Polymers in Modern Medicine (Part 2)

Polymers Used in Personalized Medicines

Sahebrao Boraste¹, *, Kartiki Bhandari¹, Deeliprao Derle², Prashant Pingale¹

¹ GES’s Sir Dr. M. S. Gosavi College of Pharmaceutical Education and Research, Nashik-422005, Maharashtra, India

² Maratha Vidya Prasarak Samaj's College of Pharmacy, MVP Campus, Gangapur Road, Shivaji Nagar, Nashik-422002, Maharashtra, India

Abstract

Personalized medicine (PM) is revolutionizing healthcare by tailoring treatments to individual patients' unique biological compositions and lifestyles. This approach considers various factors, including genetic data, lifestyle, and environmental influences, to create customized therapeutic strategies. Polymers play a crucial role in PM formulations, allowing for the creation of personalized dosage patterns without adverse effects. Smart polymers, such as thermo-responsive, photo-responsive, self-repairing, and shape-memory polymers, have garnered attention for their ability to adapt to environmental changes and stimuli. Thermo-responsive polymers like pluronics and poly(N-isopropyl acrylamide) exhibit temperature-dependent behavior, making them suitable for drug delivery and tissue engineering. Photo-responsive polymers offer spatial adaptability, allowing precise control over drug release and tissue engineering processes. Self-repairing hydrogels, with dynamic covalent and non-covalent bonds, can regenerate their structure post-injury, holding promise for various clinical applications. Shape-memory polymers can temporarily adopt multiple forms and return to their original shape upon stimulation, offering versatility in biomedical applications. Common polymers used in PM include polyvinyl alcohol (PVA), polylactic acid (PLA), and polycaprolactone (PCL). The applications of these polymers range from 3-D printing for personalized medical devices to controlled drug delivery systems. Future advancements in polymer science and genomic understanding will further enhance the effectiveness and scope of personalized medicine, leading to improved patient outcomes and reduced treatment side effects.

Keywords: Photo-responsive polymers, Polyvinyl alcohol, Polylactic acid, Polycaprolactone, Personalized medicines, Polymers, Self-repairing polymers, Shape-memory polymers, Smart polymers, Thermo-responsive polymers.

* Corresponding author Sahebrao Boraste: GES’s Sir Dr. M. S. Gosavi College of Pharmaceutical Education and Research, Nashik-422005, Maharashtra, India; Email: [email protected]

INTRODUCTION

The goal of personalized medicines (PM) is to provide people with customized clinical therapies and procedures. This method is predicated on the notion that each individual has a unique biological composition, way of living, and surroundings, which have a significant impact on their well-being and reaction to therapy. In order to create a thorough management strategy that is customized for every person, PM considers not just DNA data but additionally other elements like the individual's routine, surroundings, and past health conditions. Because of modern technological advancements and improvements in our knowledge of genomics and the causes of illness, PM has assumed greater importance in the management of ailments. When it comes to treating some malignancies, like pulmonary or breast tumors, PM has demonstrated tremendous efficacy. Through an investigation of DNA abnormalities present in an individual's cancer, medical professionals can pinpoint precise biological targeting and create customized medicines that concentrate on these alterations. Contrary to conventional radiation treatment, this method has shown better results and less negative consequences. Additionally, novel medicines for conditions like Parkinson's or dementia are being developed using it. PM is becoming more and more significant in the management of illnesses; by considering the person's surroundings, routine, and past health events, physicians can create a customized course of action [1, 2].

For instance, based on nutrition, physical activity, and various other behavioral variables, an individual having hypertension may profit from an alternate therapy approach. Physicians can create an increasingly thorough, successful course of action with minimal adverse consequences by accounting for these criteria. PM has significant effects on premature illness recognition as well as mitigation alongside its involvement in medical therapy. Clinicians may recognize people who are in elevated danger for particular illnesses and create specific strategies that prevent the condition from occurring by examining the person's genome and additional indicators of illness. In general, PM is playing an increasingly important part in the management of disorders. This method is being utilized to create novel medicines for numerous illnesses and has so far resulted in a notable advancement in the treatment of several forms of malignancies. Future developments in technological advances and our growing knowledge of genomics and biological pathways will probably make PM increasingly significant [1].

