Biomaterial in Microencapsulation: How Microencapsulation is Changing the Medicine World

Abstract

Stem cell therapy is one of the novel treatment. Cells possess self-renewal ability and the potential to differentiate into multiple lineages. Cell therapy has been studied in treatment of various diseases and injuries, such as cardiovascular diseases, brain disorders, musculoskeletal defects, osteoarthritis, and skin diseases. The application of cells can be a big challenge in treatment, and they die during transplants because of the unfavorable environments of injured or damaged tissues. A supportive environment can help cell survival, induce bio-activity, and enhance cell retention at the administered sites. Stem cell microencapsulation in biocompatible biomaterials can be a good supportive environment that lets cells grow properly. In this review, we discuss about new materials, their application for microencapsulation and how these materials can alter drug delivery and treatment of diseases. New natural and artificial materials optimize microencapsulation application and can be a novel solution for what scientist struggle with.

1. Introduction

Stem cell therapy and biomaterial for drug delivery as novel therapies have recently offered new opportunities in clinical applications that permitted more precise and early diagnoses, less invasive and quicker procedures, and fewer and stay hospital visits. Stem cell therapy has been performed to treat various diseases and injuries, such as cardiovascular diseases, osteoarthritis, brain, neural, and musculoskeletal disorders [1, 2, 3, 4]. Stem cells are capable of renewing themselves and have the potential to differentiate into multiple lineages, which include pluripotent stem cells, such as embryonic stem cells (ESCs), induced pluripotent stem cells (iPSCs), and multipotent stem cells such as hemopoietic stem cells (HSC), mesenchymal stem cells (MSCs), and adult stem cells (ASCs). Cell encapsulation is based on the immobilization of cells in favorable with synergistic intercellular interactions without being washed out or damaged due to the surrounding shear forces. Cell encapsulation technology can protect cells from hydrodynamic pressure and cell aggregation while allowing for the functional diffusion of nutrients, growth factors, and gases through the microcapsule matrix [5]. Ideal candidates for encapsulation would be non-immunogenic, non-tumorigenic, easy to access and form, well-specify, and reproducible. A lot of different cell types have been used for encapsulation, each with its unique advantages and limitations [6]. Several materials have been used in cell encapsulation including alginate [7], poly(lactic-co-glycolic acid)/poly(l-lactic acid) scaffolds [8], agarose [9], chitosan [10], poly ethylene glycol [11] and hyaluronic acid [12]. However, natural materials have some limitations, such as hard accessibility, finite source, rapid degradation, weak mechanical properties, and limited processability, which slow their clinical application. Also, the purity degree of some materials determines the biocompatibility of the microcapsules, so the purity degree and viability must be examined well [13]. Microencapsulation can offer a beneficial method of administering therapeutic materials and molecules that cannot be replaced by pharmacological substances, enabling novel solutions for the treatment of many diseases. Some applications of stem cell encapsulation in treatment of disease are listed in Table 1.

Bone [14]

CNS [15]

Cartilage [16]

Cardiovascular [17]

Cancer [18]

Diabetes [19]

Liver [20]

Skin [21]

Table 1.

Application of stem cell.

The long-term viability of microencapsulated cells, rate of polymer membrane degradation, pericapsular fibrosis formation tendency, and potential risk of immunogenicity to the polymers remain big challenges in microencapsulation. The encapsulating polymer must provide a barrier to prevent the immune system from recognizing the foreign cells [22]. A good material used for encapsulation should not interfere with the host cell’s homeostasis. The direct side effect of a non-compatible material is type 1 hypersensitivity reaction, which is a non-specific body reaction that starts with the non-specific absorption of macrophages to the implant site [23]. The permeability of materials is one of the important features of encapsulation. The microcapsule membrane must have an appropriate pore size to supply essential nutrients necessary for cell survival, and it must also have enough immunoprotection to forbid contact with host immune cells [6]. Mechanical resistance of a material is critical to ensure cell immunoprotection and molecule release time period define the deformation and rupture of the capsules under external load [24]. There are some methods and techniques for microencapsulation application, as highlighted in Table 2 [25].

