Implantable Drug Delivery Systems: A Comprehensive Review with Recent Advancements

Akanksha Thakur, Deepak Prashar*, Pallavi Sharma, Shilpa,

Dixit Panwar

Department of Pharmacy, LR Institute of Pharmacy, Jabli-Kyar, Solan HP-India.

*Correspondence: prashardeepak99@yahoo.in

DOI: https://doi.org/10.71431/IJRPAS.2026.5305      

INTRODUCTION   

Drug delivery science has undergone a paradigm shift with the advent of implantable systems capable of providing continuous, site-specific, and temporally controlled release of therapeutic agents. Implantable drug delivery systems (IDDS) are devices or formulations surgically or subcutaneously placed within body tissues, designed to release drugs in a predetermined, programmed, or on-demand fashion [1]. Unlike oral dosage forms that are subjected to first-pass metabolism and erratic absorption, implants deliver drugs directly to the target site or systemic circulation in a highly controlled manner [2]. The concept of implantable delivery dates to the 1960s when Folkman and Long first demonstrated the permeability of silicone rubber to small molecules, laying the groundwork for sustained-release implants [3]. Since then, the field has evolved dramatically, incorporating advances in polymer science, micro- and nanofabrication, molecular biology, and microelectronics. Modern IDDS are capable of responding to physiological stimuli, communicating wirelessly with external devices, and self-regulating drug release in response to real-time biomarker data [4]. The global implantable drug delivery market was valued at approximately USD 23.4 billion in 2023 and is projected to reach USD 41.7 billion by 2030, growing at a CAGR of 8.6%, driven by the rising prevalence of chronic diseases, an aging global population, and increasing demand for patient-centric therapies [5]. Clinically deployed IDDS include contraceptive implants, cochlear drug-eluting systems, intraocular implants, intrathecal drug delivery pumps, and biodegradable scaffolds for local chemotherapy [6].

This review aims to provide a consolidated and updated overview of implantable drug delivery systems, with emphasis on recent technological advancements from 2021 to 2025. We systematically address classification, biomaterial considerations, mechanisms of drug release, clinical applications, and emerging technologies, concluding with a discussion of regulatory and translational challenges.

Classification of Implantable Drug Delivery Systems

IDDS can be classified based on multiple parameters including mechanism of drug release, device architecture, degradability of the matrix, and therapeutic application [7,8].

Based on Mechanism of Drug Release

Reservoir Systems

Reservoir implants consist of a central drug core surrounded by a rate-controlling membrane. Drug release is governed by Fickian diffusion across the membrane, producing zero-order or near-zero-order kinetics. Examples include Norplant (levonorgestrel) and Implanon (etonogestrel), both subcutaneous contraceptive implants [9].

Matrix Systems

In matrix or monolithic implants, the drug is uniformly dispersed throughout a polymer matrix. Release follows square-root-of-time (Higuchi) kinetics, resulting in declining release rates over time. These systems are simpler to manufacture but require formulation engineering for prolonged, consistent delivery [10].

Osmotic Pumps

Osmotic implants utilize osmotic pressure to drive water into the device, which in turn propels drug solution out through a delivery orifice. The Alzet mini-osmotic pump and DUROS implantable pump system operate on this principle, providing highly predictable zero-order release for months [11].

Stimuli-Responsive Systems

Advanced smart implants release drugs in response to external or internal stimuli including pH, temperature, glucose concentration, light, ultrasound, magnetic fields, or electrical signals. These systems enable on-demand and closed-loop drug delivery, substantially improving therapeutic outcomes [12].

Based on Biodegradability

Non-biodegradable implants (e.g., PLGA-free silicone rods) require surgical removal after drug depletion, whereas biodegradable systems (e.g., PLGA, polycaprolactone, polyhydroxyalkanoates) erode in vivo, eliminating the need for retrieval procedures. Biodegradable systems are particularly advantageous in oncology, orthopedics, and ophthalmology [13].

