Biodegradable and removable implants for controlled drug delivery and release application

KEYWORDS:

• Implantable drug delivery system
• polymeric implants
• biodegradable implants
• removable implants
• sustainable health wellness

1. Motivation

Conventional drug delivery route has several limitations such as hepatic first-pass metabolism, gastric issues, and hypersensitivity reactions. Additionally, such approaches are not found to be patient compliant, especially for chronic diseases. Conversely, implantable, polymeric drug delivery systems provide prolonged as well as controlled release of drug from the device implanted in the body. This editorial summarizes various types of implantable drug delivery systems and their advantages and challenges. Along with this, recent advances in the genre such as shape memory-based polymeric implants, 3D-printed implants, and the challenges associated with them are also discussed.

2. Emergence of implants for drug delivery

Drug delivery via standard routes, such as oral, parenteral, transdermal, rectal, and nasal route, is advantageous and appealing since it offers several major benefits, including ease of administration and systemic effect with or without significant localized effect when needed. However, several barriers exist for each of these routes of administration for drug delivery systems. In the case of oral drug delivery systems, the gastrointestinal tract acts as a strong barrier that hinders drug absorption due to the harsh acidic environment of the gastrointestinal tract, hepatic first-pass metabolism, and also the gut microflora [1]. In addition to this, in the case of chronic diseases, frequent dosing of drugs is required, which may not be patient compliant [1]. The parenteral route shows excellent systemic absorption and bioavailability, but it is often patient non-compliant, as the technique is invasive and requires a skilled person to administer the injectable formulation [2]. These hurdles can be surmounted by the application of transdermal patches, but in that case, the stratum corneum becomes a potential barrier to drug absorption [3]. Also, it becomes troublesome for patients having a chronic disease to take multiple drug doses per day. These problems associated with the conventional routes can be bypassed by the insertion of an implant in the patient’s body, capable of releasing the drug in a controlled or sustained manner, thereby maintaining constant plasma drug concentrations to elicit the desired pharmacological action [4].

Implants allow for superior safety, enhanced bioavailability, a controlled release rate, enhanced permeation, and low toxicity [5]. Examples of such implants include drug-eluting stents, scaffolds for tissue engineering, heart valves, pacemakers, and ocular inserts, as shown in Figure 1 [6]. Ritasert®, an FDA-approved ocular insert used for the treatment of chronic uveitis, contained polyvinyl alcohol (PVA) as a polymer to sustain the drug delivery. This system sustains the drug delivery for a period of up to 3 years [4]. Similarly, polymethyl methacrylate (PMMA)-based implant is widely employed in bone-related scaffold for joint replacement therapy to achieve sustained drug delivery [7]. Bioinspired heart valves were formulated using silicone as a polymeric agent and were 3D printed. The in vitro data showed excellent hemodynamic performance of the heart valves under physiological heart conditions [8]. These implants can be formulated with biodegradable or non-biodegradable polymers. Implantable drug delivery systems have wide applications, including the diagnosis of a disease, its treatment, preventive therapies, and regenerative therapies. Clustered Regulatory Interspaced Short Palindromic Repeats (CRISPR-Cas)-based strategies help in efficient diagnosis of diseased conditions that seem to be more infectious and transmissible like COVID-19. Thus, by implementing CRISPR-Cas technique along with nanomedicine, accurate diagnosis can be done, thereby instigating the appropriate treatment [9]. Nanomedicine comprises a suitable drug carrier and the therapeutic agent, which can effectively bypass the blood–brain barrier and, hence, can be efficient in treating neurodegenerative diseases [10]. These types of drug delivery systems provide controlled drug delivery and release the drug in relation to patient genomics and medical history [11]. In fact, the controlled release of the drug-eluting implants allows drug release for a period of up to 3–5 years as in the case of Norplant, which was the first implantable drug delivery device made available to the general population in 1991 and was designed for contraception [6,12,13].

Figure 1. Biodegradable and non-biodegradable implants for drug delivery to manage disease conditions in humans. The ocular and brain inserts are useful for the sustained drug release, while drug-loaded stents have been utilized for cardiac disease management. The drug-loaded implants have demonstrated birth control application and in orthopedic problems for pain management [14–17].

Traditionally, an implantable drug delivery system is classified into two main types, drug implants and implantable pumps. The former employs the use of biodegradable and non-biodegradable polymers in order to release the drug in a controlled manner. Biodegradable implants offer the most convenient option for drug delivery as the implant needs to be placed in the body only once and it does not need to be removed. The degradation products of the biodegradable implants are assumed to be traces of carbon dioxide, water, and mineral elements [4]. In contrast, non-biodegradable implants require surgical procedure twice, as they need to be inserted and removed (once drug delivery is achieved). A copolymer of ethylene and vinyl acetate, namely ethylene vinyl acetate (EVA), is a type of non-degradable thermoplastic polymer used in drug-eluting implants. Recently, Merck commenced and accomplished clinical trials on islatravir-loaded EVA implants. The results obtained demonstrated sustained release of the drug for up to 1 year [18]. Among the different silicone compounds available, polydimethyl-siloxane (PDMS) is a popular non-biodegradable polymer used in medical devices [6].