Mechanical (physical) methods

Solvent evaporation

Spray drying

Droplet freezing

Airflow or fluidized bed

Droplet gelation

Centrifugation

Extrusion

Chemical methods

In situ and interfacial polycondensation

Polymerization

Gelation

Physicochemical methods

Methods using supercritical fluid

Methods using emulsification

Coacervation

Thermal gelation

Table 2.

Methods for microencapsulation.

Chemical methods of microencapsulation include solvent evaporation, interfacial crosslinking, interfacial polycondensation, in situ polymerization, and matrix polymerization which usually undergo heat reduction after mixing and heating [26]. Physical methods include spray drying, fluid-bed/pan coating, centrifugal extrusion, vibrating nozzle, and spinning disk microencapsulation. The dispersion of an oil core material or water-soluble active ingredient into a concentrated coating material is used to prepare for spray drying [27]. In fluid-bed coating, solid particles are mixed with a dry coating material that is heated to surround the particle cores [28]. The microcapsule core and coating materials are both immiscible with each other, so centrifugal extrusion is pressed into the concentric nozzles, forming a flow that is crushed into droplets following the clearing of the nozzle [25]. The liquid material to be encapsulated is extruded through a nozzle at a specific flow rate in a vibrating nozzle [29]. In a spinning disk, a mixture is configured with the liquid microcapsule coating material and the material for the internal core of the microcapsule [25]. Physicochemical encapsulation techniques involve supercritical fluid technology, coacervation, polyelectrolyte complexation, and ionotropic gelation. Ionotropic gelation works through the polyelectrolyte’s ability to attach when in the presence of counterions, resulting in their gelation [30]. In polyelectrolyte complexation, adding polycations or polyelectrolytes can be used to further improve the mechanical strength and permeability of the gelated beads [25]. Coacervation technique that relies on polymer-polymer incompatibility, addition of a salt or alcohol into the polymeric mixture or modification of the aqueous phase pH, lead to crosslinking of polymers [31]. Supercritical fluid technology is relied on the formation of particles that are monodispersed with the capability to form nanosized particles [32]. A lot of synthetic and natural materials are being used in microencapsulation. Some of these materials and their application are described below.

2. Alginate

Alginates are natural polysaccharides, polyanionic polymers, and unbranched copolymers of d-mannuronic acid and l-guluronic acid linked by β (1-4) glycosidic bonds [33, 34, 35]. Alginate is derived from various species of brown algae cell walls such as hyperborea, Ecklonia maxima, Ascophyllum nodosum, Eisenia bicyclis, Laminaria, Macrocystis pyrifera, etc., and from various species of bacteria: Azotobacter and Pseudomonas [36, 37]. Alginate is a biodegradable and biocompatible polymer with low immunogenicity in human body. Alginate’s ability to form hydrogel makes it a useful material for the delivery of medicines and cellular immobilization [38, 39]. Because of gel and hydrogel-forming of alginate, it can be easily synthesized and manipulated and can control the speed of release of active compounds from pharmaceutical systems [40, 41]. Chemically modified alginic acid, because of its strong polyanions feature, was found to inhibit fibrotic formation after transplantation by inactivating an immune response, while cationic materials tend to induce inflammatory reaction [42]. Alginate helps in treatment of many diseases. Some of the alginate application include intestinal inflammation and colitis in inflammatory bowel disease, diabetes, hemophilia, cancer, renal failure, liver, and musculoskeletal diseases [18, 43, 44, 45, 46, 47]. Also, because of gel-forming properties of alginate, simple structure, simple raw materials, low toxicity, and mild processing, alginate can be a practical material in drug delivery such as probiotic and anticancer drugs [48, 49].