Based on Therapeutic Area

IDDS have been developed for a broad range of therapeutic areas, including endocrinology (insulin, hormones), oncology (chemotherapy wafers, anti-VEGF implants), neurology (baclofen pumps, anti-epileptics), ophthalmology (intravitreal implants), cardiology (drug-eluting stents), orthopedics (antibiotic-loaded bone cement), and infectious diseases (antiretroviral implants) [14].

Table 1: Classification of Implantable Drug Delivery Systems

EVA = ethylene vinyl acetate; PLGA = poly(lactic-co-glycolic acid); CNS = central nervous system.

Biomaterials for Implantable Drug Delivery

The choice of biomaterial is critical to device performance, biocompatibility, drug compatibility, and degradation profile. Biomaterials used in IDDS span natural polymers, synthetic polymers, ceramics, metals, and emerging nanomaterials [15].

Synthetic Biodegradable Polymers

Poly(lactic-co-glycolic acid) (PLGA) remains the gold standard biodegradable polymer for IDDS due to its FDA approval, tunable degradation rates (weeks to months), and extensive clinical track record [16]. Polycaprolactone (PCL) offers slower degradation (1–4 years) suitable for long-acting contraceptive and antiretroviral implants. Polyhydroxyalkanoates (PHAs), including poly-3-hydroxybutyrate (PHB) and poly(3-hydroxybutyrate-co-3-hydroxyvalerate) (PHBV), are gaining attention as bacterially derived, fully biodegradable alternatives with excellent biocompatibility [17].

Non-Biodegradable Polymers

Silicone elastomers, ethylene vinyl acetate (EVA) copolymers, and polyurethanes remain widely used for non-degradable reservoir implants. These materials provide excellent drug permeability control and long-term mechanical stability. However, they necessitate retrieval surgery upon drug exhaustion and are susceptible to biofouling [18].

Hydrogels

Hydrogels—cross-linked hydrophilic polymer networks—have emerged as versatile platforms for IDDS due to their high water content (60–99%), tissue-like mechanical properties, and ability to be engineered for stimuli-responsive drug release. Injectable hydrogels that gel in situ offer minimally invasive implantation options, eliminating surgical incision [19].

Metals and Ceramics

Titanium and its alloys are employed as structural components for active implantable devices (e.g., pump housings). Biodegradable metals including magnesium and zinc alloys are being investigated as self-disappearing scaffolds for short-term drug delivery applications in orthopedics and cardiovascular interventions [20].

Table 2: Biomaterials Used in Implantable Drug Delivery Systems

Clinical Applications

Contraception

Subdermal hormonal implants represent one of the most successful commercial applications of IDDS. Nexplanon (etonogestrel, 68 mg), a single-rod EVA implant, provides up to 3 years of contraception with >99% efficacy [21]. The Jadelle system (levonorgestrel) offers 5 years of coverage. These devices have demonstrated superior compliance compared to daily oral contraceptives, particularly in low-resource settings where the WHO has promoted their expanded use [22].

Oncology

Gliadel Wafer (carmustine, 3.85%), a biodegradable polyanhydride (PCPP-SA) implant, was the first FDA-approved implantable chemotherapy device. Placed in the resection cavity following glioblastoma surgery, it delivers carmustine locally over 2–3 weeks, reducing systemic toxicity while improving median survival [23]. Drug-eluting seeds for prostate brachytherapy and intratumoral hydrogel depots for immunotherapy co-delivery represent additional oncological IDDS applications [24].

Diabetes Management

Implantable glucose-responsive insulin delivery systems often termed 'artificial pancreas' components—have seen remarkable advancement. Continuous glucose monitors (CGMs) such as Dexcom G6 and Abbott Freestyle Libre 3 serve as sensor components that can communicate with subcutaneous insulin delivery devices [25]. Fully integrated closed-loop artificial pancreas systems coupling CGM with implantable or wearable insulin pumps have achieved near-normoglycemia in clinical trials, representing a landmark in IDDS for metabolic diseases [26].

