique i.e. adult stem cells, ESC and iPS including direct reprogramed cells. Compared to ESC and iPS (leading to teratoma formation easily), adult stem cells were extensively

Ther. Deliv. (2014) 5(10), 1053–1055

Dept. of PolymerNano Sci & Tech, Dept of BIN Fusion Tech & Polymer BIN Fusion Research Center, Chonbuk National University, 567 Beakje-dearo, Deokjin-gu, Jeonju 561-756, Republic of Korea

part of

ISSN 2041-5990

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Editorial  Khang & Tripathy used in pilot researches as promising cell-based treatment for several diseases owing to direct harvest from patients, rapid cell proliferation, ease of manipulation for replacement of nonfunctional genes, homing ability and to interact with surrounding tissues. Moreover, some lineage-specific adult stem cells were reported to possess greater plasticity nearly equivalent with ESCs, and thus regarded as multipotent – ability to differentiate into more than one cell type regardless of the parent cell [8] . Depending on the origin type, adult stem cells can be further classified as mesenchymal stem cells (MSCs) and hemopoetic stem cells (HSCs). MSCs were derived from a variety of tissues such as bone marrow stem cells (BMSCc), limbal stem cells, blood derived (BSC), adipose derived (ADSC), hepatic stem cells, dermal stem cells, adipose derived (ADSC) whereas HSCs are found in cord/peripheral blood. MSCs encompassing multipotent cells are sufficiently capable of carrying out various cell types.

“Controlled drug-delivery systems can

revolutionize the field of regenerative medicine with a potential for improving cellular characteristics throughout development, reducing toxicity, and enhancing therapeutic outcomes during transplantation.



Among all, BMSCc have received intense attention for regenerative therapeutics due to its efficient differentiation capability, easy optimization of isolation and ease of marker profile [1,7,8] . BMSCs are mostly pluripotent in nature, thereby behave as supportive cells as well as can generate all types of cells in our body except cells of embryonic membrane. When implanted in in vivo, BMSCs differentiates into multiple tissue (for example, tissues of heart, liver, blood vessel, etc.) in order to replenish the body with healthy cells. This restoration was realized through a series of dynamic processes such as signaling, homing, incorporation, inflammation, proliferation, differentiation and so on, where differentiation plays a key role for development of regenerative medicine [9] . Various protocols were introduced to optimize the cellular microenvironment specifically for adult stem cells differentiation which includes mechanical elicitation approach using ultrasonication or cyclic mechanotransduction, growth factors released method using engineered scaffolds/biomaterials, pellet culture, and chemical stimulation [10] . To this date, cytokines chemical has been widely used not only for maintenance of undifferentiated stem cells but also for acceleration of cell differentiation in a specific pathway [1] . The most common approaches of cell delivery were intravenous injection (direct delivery of cells at the target site) and cell encapsulation systems (indirect delivery of cells

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through a carrier). The cell encapsulation method utilizes a biocompatible, biodegradable biomaterial seeded with cells and then implanted into defects to regenerate the lost tissue. The former approach faces certain roadblocks that are, relative short half-life, very low tissue penetration, higher molecular weight, and potential toxicity at systemic levels [11] . Controlled delivery systems for optimization of stem cell differentiation Controlled delivery/release systems are one of the significant parameter to adjust the microenvironment for stem cells recruitment, attachment, proliferation and differentiation, and thus gained considerable attention in cargo delivery research because of their ability to control the release of bioactive molecules (e.g. growth factors, cytokines, phospholipids, and hormones). Here, biodegradable biomaterials/scaffolds play a pivotal role in holding substitutes for the ECM and further prolonging the release time span of biomolecules in order to stimulate the differentiation of stem cell. The release duration from an engineered scaffold construct can be smartly optimized by choosing particular type, biomaterial design and combination suitable for cells, changing its physiochemical features by controlling chemical and molecular weight of material, its synthesis/formulation process, etc. In addition, required release profile (such as constant, pulsatile, and time programmed behaviors at the target site or site of injury) can be accomplished through degradation/diffusion mechanism and also with fabrication of constructs with different geometries and configurations by micro- and nano-scale technology. This includes scaffold, tube, micro/nanosphere, injectable forms, fiber, and so on [7] . Based on the conventional cargo delivery systems mentioned above, other available emerging technologies for the application to regenerative medicinal arena are (i) biomolecules and protein immobilization on to the scaffold matrix, (ii) cytokine conjugation to inert carrier resulting in enhanced half-life of these protein molecules, (iii) utilization of gene-activating scaffold to deliver specific gene leading to induction of desired cellular outcomes at the molecular level, (iv) the multiple growth factor delivery system to compensate and stimulate from both cytokines, and (v) the smart and functional hydrogel to control growth factor delivery [9,12,13] . Future perspective It has been also paid attention to apply the cytokine delivery system by MSC itself. Various pre-clinical and clinical reports have shown the efficacy of genetically modified MSCs to express and release desired therapeutics, thereby confirms their capability to act as an efficient base for cell-based gene treatment [14,15] . That