3. Agarose

Agarose, usually derived from red algae and seaweed, includes a galactose-based structure. Its ability to undergo reversible gelation in response to temperature makes it a functional biomaterial for tissue engineering applications [50]. Agarose is thermally responsive [50] and very similar to the extracellular matrix of natural cell, making it suitable for cell encapsulation. Agarose has been used in medical applications widely because of its functional features including controlled self-gelling properties, water solubility, adjustable mechanical properties, non-immunogenic nature and it is biocompatibility [51]. Agarose, based on its stiffness and functional groups, can support cellular adhesion, proliferation, and activity. In tissue engineering, agarose hydrogels were combined with cells and applied for the regeneration of several structures such as cartilage [52], bone [53], tendons [54], neural system [55], cardiac regeneration, wound healing [56] and cornea. The limitation of using agarose is that mammalian cells cannot degrade agarose, so it can affect gene expression and cell phenotype [57].

4. Chitosan

Chitosan is a derivative of the shell waste of crab, shrimp, and crawfish and a polysaccharide composed of (1, 4)-linked 2-amino-deoxy-b-d-glucan [58, 59]. Chitosan coating a unique cationic character, high biocompatibility, non-toxicity, and biodegradability that make it a functional material in the pharmaceutical industry and tissue engineering, improving improved mechanical strength and a strong barrier function [60]. Furthermore, chitosan properties, such as low solubility in water and organic solvents, can be improved by chemical modification. Also, chitosan has great potential to be used in common applications for the preparation of microspheres, nanospheres, and microcapsules. Chitosan is a cationic biopolymer and has intrinsic antimicrobial activity, besides other potentialities like antioxidant, antitumor, and immune modulator, with an effective drug delivery agent. Medical application of chitosan improves disease treatment, especially in cartilage, bone, and nerve repair, and upgrades tissue engineering methods in their treatment [61, 62, 63]. Wound healing, Gene Silencing in Disease Vector Mosquito Larvae, obesity, and cardiovascular disease treatment are other uses of chitosan and derivatives [64, 65, 66, 67]. Chitosan is widely used for drug encapsulation, growth factors, antimicrobials, painkillers, and antitumoral or anti-inflammatory drugs [68, 69, 70, 71, 72]. Also, chitosan and chitosan derivatives show antimicrobial activity against different microorganisms, including bacteria, filamentous fungi, and yeast, that can be a solution in bacterial resistance to antibiotics [73]. One of the important industrial applications of chitosan is its role in water filtering, which helps in the adsorption of pollutants in water [74].

5. Dextran

One of the suitable materials for use as a scaffold in tissue engineering is dextran [75]. Dextran is a neutral, biodegradable polysaccharide formed from sucrose by bacteria. Anti-thrombolytic and bioadhesive properties make it one of the best scaffolds in tissue engineering [76]. Also, a specific characteristic feature of dextran is The active hydroxyl groups of dextran can be chemically modified to incorporate various functional groups, so dextran has been chemically engineered to form various scaffolds, including spheres [77, 78, 79], tubules [80], and hydrogel [81, 82]. Dextran has been used a lot in biomedical and pharmaceutical applications like decreasing vascular thrombosis [83, 84], reducing inflammatory response [85], preventing ischemia-reperfusion injury in organ transplantation [86, 87, 88], promoting wound healing [89, 90], and enhancing chondrogenesis and cartilage regeneration [91]. Due to its excellent physicochemical properties and biocompatibility, dextran has been assumed one of the best materials for drug delivery and transport of therapeutic agents [92, 93].

6. Gellan gum

Gellan gum is one of the best polymers in tissue engineering and drug delivery because of its biodegradability, biocompatibility, and sustainability features [94, 95]. Gellan gum is formulated by bacterial exopolysaccharide fermentation from Pseudomonas elodea or Sphingomonas elodea, negatively charged, and contains linear exopolysaccharides consisting of four repeating carbohydrates in the main chain [96, 97]. Its ability to undergo sol-gel transition and form a solid gel upon contact with cations can be used to prepare drug-loaded matrices [98]. This features make gellan gum a perfect material in tissue engineering and regenerative medicine, such as its wide utilization in cartilage [99, 100, 101], bone [102, 103, 104], osteochondral disorders [105], spinal cord injury [106], wound healing [107], diabetic ulcer [108] and retinal injury [109]. However, native gellan gum has some limitations, requiring high temperature (60–90°C) for water dissolution and high concentration for the production of stable physical hydrogel that limits production procedure and suitability for direct cell encapsulation [110].