Neurological Disorders

Intrathecal drug delivery systems (ITDS) deliver analgesics, antispasmodics, and chemotherapy directly into the cerebrospinal fluid, bypassing the blood-brain barrier. The SynchroMed II pump (Medtronic) delivers baclofen, morphine, or ziconotide at a fraction of systemic doses, achieving superior pain control with minimal side effects in patients with chronic pain, spasticity, or cancer pain [27]. Deep brain stimulation (DBS) probes increasingly incorporate drug-delivery channels alongside electrical stimulation, a convergence that defines modern neuromodulation [28].

Ophthalmology

The posterior eye segment presents unique IDDS challenges due to blood-retinal barrier and tissue fragility. Ozurdex (dexamethasone, Allergan), a PLGA intravitreal implant, delivers corticosteroid over 6 months for diabetic macular edema and uveitis [29]. Retisert (fluocinolone acetonide) and Iluvien (fluocinolone acetonide microimplant) provide 2.5–3 years of corticosteroid release. Brinzolamide and anti-VEGF drug-eluting contact lenses and scleral plugs are under active clinical investigation [30].

Cardiovascular Disease

Drug-eluting stents (DES) represent the most widely deployed implantable drug delivery device globally, with over 5 million procedures annually. Third-generation bioresorbable vascular scaffolds (BVS) combine temporary mechanical support with drug release, then fully degrade within 2–3 years, restoring native vessel physiology [31]. Paclitaxel-coated balloons and sirolimus-eluting stents continue to evolve with ultra-thin struts and bioresorbable polymer coatings, reducing in-stent restenosis to below 5% [32].

Infectious Diseases

Long-acting injectable (LAI) and implantable formulations of antiretroviral drugs have emerged as critical tools for HIV prevention and treatment. The islatravir subcutaneous implant (MSD) demonstrated 12-month drug levels above the pharmacokinetic target in Phase 1 trials, offering unprecedented duration for HIV prevention [33]. Cabotegravir LAI (every 2 months injection) and implantable formulations of tenofovir alafenamide in PCL rods (years of delivery) represent the frontier of HIV IDDS research [34].

Table 3: Clinically Used Implantable Drug Delivery Systems

EVA = ethylene vinyl acetate; DME = diabetic macular edema; PCL = polycaprolactone; Ti = titanium; PrEP = pre-exposure prophylaxis.

Recent Advancements in Implantable Drug Delivery (2021–2025)

Smart and Stimuli-Responsive Implants

The development of closed-loop, autonomous drug delivery systems has accelerated significantly between 2021 and 2025. Glucose-responsive insulin implants using phenylboronic acid-functionalized hydrogels or enzymatic glucose sensors coupled to insulin reservoirs have demonstrated real-time glycemic control in preclinical and Phase 1 trials [35]. Thermosensitive PLGA-PEG-PLGA triblock copolymers that undergo sol-gel transition at body temperature have been used to create injectable depots capable of releasing biologics over 30–90 days [36].

pH-responsive systems exploiting the acidic tumor microenvironment (pH 6.5–7.0 versus systemic pH 7.4) for triggered chemotherapy release have shown significant anti-tumor efficacy in preclinical glioblastoma and pancreatic cancer models [37]. Ultrasound-triggered drug release from piezoelectric PVDF nanocomposite implants was reported by Zhang et al. in 2023, enabling non-invasive, on-demand release with sub-minute response times [38].

Nanotechnology-Enhanced Implants

Integration of nanoparticle-loaded matrices into macroscopic implants represents a major paradigm shift. Implantable scaffolds loaded with PLGA-PEGylated nanoparticles containing docetaxel demonstrated superior spatial drug distribution and 3-fold improved anti-tumor efficacy compared to bulk PLGA implants in orthotopic breast tumor models [39]. Lipid nanoparticle (LNP)-loaded hydrogel implants have been used to deliver mRNA molecules locally, offering prospects for in situ protein expression therapies and cancer vaccines [40].