Introduction to Polymers used in Personalized Medicines

PM preparation calls for a sizable quantity of particular, premium polymers that may formulate personalized dose patterns according to the patient's needs without interfering with API or other formulation components or producing adverse consequences to individuals. Throughout the last decade, the healthcare area has seen a significant development of soft components due to advancements in medical equipment, stem cell treatment, and 3-D printing for personalized medication. One class of soft polymers that adapts to shifts in the surroundings is smart polymeric materials. Heat-sensitive polymer compounds, which are frequently utilized in 3-D printing processes and as cellular transporters, are also a common type. One kind of intelligent polymer compound that may rebuild the framework upon multiple harms is self-repairing polymers, which are frequently needle-injected. Another kind of polymer that can recall its initial form is called shape memory polymer. These intelligent materials can serve as transporters of proteins, drugs, or cells. They can be used in medical personalization, surgical procedures that are less hazardous, and biological printing due to their injectability and shape-retaining properties [3].

In recent years, there has been a lot of attention paid to softer composites that have a tensile strength and elastic modulus comparable to that of biological muscles, particularly those softer substances with specific qualities that scientists have dubbed smart polymer composites. Researchers and technologists have created adjustable, customized goods using innovative substances that circumvent the restrictions posed by the human being's diverse surroundings since the idea of a one-size-fits-all approach is out of time. Smart components, sometimes referred to as responsive substances, are artificial substances whose attributes may be subtly and precisely changed in response to outside stimuli [4]. The healthcare arena is where polymerized intelligent substances are the most frequently employed because they offer both the adjustable and practical features of artificial polymers [4] and the excellent biological compatibility of organic polymers [5]. Smart substances can be stimulated by a variety of environmental factors, such as climate [6], redox processes [7], moisture [8], electrical or magnetic forces [9], variations in pH [10], and exposure to sunlight [11]. Diverse biological usages, such as biological sensors [12], controlled administration of drugs [13, 14], regenerative medicine [15], localized injection, tumor cell barriers, least intrusive surgical procedures, and three-dimensional bioprinting [16], among others, have made use of such substances with distinct prompting processes. Personalized healthcare product development is made possible by the intelligent polymer components' adjustable characteristics and atmospheric sensitivities. A trio of common polymer intelligent materials, stimulation-responsive, self-repairing, and shape-memory, is mainly highlighted. A few contemporary PM usages, including 3-D printing, stem cell treatment, and transplantation, are also in focus.

The development of innovative surgical instruments for surgeries that are less intrusive has made use of stimuli-responsive polymers. For example, at lower regional pH of an infarcted region, thermo-sensitive and pH-dependent hydrogels are frequently employed for cardiovascular treatments [17]. The regional reaction that the stimuli-responsive polymers exhibit can serve as an alarm for cellular API transport intended for organ selectivity [18]. Furthermore, 3-D chemically or physically changeable networks that may restore their initial architecture upon injury are known as self-repairing hydrogels. Comparable to how tissue from humans heals, dynamic connections control the breakdown and combination events and provide the self-treatment characteristic [19]. Consequently, to provide a setting that is conducive to cell cultivation, self-repairing hydrogels with the proper viscoelasticity and substantial level of water are used to imitate the matrix of cells. A lot of progress has been made with self-repairing hydrogels in the areas of cancer-fighting medication administration, blood vessel repair, and nervous system restoration [20-22]. Furthermore, shape memory alloys (SMAs) and shape memory polymers (SMPs) are the main categories into which shape memory materials (SMMs) are typically divided. When presented with appropriate stimulation, SMMs can regain their former forms despite experiencing significant and quasi-plastic distortions [23]. While SMPs can be employed in heart valves, dialysis treatments for the kidneys, and neural prostheses [24], SMAs are typically employed for coronary implants or dental implants [25]. In the near future, biocompatible and biodegradable SMPs can be used as building blocks for a wide range of cutting-edge usage, including 4D printers, soft robots, or skin substitutes [26-28].

The PM is a cutting-edge medical specialty that is based on an individual's medical, biological, and environment-related variables. Massive physiological records, surgical instruments, pathological conditions, intelligent biologic materials, and healthcare equipment must all be integrated for precision medicine to be realized [29]. Precision medicine may advance more quickly with the creation of intelligent polymer compounds with excellent compatibility and flexibility since these substances' features can be tailored to be more individualized [20].

