Injectable Carriers Research Articles

Enhanced efficacy of transforming growth factor-β1 loaded an injectable cross-linked thiolated chitosan and carboxymethyl cellulose-based hydrogels for cartilage tissue engineering

Growth factors (GFs) are soluble proteins extracellular that control a wide range of cellular processes as well as tissue regeneration. While transforming growth factor beta-1 (TGF-β1) promotes chondrogenesis, its medical use is restricted by its potential protein instability, which necessitates high doses of the protein, which can result in adverse side effects such as inefficient cartilage formation. In this work, we have developed a novel hydrogel composite based on the polymer, cross-linked thiolated chitosan; TCS and carboxymethyl cellulose; CMC (TCS/CMC) hydrogel system was utilized as injectable TGF-β1 carriers for cartilage tissue engineering applications. Rheological measurements showed that the elastic modulus of TCS/CMC hydrogels with an optimized CMC concentration could reach around 2.5 kPa or higher than their respective viscous modulus, indicating that they behaved like strong hydrogels. Crosslinking significantly alters the overall network distribution, surface morphology, pore size, porosity, gelation time, swelling ratio, water content, and in vitro degradation of the TCS/CMC hydrogels. TCS/CMC hydrogels maintain more than 90% of their weight and retain their original form after 21 days. TGF-β1 released marginally from TCS/CMC hydrogels as incubation time increased, up to 21 days, with around 18.6 ± 0.9% of the drug stored inside the TCS/CMC hydrogels. On day 21, BMSC treated with TGF-β1 in medium or TGF-β1-loaded TCS/CMC hydrogels grew faster than the other groups. For in vivo cartilage repair, full-thickness cartilage defects were induced on rat knees for 8 weeks. The optimal ability of this novel TGF-β1-loaded TCS/CMC hydrogel system was further demonstrated by histological analysis, resulting in a novel therapeutic strategy for repairing articular cartilage defects.

Conductive single-wall carbon nanotubes/extracellular matrix hybrid hydrogels promote the lineage-specific development of seeding cells for tissue repair through reconstructing an integrin-dependent niche

BackgroundThe niche of tissue development in vivo involves the growth matrix, biophysical cues and cell-cell interactions. Although natural extracellular matrixes may provide good supporting for seeding cells in vitro, it is evitable to destroy biophysical cues during decellularization. Reconstructing the bioactivities of extracellular matrix-based scaffolds is essential for their usage in tissue repair.ResultsIn the study, a hybrid hydrogel was developed by incorporating single-wall carbon nanotubes (SWCNTs) into heart-derived extracellular matrixes. Interestingly, insoluble SWCNTs were well dispersed in hybrid hydrogel solution via the interaction with extracellular matrix proteins. Importantly, an augmented integrin-dependent niche was reconstructed in the hybrid hydrogel, which could work like biophysical cues to activate integrin-related pathway of seeding cells. As supporting scaffolds in vitro, the hybrid hydrogels were observed to significantly promote seeding cell adhesion, differentiation, as well as structural and functional development towards mature cardiac tissues. As injectable carrier scaffolds in vivo, the hybrid hydrogels were then used to delivery stem cells for myocardial repair in rats. Similarly, significantly enhanced cardiac differentiation and maturation(12.5 ± 2.3% VS 32.8 ± 5%) of stem cells were detected in vivo, resulting in improved myocardial regeneration and repair.ConclusionsThe study represented a simple and powerful approach for exploring bioactive scaffold to promote stem cell-based tissue repair.Graphic abstract

Photoacoustic image-guided corpus cavernosum intratunical injection of adipose stem cell-derived exosomes loaded polydopamine thermosensitive hydrogel for erectile dysfunction treatment