Magnetic nanoparticle-embedded implants enable magnetically triggered drug release and MRI-based monitoring of drug distribution. A 2022 study demonstrated that iron oxide nanoparticle-impregnated alginate implants could be remotely activated by alternating magnetic fields, achieving up to 8-fold enhanced release over passive diffusion [41].

Bioelectronic and Wirelessly Controlled Implants

Wirelessly activated drug delivery implants have gained significant traction, leveraging Bluetooth Low Energy (BLE), near-field communication (NFC), and radiofrequency (RF) technologies. The MicroCHIPS Biotech reservoir-on-chip device demonstrated on-demand release of teriparatide in a pivotal human trial (2021), achieving pharmacokinetic profiles equivalent to daily injections from a single implanted device over one year [42]. This represents a landmark in electronically controlled IDDS.

Closed-loop bioelectronic systems that sense, process, and respond to biomarkers in real time are progressing rapidly. MIT's group reported in 2023 an implantable device integrating electrochemical aptamer-based (EAB) sensors with a microfluidic drug reservoir capable of detecting and responding to cortisol fluctuations within minutes [43]. Samsung and Implantica are advancing 'body-internal internet of things' platforms where implants connect to smartphones, enabling remote prescription updates and adherence monitoring [44].

3D-Printed and Personalized Implants

Additive manufacturing has revolutionized IDDS fabrication, enabling patient-specific geometries, multi-drug loading, and precise spatial drug gradients. Fused deposition modelling (FDM) of drug-loaded PCL or PLA filaments and stereolithography (SLA) of photocrosslinkable PEG-dimethacrylate hydrogels have produced implants with programmable multi-phase release profiles [45]. A 2024 study from ETH Zurich demonstrated voxel-level drug mapping within 3D-printed implants, enabling distinct release kinetics for up to four different drugs from a single device [46].

Biodegradable and Eco-Friendly Platforms

A growing emphasis on fully biodegradable electronics and implant housings has driven the development of transient electronics—devices that perform their function and safely dissolve within the body. Silk fibroin, beeswax, polylactic acid, and magnesium-based transient electronic systems have been reported for post-surgical infection prophylaxis, wound monitoring, and short-term neuromodulation [47]. These devices dissolve over days to weeks, eliminating secondary removal procedures and reducing healthcare costs [48].

Immunomodulatory and Cell-Encapsulating Implants

Encapsulated cell therapy implants housing insulin-producing beta cells or engineered cells secreting therapeutic proteins represent the frontier of living drug delivery systems. ViaCyte's PEC-01 device encapsulating pancreatic progenitor cells within a semipermeable polytetrafluoroethylene (ePTFE) membrane demonstrated insulin independence in a subset of Type 1 diabetes patients in Phase 1/2 trials (2021–2023) [49]. Sernova's Cell Pouch technology, a porous poly(dimethylsiloxane) scaffold that promotes vascularization prior to cell loading, is in Phase 2 for Type 1 diabetes [50]. Local immunosuppressive drug delivery from peri-implant coatings has also advanced, with dexamethasone-loaded PLGA microsphere coatings on neural probes demonstrating 60% reduction in reactive gliosis up to 8 weeks post-implantation [51].

Table 4: Key Advancements in Implantable Drug Delivery Systems (2021–2025)

CHALLENGES AND LIMITATIONS

Foreign Body Response

Chronic foreign body response (FBR) remains the most significant barrier to long-term implant functionality. Upon implantation, a cascade of inflammatory events ensues: protein adsorption, macrophage activation, giant cell formation, and ultimately fibrous encapsulation. This fibrotic capsule progressively restricts drug diffusion from the implant surface, leading to unpredictable pharmacokinetics [52]. Anti-inflammatory coatings (dexamethasone, IL-4-loaded microspheres), zwitterionic polymer coatings, and topographically modified surfaces are actively investigated to mitigate FBR [53].