The 3 fundamental principles of PM are gathered for the connection within the PM and content in Fig. (1), temporal, individual, and geographical. The temporal viewpoint is concerned with striking an equilibrium between individuals' therapeutic duration and the intelligent polymeric substances' disintegration period. API transporters, dressings for injuries, and bioglue are examples of polymer compounds for in vivo purposes that are generally biodegradable or soluble following therapy; the breakdown byproducts should not be hazardous or poisonous [30]. From an individual standpoint, it should be possible for individuals' genomes or stem cells to be transferred using intelligent polymer compounds for genetic or cellular treatment [31]. From a spatial standpoint, the components ought to react to specific triggers and deliver medications at predetermined sites. The integration of technique and resources is strongly desired to meet each of these views. One effective method for creating tailored medical equipment, for instance, is the 3-D bioprinting of shape-retaining polymers [21]. Clinicians can use the patient-oriented solution to carry out surgeries that are less intrusive.

Fig. (1))

An outline of the medical personalization workflow highlighting the main ideas of regional transportation, tailored layout, and activation time.

Types of polymers used in personalized medicines

The pharmaceutical device sector can make use of distinct features of intelligent materials such as stimuli-reactive, self-repairing, and shape-recalling properties. In personalized medications, all of these traits together are advantageous. Table 1 provides a summary of the key ideas and benefits of intelligent polymer substances with all three distinct criteria in customizable medications.

Table 1 Working technique, elements, and uses of intelligent polymers in PM [3].

Thermo-Responsive Polymers

Pluronics, which are often referred to as Poloxamers, are non-ionic three-block blends made up of aqueous polyethylene oxide (PEO) units on each side of a core hydrophobic polypropylene oxide (PPO) unit. Pluronics build themselves in watery solutions owing to their hydrophobic contact. Heat and levels both have a major influence on the micelle production process of pluronics [32, 33]. When the content exceeds the critical micelle concentration (CMC) and the heat is less than the critical solution temperature (LCST), the hydrophobic sections of pluronic assemble to minimize the surface tension [34, 35]. Additionally, amphibious materials have certain drawbacks, such as quick dissolving, brief resident times, and low durability. The alteration of the hydroxyl chains at the tip of the linkage offers an excellent chance to address the issues and get beyond the drawbacks that were previously highlighted [36]. Pluronics (L121, P123, F127, etc.) with various proportions of bioinert PEO and PPO fragments exhibit minimal foreign body responses and possess adjustable characteristics to enable tailored PM. When combined, Pluronic and its analogs show an extensive list of applications, including scaffolding for regenerating tissues [37], transporting antineoplastics [38], extremely durable hydrogel [39], and bactericidal adhesion [40]. A class of temperature-sensitive polymers known as poly (N-isopropyl acrylamide) (PNiPAAm) changes from aqueous to lipophilic when immersed in water at the LCST, or roughly 32°C. Whenever the temperature is lower than the LCST, the PNiPAAm exhibits aqueous behavior for hydrogen bonding involving amide clusters with aqueous particles. As particles of water are driven out of PNiPAAm's aqueous area as temperatures rise over LCST, PNiPAAm turns water-repellent. PNiPAAm is being used to construct a range of intelligent biological entities, including API or cell-based transporters, scanning or monitoring, fiber matting for cellular healing, and stress detectors, because of its thermal reactiveness at room temperature and biological temperatures [41].

It has been revealed that polyurethane nanoparticles (PU NPs) with varying ratios of disintegrating oligodiols as the softer component are temperature sensitive. Due to varying levels of crystallization and hydrogen coupling intensity in softer section arrangements, PU NPs' structural changes and rheological behavior are temperature-dependent. PU NPs' thermosensitive property allows for creations such as biological inks, biocompatible stents, or cellular carriers [3].