Stem cell-derived exosomes (SC-EXO) was an emerging therapeutic agent in regenerative medicine. Intratunical injection of SC-EXO is considered as a prospective approach for erectile dysfunction (ED) treatment. However, high vascularization of cavernous body makes effective retention a major challenge for SC-EXO intratunical injection. In this study, a Polydopamine nanoparticles (PDNPs) incorporated poly (ethylene glycol)-poly(ε-caprolactone-co-lactide) (PDNPs-PELA) thermosensitive hydrogels were fabricated by a facile in situ polymerization for intratunical administration of adipose stem cell-derived exosomes (EXO). The hydrogels exhibited sol-gel transition at body temperature. Moreover, the in-situ polymerization of PDNPs using poly (ethylene glycol)-poly(ε-caprolactone-co-lactide) (PELA) block copolymer as a template was found to be more stable dispersion in the gel system. After being encapsulated into the hydrogel, EXO shows sustained release behavior within two weeks. In vivo animal experiments revealed that exosomes released from hydrogel lead to the healing of endothelial cells and neurons, increase of the cavity's pressure, thereby restoring the erectile function. In particular, since the PDNPs in thermosensitive gels have excellent photoacoustic performance, the hydrogel can be accurately delivered into the tunica albuginea by the guidance of real-time photoacoustic imaging. These results suggest that the as-prepared PDNPs-PELA has a promising future as an injectable exosome carrier for ED treatment.

In vivo evaluation of temperature-responsive antimicrobial-loaded PNIPAAm hydrogels for prevention of surgical site infection.

Surgical site infections (SSIs) are a persistent clinical challenge. Local antimicrobial delivery may reduce the risk of SSI by increasing drug concentrations and distribution in vulnerable surgical sites compared to what is achieved using systemic antimicrobial prophylaxis alone. In this work, we describe a comprehensive in vivo evaluation of the safety and efficacy of poly(N-isopropylacrylamide-co-dimethylbutyrolactone acrylamide-co-Jeffamine M-1000 acrylamide) [PNDJ], an injectable temperature-responsive hydrogel carrier for antimicrobial delivery in surgical sites. Biodistribution data indicate that PNDJ is primarily cleared via the liver and kidneys following drug delivery. Antimicrobial-loaded PNDJ was generally well-tolerated locally and systemically when applied in bone, muscle, articulating joints, and intraperitoneal space, although mild renal toxicity consistent with the released antimicrobials was identified at high doses in rats. Dosing of PNDJ at bone-implant interfaces did not affect normal tissue healing and function of orthopedic implants in a transcortical plug model in rabbits and in canine total hip arthroplasty. Finally, PNDJ was effective at preventing recurrence of implant-associated MSSA and MRSA osteomyelitis in rabbits, showing a trend toward outperforming commercially available antimicrobial-loaded bone cement and systemic antimicrobial administration. These studies indicate that antimicrobial-loaded PNDJ hydrogels are well-tolerated and could reduce incidence of SSI in a variety of surgical procedures.

Fullerol-hydrogel microfluidic spheres for in situ redox regulation of stem cell fate and refractory bone healing

The balance of redox homeostasis is key to stem cell maintenance and differentiation. However, this balance is disrupted by the overproduced reactive oxygen species (ROS) in pathological conditions, which seriously impair the therapeutic efficacy of stem cells. In the present study, highly dispersed fullerol nanocrystals with enhanced bioreactivity were incorporated into hydrogel microspheres using one-step innovative microfluidic technology to construct fullerol-hydrogel microfluidic spheres (FMSs) for in situ regulating the redox homeostasis of stem cells and promoting refractory bone healing. It was demonstrated that FMSs exhibited excellent antioxidant activity to quench both intracellular and extracellular ROS, sparing stem cells from oxidative stress damage. Furthermore, these could effectively promote the osteogenic differentiation of stem cells with the activation of FoxO1 signaling, indicating the intrinsically osteogenic property of FMSs. By injecting the stem cells-laden FMSs into rat calvarial defects, the formation of new bone was remarkably reinforced, which is a positive synergic effect from modulating the ROS microenvironment and enhancing the osteogenesis of stem cells. Collectively, the antioxidative FMSs, as injectable stem cell carriers, hold enormous promise for refractory bone healing, which can also be expanded to deliver a variety of other cells, targeting diseases that require in situ redox regulation.

Injectable open-porous PLGA microspheres as cell carriers for cartilage regeneration.