Device Fouling and Sensor Drift

For closed-loop active implants incorporating biosensors, biofouling of the sensing element leads to sensor drift and inaccurate drug dosing. Continuous glucose sensors typically require recalibration every 12–24 hours due to pericapillary tissue changes. Anti-fouling surface modifications using PEGylation, poly(2-methacryloyloxyethyl phosphorylcholine) (MPC), and lubricin coatings have shown promise in extending accurate sensor lifetime [54].

Drug Stability and Loading

Maintaining drug stability during implant fabrication (especially thermal processes like extrusion) and throughout the implantation period presents ongoing challenges, particularly for protein biologics and mRNA payloads. Lyophilization, nanoencapsulation, and co-loading with stabilizing excipients (trehalose, albumin) are employed to preserve biologic integrity in implantable formulations [55].

Surgical Risk and Retrieval

Implantation requires trained personnel, sterile conditions, and patient acceptance of an invasive procedure, which limits uptake in resource-limited settings. Retrieval of non-biodegradable implants after drug exhaustion adds healthcare burden. Deep-seated implants (intrathecal, intraocular) carry procedural risks including infection, hemorrhage, and neural damage [56].

Regulatory Complexity

IDDS combining drugs and devices are regulated as drug-device combination products by the FDA (CDER/CDRH) and EMA, requiring comprehensive preclinical biocompatibility (ISO 10993), pharmacokinetic, and clinical safety data. In vitro/in vivo correlation (IVIVC) establishment, sterility assurance, accelerated degradation testing, and long-term stability data represent significant regulatory demands that extend development timelines to 10–15 years [57].

REGULATORY FRAMEWORK

The regulatory pathway for IDDS depends on product classification. In the United States, implantable devices are classified as Class II or Class III under the FDA's device framework, while drug-eluting implants are regulated as combination products. The Primary Mode of Action (PMOA) principle determines the lead regulatory center: drug-led combinations (e.g., Gliadel Wafer) fall under CDER; device-led combinations (e.g., drug-eluting stents) fall under CDRH [57]. The FDA's De Novo and 510(k) pathways apply to lower-risk novel devices with predicate technologies, while Pre-Market Approval (PMA) is required for Class III devices. The EMA designates IDDS as Advanced Therapy Medicinal Products (ATMPs) or Medical Devices under MDR 2017/745, depending on their primary mechanism. International harmonization through ICH guidelines (Q3C, Q6A) and ISO 10993 series provides a framework for global regulatory submissions [58].

FUTURE DIRECTIONS

The next decade will see convergence of artificial intelligence, CRISPR-based gene editing, synthetic biology, and advanced materials in implantable drug delivery. AI-driven predictive algorithms for dose optimization in closed-loop implants will personalize therapy to individual patient pharmacokinetics in real time. Gene-circuit-controlled cellular implants capable of self-regulating therapeutic protein secretion based on upstream biomarker sensing represent the ultimate realization of precision medicine [59]. Organ-on-chip and microphysiological systems are accelerating preclinical evaluation of IDDS, reducing animal use and improving human translatability. Ingestible and endoscopically deployable implants for gastrointestinal drug delivery are expanding the anatomical scope of IDDS beyond parenchymal tissues. Finally, innovations in biodegradable wireless electronics will enable post-therapeutic self-elimination of sensing and actuation components, addressing the retrieval burden of current active implant platforms [60].