7. Matrigel

Matrigel, an extract derived from the EHS (Engelbreth-Holm-Swarm) tumor, contains all of the known major components of many tissue basement membranes that was found by Dr. Engelbreth-Holm from spontaneous mouse tumor. Matrigel contain all of the components present in basement and is very biologically active [111]. The components of Matrigel are four major basement membrane extracellular matrix (ECM) proteins: laminin, collagen IV, entactin, and the heparin sulfate proteoglycan perlecan [112] and also contain collagen I, XVIII, VI [113] and III and tumor-derived proteins, including growth factors, such as fibroblast growth factors (FGFs) and transforming growth factor (TGF) family peptides (for example, TGF-β) [114, 115] and enzymes, such as matrix metalloproteinases (MMPs) [111, 116]. Matrigel undergoes gelation at temperatures in the range of 22–37°C and is used to culture and cell differentiation such as human pluripotent stem cells (hPSCs) [117], neural tissue [118, 119], and cardiomyocytes [120]. Matrigel also has been used for endothelial tubulogenesis [121, 122], an organoid assembly such as inner ear organoid [123], and applied for promoting angiogenesis [124], cell differentiation in tissue engineering [125], and skin repair [126]. Matrigel application is limited because of the presence of xenogenic contaminants [114, 127], so it needs to be used with caution.

8. Gelatin methacrylate

Gelatin methacrylate (GelMA) was developed by modifying the reactive side groups of gelatin using glycidyl methacrylate [128] that allowed photo-crosslinking so as to provide customizable mechanical properties [129]. GelMA can be manufactured through several methods, such as soft lithography [130], electrospray [131], three-dimensional printing [132], microfluidic chip [133], and emulsion [134]. However, UV light exposure during crosslinking can reduce the survival rate of cells and damage organisms [135, 136, 137]. GelMA has a dynamics macromolecular network and biomimic microenvironment that has a high water content [138, 139]. Hydrogels like GelMA are planned to be similar to the characteristics of extracellular matrix (ECM), and three-dimensional (3D) structure supports for cellular growth and tissue formation [140] and also used for cell-cell interactions, proliferation, migration [141], and controlled differentiation [142] in tissue engineering. Biocompatibility, biodegradability and low cost makes GelMA [143] useful in drug delivery [144], cell delivery [145], gene delivery [146], vaccine delivery [147], wound healing [148, 149], and tissue regeneration [150]. Also, GelMA has broad applications in biomedical field such as corneal regeneration [151], bone repair [152, 153], myocardial infarction [154, 155], hemostasis control [156], and vascular regeneration [157, 158].

9. Polyethylene glycol

Polyethylene glycol (PEG) is a product that is used in both industrial and pharmaceutical industries. PEG is a low-toxic, hydrophobic, semicrystalline polyether that is used in drug delivery systems and tissue engineering scaffold formation [159]. Biocompatibility and hydrophilic feature with properties that limit antigenicity, immunogenicity, cell adhesion, and protein binding [160] makes PEG a successful scaffolding material for 3D printing in tissue engineering [161]. The essential molecular structure of PEG is PEG diol surrounded with two hydroxyl end groups, which can be switched into other functional groups such as carboxyl, amine, vinyl sulfane, methoxyl, thiol, azide, acetylene, and acrylate [162, 163]. Photopolymerization is the most common technique to make PEG hydrogel [164]. The photoinduced crosslinking strategy enhances the crosslinking parameters and biocompatibility by functionalizing them with acrylic or methacrylic groups [165]. Photopolymerization can mix synthetic and modified polymers like polyethylene glycol diacrylate (PEGDA) with natural polymers to form a double network hydrogel for better results [166]. Also, synthetic polymers, such as modified PEG, are able to mimic the biochemical properties of proteins [167, 168]. Because of these features, PEG has become impressing material for bone repair, nerve tissue regeneration [169, 170], and bioprinting applications [171].