Minimally invasive treatment via injectable delivery of cells has drawn extensive attention for tissue regeneration because it reduces the need for substantial open surgery and fits tissue defects with complex shapes, making it a suitable option for repairing articular cartilage defects. This work presents an alkaline treatment method to fabricate open-porous poly (lactic-co-glycolic acid) microspheres (OPMs) as bone marrow stromal cells (BMSCs) carriers for cartilage regeneration. OPMs have better biodegradation property and the extended pores can provide easier access for cells to the internal space. The BMSCs cultured with OPMs can display enhanced cell proliferation, up-regulated expression of cartilage-related mRNAs and proteins, and improved cartilage regeneration in vitro and in vivo. These results highlight the advantage and potential of using OPMs fabricated via simple alkaline treatment as injectable stem cell carriers for cartilage regeneration through minimally invasive procedures.

Precise engineering of iron oxide nanoparticle-encapsulated protein hydrogel: Implications for cardiac toxicity and ultrasound contrast agents

In the present study, we developed and assessed novel injectable hydrogel matrices combined with nanoparticles and secretome biomolecules to reduce Doxorubicin (DOX)- induced cytotoxicity in human stem cell-derived cardiomyocytes. A Fe2O3 nanoparticle-loaded biocompatible silk sericin (MSS) nanocomposite form was fabricated and used as an injectable carrier for secretome for in vivo cardiomyocyte metabolism. Biological analyses revealed that the secretome-encapsulated Fe3O2-Silk sericin (Sec@MSS) hydrogel markedly reduced acridine orange/ethidium bromide (AOEB) dual staining in cardiomyocytes, revealing significantly induced apoptosis. Furthermore, we evaluated the mitochondrial membrane potential for DOX and Sec@MSS hydrogel, and demonstrated apoptosis of the cardiomyocytes in the DOX-alone and Sec@MSS groups. However, the cardiotoxicity of Sec@MSS sericin was much lower than that in the DOX group. The acoustic behaviors of the functionalized Sec@MSS were examined. The results indicate that Sec@MSS hydrogel might serve as an effective treatment agent in cardiac diseases in the future.

Preparation and characterization of an elastin nanogel with enhanced biocompatibility and improved entrapment efficiency in prostate cancer cells

Nanogels represent an emerging class of drug delivery systems with enhanced renal clearance and serum half-life. However, synthetic polymeric nanogels are immunogenic and less biodegradable than other systems. Protein nanogels, being non-immunogenic; biodegradable; biocompatible; and mechanically, spatially, and temporally tunable, are gaining widespread attention. Elastin, a natural structural component of connective tissue, has enhanced vascular mobility and is highly biodegradable, biocompatible, temperature and pH sensitive, inert in the bloodstream, able to self-assemble, and able to permeate the blood-brain-barrier. In this study, the development of an Elastin Nanogel (ENG) and its functional capacity as a next generation injectable nano-drug carrier was studied. ENG was prepared via an inverse mini-emulsion technique and was characterized and found to be stable at room temperature and cytocompatible with five different prostate cancer cell lines of varied etiologies. Rhodamine-loaded ENG showed enhanced cellular uptake. Blood smear, hemolysis, CBC, PT/APTT, and C3a complement activation assays showed that ENG is vascular tissue compatible and hence meets the objectives of injectable nanogels. The formulated ENG can be efficiently used as an injectable nano-drug carrier for cancer therapy. Moreover, ENG has the potential to encapsulate hydrophobic drugs for targeted drug delivery.

Injectable gelatin microspheres loaded with platelet rich plasma improve wound healing by regulating early inflammation.

We investigated the potential of gelatin microspheres (GMs) loaded with platelet-rich plasma (PRP) to enhance their wound healing effect. Platelets from the PRP were immobilized onto GMs to form biomimetic bioreactor GM+PRP. The therapeutic effect of this agent was further investigated in vivo on a wound-healing model in rats. Wounds were locally injected with phosphate buffered saline (PBS), GM, PRP, and GM+PRP. Wound healing rate, vessel density, and inflammation level were measured histologically, by RT-PCR, and by Western blotting at days 3, 7, 14, and 21. Platelets on GM caused a continuous high release in both interleukin-10 and metalloproteinase-3 compared with PRP alone. Both GM+PRP and PRP successfully accelerated the wound healing process, while GM alone did not improve the wound healing process compared with the untreated control. Wounds treated with GM+PRP resulted in shorter healing period and improved dermal structure. GM+PRP improved angiogenesis in the wound by increasing expression of angiogenic factors. GM+PRP prolonged and enhanced the cytokine release profile compared with PRP. By promoting the inflammatory and angiogenic responses, GM+PRP has the potential to improve wound healing. Our findings demonstrate that GMs are an injectable carrier that enhanced the therapeutic effects of PRP.