Photo-responsive Polymers

The light-sensitive or photo-reactive polymeric compounds have the advantage of fine spatial adaptability. Among the frequent photochemical processes are structural modification, isomer creation, splitting, and building bonds [42]. It is possible to control the physical features of temperature-sensitive materials by varying the light dose, light inducers, and light supplies. Irgacure 2959 (2-Hydroxy-1-(4-(2-hydroxyethoxy)phenyl)-2-methyl-1-propano), LAP (lithium phenyl-2,4,6-trimethylbenzoylphosphinate), eosin-Y, and VA-086 (2,2’-Azobis [2-methyl-N-(2-hydroxyethyl)propionamide]) are light inducers that are frequently employed in biotechnology uses because of their minimal cellular damage and dissolution in water [43-45]. Two main benefits of employing light-sensitive polymers as biomaterials are their accurately controllable exposure period and light-related procedure amplitude [46, 47]. Among the initial light-sensitive polymers used in oral usage, such as fillings and restorations, was epoxy resin. On-location procedures and in situ crosslinking were made possible by the resins [48]. In order to create lightweight sheets for use in biomedicine, acylate-derived monomers are exposed to UV light, which causes radical polymerization [47]. Light-responsive components, namely O-nitrobenzyl succinate and disulfide, were employed to enable the regulated transport of drugs vehicle manufacturing of micelles and nanoparticles [49, 50]. A double-threaded rotaxane duplex containing stilbene and α-cyclodextrin was an illustration of a photo-responsive moiety that might help create synthetic tendons [51]. Additionally, it was noted that a photographic PU hydrogel showed promise as a 3-D biological printing material, especially for cerebral tissue engineering purposes. Using gelatin and methacryloyl components, gelatin methacryloyl (GelMA) was a semisynthetic biomaterial that was commonly utilized and photocrosslinked by UV or visible rays [52]. GelMA hydrogels might be filled with various cell types for 3-D bioprinting or tissue engineering [53-55]. Furthermore, GelMA cryogels were created as a scaffold for trigger-sensitive cell treatment and tissue creation [56]. Since it is easy to synthesize, biocompatible, printable, and may be used to achieve cell treatment and PM, GelMA is one of the most commonly employed photosensitive composites.

Self-repairing Polymers

One well-known category of intelligent polymers is self-treatment polymers, which can rebuild their design and performance following sustained injury [16]. Given their substantial level of water and adjustable rheological characteristics, self-treatment hydrogels are particularly intriguing [57, 58]. Self-repairing hydrogels mirror external networks and have the aforementioned properties, which makes them an attractive category of intelligent polymers for clinical uses [19].

Two self-treatment hydrogel principles are suggested to account for the dynamic and changeable coupling: dynamical covalent links and non-covalent connections. Hydrogen bonds, host-guest relationships, electrostatic forces, π-π couplings, and hydrophobic associations are examples of non-covalent connections. The bidirectional building and dissociation of self-repairing hydrogels are facilitated by the fragile cross-molecular pull of non-covalent partnerships. Diels-Alder processes, boronate ester linkages, disulfide linkages, and imine linkages are examples of dynamical covalent bindings [3, 59, 60].

Self-repairing hydrogels can have their rheological characteristics precisely adjusted, and those that exhibit shrinking tendencies may be injected. Because hydrogels retain their structural integrity despite being administered with needles, patient tissues can be loaded into them for PM and cellular treatments [61]. Furthermore, it has been observed that self-repairing hydrogels are used as bioelectronics gadgets, stress detectors, cellular / API / protein transporters, and surgical coverings [62-68]. The most researched hydrogels for self-treatment are those made with hyaluronic acid and chitosan due to their biological compatibility and biodegradable properties. Additionally, they have proved efficient in numerous clinical settings and can be incorporated with unique biological categories [65, 69].

Shape-memory Polymers (SMPs)

SMPs are polymers that, when exposed to environmental factors like heat, light, pollutants, or pH levels, can momentarily establish multiple forms and then return to their initial state [18]. Generally speaking, dynamical covalent connections or supramolecular connections cause SMPs to exhibit their shape recall characteristic. Fig. (2) illustrates the many uses for SMPs. Through supramolecular relationships, such as hydrogen links, host-guest connections, and metal-ligand collaboration, SMPs uncouple and recouple non-covalent forces. SMPs, on the other hand, depend on the disintegration and reconstitution of flexible covalent bonds, such as disulfide, imine, and boronate ester bonds [19, 70, 71]. SMPs that are suitable for use in healthcare fields include those that respond to outside stimuli beneath biological factors. It was discovered that aquatic particles might induce the shape retention capacity of the cellularly constructed nanofibrous hydrogel. By varying the pH, boranate ester hydrogel might be made to have shape-preserving properties. It was observed that the hydrogel made of N,N-dimethylacrylamide, along with additional acrylate subunits, might change its form when exposed to UV rays. PU NPs containing various oligodiols as the softer region have demonstrated thermally driven shape-storing habits in earlier studies. In summary, because of its biological compatibility and ability to be printed, polymeric unity (PU) is among the best-selling shape-retention polymers for use in cellular treatment and PM [3].