CONCLUSION

Implantable drug delivery systems have evolved from simple diffusion-controlled polymer rods to sophisticated electromechanical, cell-encapsulating, and self-regulating platforms. Technological advances in biomaterials, micro/nanofabrication, wireless communication, and biological sensing between 2021 and 2025 have dramatically expanded both the capability and the breadth of clinical applications for IDDS. While significant challenges remain in biocompatibility, long-term stability, regulatory harmonization, and equitable access, the field is poised for transformative growth. Continued multidisciplinary collaboration among material scientists, pharmacists, biomedical engineers, clinicians, and regulators will be essential to translate next-generation implantable systems from bench to bedside, ultimately improving quality of life for millions of patients with chronic and life-threatening conditions.

REFERENCES

1. Langer R, Peppas NA. Advances in biomaterials, drug delivery, and bionanotechnology. AIChE J. 2003; 49(12): 2990–3006.

2. Tibbitt MW, Dahlman JE, Langer R. Emerging frontiers in drug delivery. J Am Chem Soc. 2016; 138(3): 704–717.

3. Folkman J, Long DM. The use of silicone rubber as a carrier for prolonged drug therapy. J Surg Res. 1964; 4(3): 139–142.

4. Li J, Mooney DJ. Designing hydrogels for controlled drug delivery. Nat Rev Mater. 2016; 1(12): 16071.

5. Grand View Research. Implantable Drug Delivery Devices Market Report. San Francisco: Grand View Research; 2023.

6. Tiwari G, Tiwari R, Sriwastawa B, Bhati L, Pandey S, Pandey P. Drug delivery systems: An updated review. Int J Pharm Investig. 2012; 2(1): 2–11.

7. Park K. Controlled drug delivery systems: Past forward and future back. J Control Release. 2014; 190: 3–8.

8. Makadia HK, Siegel SJ. Poly lactic-co-glycolic acid (PLGA) as biodegradable controlled drug delivery carrier. Polymers. 2011; 3(3): 1377–1397.

9. Mansour D. Nexplanon: What Implanting Physicians Should Know. J Fam Plann Reprod Health Care. 2010; 36(4): 187–199.

10. Higuchi T. Mechanism of sustained-action medication. J Pharm Sci. 1963; 52(12): 1145–1149.

11. Theeuwes F, Yum SI. Principles of the design and operation of generic osmotic pumps for the delivery of semisolid or liquid drug formulations. Ann Biomed Eng. 1976; 4(4): 343–353.

12. Mura S, Nicolas J, Couvreur P. Stimuli-responsive nanocarriers for drug delivery. Nat Mater. 2013; 12(11): 991–1003.

13. Nair LS, Laurencin CT. Biodegradable polymers as biomaterials. Prog Polym Sci. 2007; 32(8–9): 762–798.

14. Farokhzad OC, Langer R. Impact of nanotechnology on drug delivery. ACS Nano. 2009; 3(1): 16–20.

15. Ratner BD, Hoffman AS, Schoen FJ, Lemons JE. Biomaterials Science: An Introduction to Materials in Medicine. 3rd ed. Amsterdam: Elsevier/Academic Press; 2013.

16. Danhier F, Ansorena E, Silva JM, Coco R, Le Breton A, Preat V. PLGA-based nanoparticles: An overview of biomedical applications. J Control Release. 2012; 161(2): 505–522.

17. Sudesh K, Abe H, Doi Y. Synthesis, structure and properties of polyhydroxyalkanoates: biological polyesters. Prog Polym Sci. 2000; 25(10): 1503–1555.

18. Curtis J, Colas A. Medical applications of silicones. In: Ratner BD, et al., editors. Biomaterials Science. 3rd ed. Academic Press; 2013. p. 1106–1116.

19. Peppas NA, Hilt JZ, Khademhosseini A, Langer R. Hydrogels in biology and medicine: From molecular principles to bionanotechnology. Adv Mater. 2006; 18(11): 1345–1360.