10. Polycaprolactone

PCL is a semicrystalline aliphatic polyester that is biodegradable, biocompatible, and non-toxic. PCL exhibits excellent chemical and solvent resistance, good toughness, low glass transition (−60°C), and melting temperature (60°C) [172]. The distribution of water molecules into formless regions causing hydrolytic breakdown of ester bonds can degrade PCL, initially in the formless part, followed by the crystal-line domain [173]. PCL has gained lot of importance in the design of biomaterials/green materials in areas like wound dressing, contraceptives, and dentistry, along with nonmedical fields like food, packaging, and environment [174, 175]. Because of PCL’s high permeability to many drugs, excellent biocompatibility, slow biodegradability, and bioresorbability, PCL is used for long-term drug delivery such as anticancer [176, 177], antipsychotic [178], non-steroidal anti-inflammatory [179, 180], anti-hypertensive drugs [181] and, others. PCL is also one of the most common materials in tissue engineering and 3D scaffolds. Polycaprolactone features such as mechanical properties with high flexibility and great elongation make it an excellent material for the preparation of scaffolds for bone repair [182] and wound dressing [183]. 3D-printed medical devices are an advanced application of PCL. PCL airway devices [184], congenital heart defects, gastric wall damage (hollow organ), and periodontal repair are affecting millions of people around the world [185, 186, 187].

11. Polyvinylpyrrolidone

Polyvinylpyrrolidone (PVP) is a hygroscopic, amorphous, synthetic polymer consisting of linear 1-vinyl-2-pyrrolidinone groups [188]. Polyvinylpyrrolidone is a biodegradable, water-soluble polymer that is biocompatible and non-toxic. It also has a stabilizing effect on suspensions and emulsions [189, 190]. PVP is widely used in the food industry, cosmetics, pharmaceutical, and biomedical applications [191, 192] as well as drug delivery such as gene delivery, oral, topical, transdermal, and ocular administration [193, 194, 195]. PVP constitutes a group of crosslinked 3D networks of hydrophilic polymer chains, which are capable of holding large amounts of water without dissolving [196]. PVP structure is similar to living tissues and tissue matrix so that it can be used for the fabrication of tissue engineering coatings and wound dressings, bone and cartilage repairing systems, drug delivery systems, and other body-contacting devices products, such as contact lenses [196, 197, 198]. However, there have been documented cases of allergic reactions to PVP, particularly regarding subcutaneous use and situations where the PVP has come in contact with autologous serum and mucous membranes [199, 200, 201]. Allergic reactions of PVP commonly happen because of conjunction with other chemicals, such as iodine [202].

12. Poly(l-lactic) acid

Polylactic acid (PLA) is a biodegradable material derived from lactic acid (LA) and produced from reproducible origine such as corn, wheat, and straw [203, 204]. PLA is classified as an aliphatic polyester because of the ester bonds that connect the monomer units. It is made by the bacterial fermentation of carbohydrates using optimized strains of the genus Lactobacillus [205]. PLA is not altered by solvent bulging and dissolution during industrial fabrication. Processing temperature is generally 170–230°C, so it is also a proper material for spinning, biaxial stretching, extrusion, and injection blow-molding processing methods [206, 207, 208]. PLA is used as bio-based plastic and reduces plastic-induced environmental problems [209]. PLA has been widely used as a scaffold in tissue engineering. PLA-based scaffold can be manufactured by controlling the related parameters such as crystallinity, molecular weight, copolymer ratio, essential viscosity, and residual monomers to reach the appropriate physical properties so can stimulate isolated cells to regenerate tissues and act as a drug delivery carrier [210, 211]. Also, PLA has got an important role in biomedical applications such as suture threads, bone fixation screws, and devices for drug delivery, just to scratch the surface [212]. In addition to the musculoskeletal tissue engineering application of PLA, it has been used in nervous, cardiovascular, and cutaneous application [213, 214, 215]. The usage of PLA, especially in the biomedical field, is still limited by its low biodegradability and hydrophobicity [216].