3. Advancements in implant technology

One of the main drawbacks of implants, along with host immune rejection, is the surgical procedures. Once the implants are placed in the body, the defense systems recognize it as a foreign body, and this results in the initiation of immune reactions such as inflammation, hypersensitivity reactions, and rejection of implants. This renders the activation of innate immunity, which helps in the protection of body against foreign materials [19]. Activation of innate immunity leads to production of helper T-cells and interleukins in the inflammatory phase (Vroman effect) that ultimately leads to fibrotic encapsulation [20]. As macrophages are phagocytic, macrophages will attempt to remove debris and destroy any foreign substance. In the recent years, researchers have used surface modification and different stimuli-responsive diffusive systems to overcome the rejection issues [20]. Advancement in technology led to administration of noninvasive implants using injectable solid implants. According to a study, fluorouracil-based pellets were formulated and extruded to a sufficient injectable diameter for the delivery of the anti-neoplastic agent. It showed good in-vivo release and robust in vitro in vivo correlation. Almost 100% drug release was observed after a period of 14 days [21]. Thus, fluorouracil-based implants were found to be suitable as an adjunct therapy for the treatment of cancer and patients undergoing tumor excision.

Most of the injectable implants are composed of low-viscosity polymers to form in-situ gels. A very well-known example of this type of polymer is polylactic-co-glycolic acid (PLGA), which is an FDA-approved polymer that can be physiologically degraded by biological mechanisms. Ohan et al. evaluated the efficacy of levonorgestrel microspheres-loaded injectable implants. The microspheres were formulated using poly-caprolactone (PCL) as a polymer and were deposited in a rod-shaped implant, followed by injection of the implant by intramuscular route. The in vitro dissolution studies revealed that the release was Fickian diffusion controlled, and release rate was prolonged for up to 4 months [22]. Table 1 gives the summary of recent research about biodegradable implant-based delivery for various biomedical applications.

Table 1. Summary of research outcomes based on biodegradable implants.

Compositions	Preparation method	Outputs	Ref.
Gold nanoparticles (AuNP)	AuNP incorporation in composite and pristine-based hydrogel matrix and mounting on the cell culture	AuNPs decreased reactive oxygen species (ROS) by its absorption in the hydrogel matrix	[23]
Paclitaxel	PLGA-based in situ implant was prepared.	In vitro drug released was sustained for up to 1 month	[24]
Demineralized bone matrix	Injectable scaffolds were prepared by using polyvinyl alcohol (PVA)	Good cell viability in bone marrow mesenchymal stem cells Good degradability within a month (in vitro and in vivo)	[25]
Doxorubicin	pH-responsive hydrogel-based implant was prepared using laponite nano-disks along with drug to form aldehyde functionalized-PEG hydrogels	Good gelation properties and stability Biocompatibility and prolonged drug release profile.	[26]
Tantalum–titanium alloy	Tantalum–titanium alloy were 3D printed by directed energy deposition method	Good biocompatibility Early osteoid formation	[27]
Dexamethasone (Ozurdex)	PLGA-based intravitreal implants prepared by modified injection technique	Efficacy for 3–6 months Implant degradation by itself in the vitreous cavity	[28]
Bioresorbable stents (BRS)	BRS manufactured by laser cutting method using magnesium alloy and PLA	The use of polymer reduced the risk of stent-related thrombus formation	[29]
Dexamethasone	Polyurethane-based drug-eluting stents were prepared and studied for its shape memory effects	The implant showed promising recovery ratios, and the recovery time was nearly 6 s	[30]
Polycaprolactone–Polydimethyl Siloxane (PCL–PDMS)	Fibrous scaffolds were prepared for bone tissue regeneration using PCL–PDMS	Recovery time of 55 s Implants were biocompatible and led to osteoblast proliferation	[31]
Naproxen	Drug-loaded films were prepared by hydroxy propyl cellulose-g-polycaprolactone	Prolonged release for 60 days Satisfactory shape recovery	[32]

AuNP: gold nanoparticle; ROS: reactive oxygen species; PLGA: poly lactic-co-glycolic acid; PEG: polyethylene glycol; BRS: bioresorbable stent; PLA: poly lactic acid; PCL-PDMS: polycaprolactone-poly dimethyl siloxane.