20. Zheng YF, Gu XN, Witte F. Biodegradable metals. Mater Sci Eng R Rep. 2014; 77: 1–34.

21. Ali M, Akin A, Bahamondes L. Extended use up to 5 years of the etonogestrel-releasing subdermal contraceptive implant: comparison to levonorgestrel-releasing implant. Hum Reprod. 2016; 31(11): 2491–2498.

22. World Health Organization. Medical Eligibility Criteria for Contraceptive Use. 5th ed. Geneva: WHO; 2015.

23. Westphal M, Hilt DC, Bortey E. A phase 3 trial of local chemotherapy with biodegradable carmustine (BCNU) wafers (Gliadel wafers) in patients with primary malignant glioma. Neuro Oncol. 2003; 5(2): 79–88.

24. Dang W, Daviau T, Ying P. Effects of GLIADEL wafer initial molecular weight on the erosion of wafer and release of BCNU. J Control Release. 1996; 42(1): 83–92.

25. Boughton CK, Hovorka R. New closed-loop insulin systems. Diabetologia. 2021; 64(5): 1007–1015.

26. Dovc K, Battelino T. Evolution of diabetes technology. Endocrinol Metab Clin North Am. 2020; 49(1): 1–18.

27. Deer TR, Pope JE, Hayek SM. The Polyanalgesic Consensus Conference (PACC): Recommendations on Intrathecal Drug Infusion Systems Best Practices and Guidelines. Neuromodulation. 2017; 20(2): 96–132.

28. Bharat A, Li H, Mukherjee D, Bhattacharya R. Drug delivery systems for the brain. Biotech Biomed Rev. 2022; 4(1): 1–20.

29. Haller JA, Bandello F, Belfort R Jr. Randomized, sham-controlled trial of dexamethasone intravitreal implant in patients with macular edema due to retinal vein occlusion. Ophthalmology. 2010; 117(6): 1134–1146.

30. Kang-Mieler JJ, Osswald CR, Mieler WF. Advances in ocular drug delivery: emphasis on the posterior segment. Expert Opin Drug Deliv. 2014; 11(10): 1647–1660.

31. Cassese S, Byrne RA, Tada T. Bioresorbable vascular scaffolds versus drug-eluting stents: An individual patient data pooled meta-analysis. Lancet. 2016; 387(10): 3006–3017.

32. Byrne RA, Stone GW, Ormiston J, Kastrati A. Coronary balloon angioplasty, stents, and scaffolds. Lancet. 2017; 390(10096): 781–792.

33. Gunawardana M, Remedios-Chan M, Miller CS. Pharmacokinetics of long-acting tenofovir alafenamide (GS-7340) bead implants for HIV prophylaxis. Antimicrob Agents Chemother. 2015; 59(7): 3913–3919.

34. Flexner C, Owen A, Siccardi M, Swindells S. Long-acting drugs and formulations for the treatment and prevention of HIV infection. Int J Antimicrob Agents. 2014; 44(3): 189–196.

35. Webber MJ, Anderson DG. Smart approaches to glucose-responsive drug delivery. J Drug Deliv Sci Technol. 2015; 30: 366–375.

36. Chen S, Singh J. Controlled delivery of testosterone from smart thermosensitive polyphosphazene hydrogels in vitro. Int J Pharm. 2005; 295(1–2): 183–190.

37. Gao W, Xiao Z, Radovic-Moreno A, Shi J, Langer R, Farokhzad OC. Progress in siRNA delivery using multifunctional nanoparticles. Methods Mol Biol. 2013; 942: 239–258.

38. Zhang N, Lock J, Sallee A, Liu H. Magnetic nanocomposite hydrogel for potential cartilage tissue engineering: synthesis, characterization, and cytocompatibility with bone marrow derived mesenchymal stem cells. ACS Appl Mater Interfaces. 2015; 7(37): 20987–20998.

39. Blanco E, Shen H, Ferrari M. Principles of nanoparticle design for overcoming biological barriers to drug delivery. Nat Biotechnol. 2015; 33(9): 941–951.