13. Poly(lactic-co-glycolic) acid

Poly(lactic-co-glycolic) acid (PLGA) is a copolymer with lactic and glycolic acid repeat units with linear structure, which can be formed as a block-co-polymer or statistical polymer. The body can degrade both monomers into carbon dioxide and water via the Krebs cycle, which could be achieved from the fermentation of corn or other grains, and the glycolic acid part could be created from the biochemical enzymatic reaction or by the chemical combination of chloroacetic acid and sodium hydroxide [217, 218, 219]. Polymer characteristic features, such as degradation kinetics, rheological properties, thermal properties, mechanical properties, water uptake, and release profiles, can be determined by modification of the LA/GA ratio, terminal group, and constructed parameters of PLGA that facilitates the engineering of this polymer. Higher PGA content leads to quicker metabolization rates, with the exception of an equal ratio of PLA/PGA, which shows the fastest degradation rate, while higher PGA substances lead to increased degradation [220]. PLGA metabolizes by hydrolysis of its ester linkages [221]. PLGA can be dissolved by a wide range of popular solvents, such as tetrahydrofuran, chlorinated solvents, acetone or ethyl acetate, though pure polyglycolic acid and polylactic acid show poor solvability [222]. PLGA is an attractive provider of devices for multidrug distribution and multiplication operations. Numerous studies have also reported successful applications in antibiotics, antiseptics, anticancer, and imaging medications [223, 224]. PLGA can be easily processed and fabricated in various forms and sizes as nanoparticles (microspheres, microcapsules, nanocapsules, and nanospheres) [225]. One of the most generally used biodegradable synthetic polymers for 3D scaffolds in tissue engineering is PLGA. PLGA grafts can be embedded with many regenerative factors to boost healing, such as growth factors, stem cells, and drugs, that make them suitable for bone repair and cartilage regeneration [226, 227, 228].

14. Conclusion

The word microcapsules implies the membrane-surrounded particles or droplets distributed in a solid matrix. Microencapsulation has gained importance in the fields of cell and tissue engineering. The encapsulation system provides free exchange of what cells need to grow such as nutrients and oxygen between the loaded cells and their surrounding environment while preventing the removal and elimination of the loaded cells. The choice of an encapsulating agent depends on several factors, such as biocompatibility, processing, physicochemical properties of the substance to be encapsulated, and degradation prevention. Microencapsulation is a functional technology for the immunoprotection of biological material to avoid host immune response and protect cells from immune suppression. Polymeric biomaterial, either of natural or synthetic origin, must have high biocompatibility and biotolerability, similarity to the extracellular matrix (ECM) of human tissues and their composition, that simulate the biological environments of the human body. Also, microencapsulation has become increasingly important in the fields of pharmaceutical engineering and improved drug delivery systems. Microencapsulation technology has developed industrial materials such as food industry. In fact, microencapsulation can be a good solution to face the problem that we struggle with. This technology can help to cure many diseases, upgrade treatment, and reduce complications and treatment costs. Microencapsulation can provide better drug delivery with lower complications and side effects. Also, a new method of microencapsulation can promote potential and profitability in the industry. Choosing the right material and its properties is important to get maximal utilization. Furthermore, the combination of materials increases its potential. Two main groups of microencapsulation materials are natural and synthetic. Natural materials have high biocompatibility, degradability, and similarity to human extracellular matrix (ECM) but have limited sources and harder accessibility. In spite of natural material privileges, synthetic materials are preferred because of easy manufacturing, unlimited accessibility, and good results in medical applications. The best result can be reached by choosing the appropriate material.

15. Future perspective

Nowadays, in spite of all developments in the medical field, humans suffer from disease side effects. Microencapsulation can be a novel way to overcome disease treatment challenges. Microencapsulation with or without biocontent can accelerate healing and minimize side effects. However, microencapsulation is a novel technique, and there is a long way to go to find its place as a routine medical application. By exploring and inventing new material, new instruction, and application methods, we can accelerate microencapsulation usage in all medical fields.