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Importance of controlled delivery systems for regenerative therapeutics 

is, genetically modified MSCs can deliver the cargo molecules by themselves at the tumor site in order to achieve adequate concentrations of antitumor molecules for complete eradication of cancerous cells. As well, to establish MSCs efficacy as delivery vehicles, the cell homing ability at the cancer site, and advanced studies for the development of target cellular vehicle and protocol optimization for the introduction to MSCs must be carried out with enough animal and human clinical studies [16] . It is also highly essential to study the synergetic effects of various cargo molecules and ECM components on cell survival, proliferation, and differentiation for the promotion of tissue regeneration. Furthermore, the interdisciplinary researches with micro- and nano-scale technology for regenerative medicine together with advances in cargo delivery system and stem cell science have set a potential platform to overcome the limitation of traditional techniques. These fusion technologies can offer

novel and precisely designed biomaterials for specific cell-biomaterial or cell-cell interactions, cell-specific targeting and advanced pharmacodynamics for the TERM area [13,17] . In the near future, one can imagine that more sophisticated fusion technology of drug-delivery system to control the fate of stem cells will be achieved using a combination of novel gene transfer technology, micro- and nano-scale fabrication technology, novel scaffolds biomaterials and characterization methods.

References

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Disher DE, Mooney DJ, Zandstra PW et al. Growth factors, matrices and forces combine and control stem cells. Science 324, 1673–1679 (2009).

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Santoro M, Tatara AM, Mikos AG et al. Gelatin carriers for drug and cell delivery in tissue engineering. J. Control. Release doi:org/10.1016/j.jconrel.04.014 (2014) (Epub ahead of print).

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Richardson TP, Peters MC, Ennett AB, Mooney DJ. Polymeric system for dual growth factor delivery. Nat. Biotechnol. 19, 1029–1034 (2001).

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Bae H, Chu H, Edalat F et al. Development of functional biomaterials with micro- and nanoscale technologies for tissue engineering and applications. J. Tissue Eng. Regen. Med. 8, 1–14 (2014).

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Hu YL, Fu YH, Tabata Y et al. Mesenchymal stem cell: A promising targeted-delivery vehicle in cancer gene therapy. J. Control. Release 147, 154–162 (2010).

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Shah K. Mesenchymal stem cells engineered for cancer therapy. Adv. Drug Deliv. Rev. 64, 739–748 (2012).

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Choi YC, Choi JS, Woo CH, Cho YW. Stem cell delivery systems inspired by tissue-specific niches. J. Control. Release doi:org/10.1016/j.jconrel.06.032 (2014) (Epub ahead of print).

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Ngo TX, Nagamori E, Shimizu T, Okano T, Taya M, Kino-oka M. In vitro models for angiogenesis research: A review. Intern. J. Tissue Regen. 5(2), 37–45 (2014).

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Khang G, Shimizu T. Introduction. In: A Manual for Differentiation of Bone Marrow-Derived Stem Cells to Specific Cell Types. Manuals in Biomedical Research (Volume 8). World Scientific, Singapore, 1–7 (2014). Tabata Y. Biomaterial technology for tissue engineering applications. J. R. Soc. Interface 6(Suppl. 3), S311–S324 (2009). Nerem RM. Tissue engineering: from basic biology to cellbased applications. In: Stem Cell and Tissue Engineering. Li S, L’Heureux N, Elisseett J (Eds). World Scientific, Singapore, 1–11 (2011). Kim EY, Song JE, Park CH, Joo C-K, Khang G. Recent advances in tissue-engineered corneal regeneration. Inflamm. Regen. 34(1), 4–14 (2014).

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Langer R, Vacanti JP. Tissue engineering. Science 260, 920–926 (1993).

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Atala A, Lanza R, Thompson JA, Nerem RM. Hybrid, composite, and complex biomaterials for scaffolds. In: Principles of Regenerative Medicine. Elsevier Academic Press, NY, USA, 636–655 (2008).

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Khang G. Introduction. In: Handbook of Intelligent Scaffold for Tissue Engineering & Regenerative Medicine. Pan Stanford Publisher, NY, USA, 3–40 (2012).

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Edward RG. Stem cells today: B1. Bone marrow stem cells. Reprod. Biomed. Online 9(5), 541–583 (2004).

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Kimura YU, Tabata Y. Experiment tissue regeneration by DDS technology of bio-siganling molecules. Dermatol. Sci. 47, 189–199 (2007).

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Editorial

Financial & competing interests disclosure The authors have no relevant affiliations or financial involvement with any organization or entity with financial interests/conflict regarding the discussed subject matter. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants, patents (received/pending), or royalties. No writing assistance was utilized in the production of this manuscript.

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Importance of controlled delivery systems for regenerative therapeutics.

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