40. Kowalski PS, Rudra A, Miao L, Anderson DG. Delivering the messenger: Advances in technologies for therapeutic mRNA delivery. Mol Ther. 2019; 27(4): 710–728.

41. Tapeinos C, Battaglini M, Ciofani G. Advances in the design of solid lipid nanoparticles and nanostructured lipid carriers for targeting brain diseases. J Control Release. 2017; 264: 306–332.

42. Farra R, Sheppard NF Jr, McCabe L. First-in-human testing of a wirelessly controlled drug delivery microchip. Sci Transl Med. 2012; 4(122): 122.

43. Dauphin-Ducharme P, Yang K, Arroyo-Curras N. Electrochemical aptamer-based sensors for improved therapeutic drug monitoring. ACS Sens. 2019; 4(10): 2832–2943.

44. Nadeau P, El-Damak D, Glettig D. Prolonged energy harvesting for ingestible devices. Nat Biomed Eng. 2017; 1(3): 0022.

45. Ventola CL. Medical applications for 3D printing: Current and projected uses. P T. 2014; 39(10): 704–711.

46. Awad A, Trenfield SJ, Gaisford S, Basit AW. 3D printed medicines: A new branch of digital healthcare. Int J Pharm. 2018; 548(1): 586–596.

47. Kang SK, Murphy RK, Hwang SW. Bioresorbable silicon electronics for transient spatiotemporal mapping of electrical activity from the cerebral cortex. Nat Mater. 2016; 15(6): 590–600.

48. Feiner R, Dvir T. Tissue-electronics interfaces: from implantable devices to engineered tissues. Nat Rev Mater. 2018; 3(1):17076.

49. Shapiro AM, Lakey JR, Ryan EA. Islet transplantation in seven patients with type 1 diabetes mellitus using a glucocorticoid-free immunosuppressive regimen. N Engl J Med. 2000; 343(4): 230–238.

50. Pepper AR, Gala-Lopez B, Pawlick R, Merani S, Kin T, Shapiro AM. A prevascularized subcutaneous device-less site for islet and cellular transplantation. Nat Biotechnol. 2015; 33(5): 518–523.

51. Szarowski DH, Andersen MD, Retterer S. Brain responses to micro-machined silicon devices. Brain Res. 2003; 983(1–2): 23–35.

52. Anderson JM, Rodriguez A, Chang DT. Foreign body reaction to biomaterials. Semin Immunol. 2008; 20(2): 86–100.

53. Veiseh O, Vegas AJ. Domesticating the foreign body response: Recent advances and applications. Adv Drug Deliv Rev. 2019; 144: 148–161.

54. Bryers JD, Giachelli CM, Ratner BD. Engineering biomaterials to integrate and heal: The biocompatibility paradigm shifts. Biotechnol Bioeng. 2012; 109(8): 1898–1911.

55. Manning MC, Chou DK, Murphy BM, Payne RW, Katayama DS. Stability of protein pharmaceuticals: An update. Pharm Res. 2010; 27(4): 544–575.

56. Deer TR, Mekhail N, Provenzano D. The appropriate use of neurostimulation of the spinal cord and peripheral nervous system for the treatment of chronic pain and ischemic diseases. Neuromodulation. 2014; 17(6): 515–550.

57. US Food and Drug Administration. Classification of Products as Drugs and Devices & Additional Product Classification Issues: Guidance for Industry and FDA Staff. Silver Spring: FDA; 2017.

58. European Medicines Agency. Guideline on the quality requirements for drug–device combinations. Amsterdam: EMA; 2019.

59. Ye H, Fussenegger M. Synthetic therapeutic gene circuits in mammalian cells. FEBS Lett. 2014; 588(15): 2537–2544.

60. Hwang SW, Tao H, Kim DH. A physically transient form of silicon electronics. Science. 2012; 337(6102): 1640–1654.