Apart from injectable implants, the stimuli-responsive implants and expandable implants can also be used for the treatment. For the engineering of these devices, shape memory polymers are used. Shape memory polymers are a class of smart polymers or also well known as actively moving polymer, as they can change their shape temporarily. The drug release from the device is stimulated by the application of ultrasound, alternating magnetic field, or infrared radiation [33]. Polyurethane-based shape memory polymers (PUSMP) are widely in use in medical field for manufacturing of sutures, ocular inserts, stents, and bandages that are non-biodegradable in nature [34]. Actuators formulated using PUSMP can be used in the treatment of heart diseases, like ischemia, thrombus, and embolus formation [34]. As shown in Figure 1, a biodegradable stent having a shape memory property was prepared using chitosan as a polymer along with poly(ethylene) oxide and glycerol. The mechanical strength of the polymeric stent was found to be satisfactory as compared to the metallic stent. Other than that, the polymeric stent could bare deformations up to 30% and regain its originality. In preclinical study trials, the stent remained intact in the blood vessels, without any clot formation or vessel damage [35]. Similarly, sirolimus–chitosan-based drug eluting stent was formulated for the treatment of atherosclerosis. The crosslinking was done using an epoxy compound. Extended crosslinking led to a significant increase in the mechanical ability, expansion time, and shape memory of the device. In vitro studies indicated no major harm to the cellular tissues. The ability of sirolimus-based stents to inhibit neointimal hyperplasia formation was checked in rabbits. The results showed that neointimal formation was inhibited in arteries after a specific time. In comparison, the controlled group, treated with drug-unloaded stents, showed a noteworthy neointimal formation [36]. The results suggested that sirolimus-based stent could be a possible option for the treatment of atherosclerosis. Challenges associated with shape memory polymers include the sterilization process, toxicity, and biocompatibility issues.

5. Expert opinion

Advancement in technology led to the innovative application of 3-dimensional (3D) printing for the development of drug delivery system, which offers patient-specific personalized medicine and has been also applied to implants manufacturing. 3D printing offers highly intendable products that can be manufactured from different materials. It is a layer-by-layer process that allows for precise delivery of drugs with low dose, formulation of composite dosage design, and geometry of the dosage form. PCL implants incorporated with lidocaine were formulated using an extrusion-based 3D printer. In vitro studies were performed using USP-Type IV apparatus, and results demonstrated that the sustained release rate was controlled due to the presence of PCL as a polymer [37]. Similarly, a PLGA-based tube was formulated and coated with a 3D-printed alginate layer and then loaded with fluorescein and rhodamine. Cytotoxicity studies showed no damaging effects on the viability of cells, and release studies indicated an initial burst release of fluorescein from the alginate coat and a sustained drug release profile for 24 h, followed by release of rhodamine for the next 72 h [38]. Thus, controlled release is achieved in case of 3D-printed implants using suitable polymers. 3D-printed scaffolds containing calcium phosphate for bone repairment controlled the release of calcium, and the implant was biocompatible and showed no toxicity. In this diffusion-based approach, the characteristics of the drug, solvent, and polymer restrict the possible drug loadings. Biodegradable polymer-based rate-controlling membranes produced in conjunction with 3D-printed technology (alter the physical and chemical properties of membrane) provide better controlled drug release [39].

The major challenge in case of non-biodegradable implants is that a surgical procedure needs to be employed to remove the device from the body. If not done, it may cause toxicity to the target tissue or organ. If failure of the device occurs, it may lead to burst release and dose dumping, which reduces the bioavailability. Before administration of the implant, accuracy of dose release and validity of the device also need to be checked. In addition to this, the polymer present in the implant must be compatible with the surrounding tissue. In case of tumor targeting, implants for treatment of cancer shows average diffusivity in the ablated tumors.

To manage above-discussed challenges, controlled release implants can provide an opportune chance to deliver safer medications for the treatment of both chronic and infectious disease, which is not feasible with conventional delivery systems. If implantable technology is adopted extensively, probabilities of successful treatments are envisaged, particularly in diseases such as Alzheimer’s disease, schizophrenia, and cancers [40]. Stem cell-based implants have been used in neurodegenerative diseases in order to repair the brain tissues. Scientists implanted these cells in hippocampus of mice suffering from Alzheimer’s disease. The postmortem studies showed a decrease in plague deposition [41]. Similarly, according to a study, cochlear implants were inserted in patients suffering from hearing impairment. The study was carried out for a period of 4–5 years. The results were positive after the therapy and were assessed based upon the Mini–Mental state examination (MMSE) [42]. In the next decade, implantable delivery systems have the latent to become more patient adherent, allowing its use in a wide number of diseases, leading to decrease in difficulty of curing diseases, particularly those of chronic nature. Artificial intelligence and machine learning-based process optimization will help in the management of process-related constrains observed during the current implantable product development. This editorial is a promotional act to promote bio-degradable and removable implants in every dimension to support research focus on laboratory to clinical to human wellness.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Acknowledgments

Vivek P Chavda wants to dedicate this work to L M College of pharmacy as a part of the 75^th year celebration of the college. Vivek P Chavda is grateful to the L.M. College of Pharmacy, Ahmedabad, India, for providing necessary support in carrying out the literature search. Figure is created using Biorender.com.

Additional information

Funding

This paper was not funded.