Common Polymers used in Personalized Medicines

Polyvinyl Alcohol (PVA)

The manmade viscoelastic material known as polyvinyl alcohol (PVA) is permeable in aqueous solutions but resistant in most of the organic solutions. It also has a limited absorption of ethanol. It has excellent physical attributes and is flavorless and odorless. It is created by removing the acetate moieties from polyvinyl acetate through half or complete hydrolysis [30, 31]. The arbitrary, chemical, and physical characteristics of the polymer are influenced by its degree of hydroxylation. The melting point (Tm) of PVA varies between 180°C (partly degraded) to 220°C (completely degraded), depending on the extent of acetate molecule hydrolysis. The viscosity index of the polymers is determined by the extent of hydrolyzation, and it varies between 3.4 to 52 mPa·s for moderately hydrolyzed PVA to 4 to 60 mPa·s for entirely hydrolyzed PVA [7, 30]. PVA is more soluble when dissolved in water and crystallizes more readily with fewer stages of hydrolysis and polymerization [30]. Additionally, a lesser rate of hydrolyzation results in a larger molecular mass for the polymer [31]. PVA degrades at temperatures between 350 and 450°C, with a glass transition point (Tg) of 85°C.

Fig. (2))

Diagrammatic illustration of mechanics, means of stimuli, and possible uses of shape-retaining polymers.

PVA is water soluble; hence, in order to create hydrogels, it must be conjugated. Due to the stability, the hydrogel's framework expands when it comes into contact with physiological liquids or water. The polymer's diffusional and physiological characteristics are determined by the extent of bridging. PVA is categorized as a non-hazardous polymer due to its elevated oral LD50 (between 15 and 20 g/kg) and limited gastrointestinal uptake. It is appropriate for physiological therapeutic uses due to its superior breakdown and minimal negative consequences [30].

The use of 3-D printing represents a few of the implementations. PVA has been utilized in the ink-jet printing process (XYPrint100Z Hybrid printer with Konica Minolta KM512 print head) to create multilayered structures of the polymer for additional construction. To prevent nozzle obstruction, the designed ink was made up of aqueous PVA mixtures with humectants (glycerine or monopropylene glycol) and color (duasyn acid violet). Different dyes were made by combining PVA with both large and small atomic masses. Because of the thickness of the ink, molecular mass has an impact on inkjet printing capabilities. During a period of half a year, inks made from large molecules of PVA maintained their excellent durability and did not acquire any new hues. Conversely, over half a year, the inks create lesser molecular mass PVA gels that resemble milk, proving that the specifications for ink-jet printing were not met. It is remarkable that at lower shear stages, the majority of the inks displayed an array of pseudoplastic as well as thixotropic behavior, while at elevated stages, Newtonian patterns [32].

In addition to inkjet printers, PVA has been effectively applied to FDM. The infill volume typically varies between 0% for porous parts to 100% for hard cores. The extruder's velocity, the level heights, and the temperature of the construction sheet and injectors are the characteristics that must be closely monitored while employing this method. For FDM, the typical rate is 90 mm/s, and the width ranges from 100-400 μm. PVA strands may occasionally be preloaded by impregnating and incubating in a concentrated solvent mix that contains an API that has been absorbed. These strands are then dried and deployed for print following the incubation phase [7].

It has been demonstrated in multiple articles that PVA strands can carry up to 10% of medication. Goyanes et al., for instance, preloaded PVA strands with coffee and paracetamol through a hot-melted extraction. An FDM printer was configured as follows: To create solid doses with API payload that varied between 4-10%, the following parameters were applied: an extrusion temperature of 200°C, an infill quantity of 100%, and an extrusion velocity of 90 mm/s. Among these strands where the API payload was smaller, the absorption of drugs was reduced [33].

Case Study

Nifedipine, a blood pressure-lowering medication, was converted into a rigid monofilament form for administration using PLA as a polymer and water-based backing. An API dosage of about 3% w/w was attained. According to publicly accessible oral doses of administration of nifedipine, 3-D printed pills made with PVA-derived strands were shown to be effective for the purpose of dissolving (with an extended distribution across 24 hours) and anticipated chemical resistance (>3 years at°C/60% relative rh). This might be readily utilized in medical facilities to produce customized PMs inlarger amounts that may be kept for a longer duration, much like solid doses produced in factories. PVA strands additionally demonstrated an adequate ability to carry drugs (2.2% w/w); nevertheless, the absorption from the polymer framework during the course of a 24-hour immersion of the packed tablet in the dissolve used for absorption was unfinished. This can be remedied by using PVA strands made using relatively small strands of polymers, which guarantee tablet breakdown at a moderate temperature (37°C) and with acceptable mixing times. Last but not least, it is critical that threads be created using pharma-grade additives and that they come with thorough description information, which will guarantee consistency of the attributes that affect the printed formulations' effectiveness and security. Tablets made with a combination of PVA and water can be printed to quickly provide