Balancing biological and biomechanical performance in intervertebral disc repair: a systematic review of injectable cell delivery biomaterials.

Discogenic back pain is a common condition without approved intervertebral disc (IVD) repair therapies. Cell delivery using injectable biomaterial carriers offers promise to restore disc height and biomechanical function, while providing a functional niche for delivered cells to repair degenerated tissues. This systematic review advances the injectable IVD cell delivery biomaterials field by characterising its current state and identifying themes of promising strategies. Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were used to screen the literature and 183 manuscripts met the inclusion criteria. Cellular and biomaterial inputs, and biological and biomechanical outcomes were extracted from each study. Most identified studies targeted nucleus pulposus (NP) repair. No consensus exists on cell type or biomaterial carrier, yet most common strategies used mesenchymal stem cell (MSC) delivery with interpenetrating network/co-polymeric (IPN/CoP) biomaterials composed of natural biomaterials. All studies reported biological outcomes with about half the studies reporting biomechanical outcomes. Since the IVD is a load-bearing tissue, studies reporting compressive and shear moduli were analysed and two major themes were found. First, a competitive balance, or ‘seesaw’ effect, between biomechanical and biological performance was observed. Formulations with higher moduli had inferior cellular performance, and vice versa. Second, several low-modulus biomaterials had favourable biological performance and matured throughout culture duration with enhanced extracellular matrix synthesis and biomechanical moduli. Findings identify an opportunity to develop next-generation biomaterials that provide high initial biomechanical competence to stabilise and repair damaged IVDs with a capacity to promote cell function for long-term healing.

Thermoinduced aggegation of chitosan systems in perikinetic and orthokinetic regimes

Thermoresponsive colloidal chitosan systems forming the polymer structure in situ are an example of promising solutions in tissue engineering as an injectable scaffolds or drug carriers. Their application method, and thus shearing, may affect the aggregation process in accordance with the colloidal engineering approach. The aim of the study is to compare the kinetics of chitosan aggregation in the perikinetic regime (limited by Brownian motions) with the orthokinetic process carried out under the influence of an external shear field. The research was carried out using static multiple light scattering (S-MLS) and rheometric measurement techniques coupled with small-angle light scattering (Rheo-SALS). It has been found that the introduction of an external shear field (orthokinetic regime) accelerates the aggregation of chitosan systems. Simultaneously, the rotational measurements can even lead to spontaneous gelation, most likely caused by changes in the conformation of chitosan molecules, their deformation and ordering along the shear field.

Neural Progenitor Cells Alter Chromatin Organization and Neurotrophin Expression in Response to 3D Matrix Degradability.

Neural progenitor cells (NPCs) are promising therapeutic candidates for nervous system regeneration. Significant efforts focus on developing hydrogel-based approaches to facilitate the clinical translation of NPCs, from scalable platforms for stem cell production to injectable carriers for cell transplantation. However, fundamental questions surrounding NPC-hydrogel interactions remain unanswered. While matrix degradability is known to regulate the stemness and differentiation capacity of NPCs, how degradability impacts NPC epigenetic regulation and secretory phenotype remains unknown. To address this question, NPCs encapsulated in recombinant protein hydrogels with tunable degradability are assayed for changes in chromatin organization and neurotrophin expression. In high degradability gels, NPCs maintain expression of stem cell factors, proliferate, and have large nuclei with elevated levels of the stemness-associated activating histone mark H3K4me3. In contrast, NPCs in low degradability gels exhibit more compact, rounded nuclei with peripherally localized heterochromatin, are non-proliferative yet non-senescent, and maintain expression of neurotrophic factors with potential therapeutic relevance. This work suggests that tuning matrix degradability may be useful to direct NPCs toward either a more-proliferative, stem-like phenotype for cell replacement therapies, or a more quiescent-like, pro-secretory phenotype for soluble factor-mediated therapies.

Injectable diblock copolypeptide hydrogel provides platform to deliver effective concentrations of paclitaxel to an intracranial xenograft model of glioblastoma.

IntroductionSurgical resection and systemic chemotherapy with temozolomide remain the mainstay for treatment of glioblastoma. However, many patients are not candidates for surgical resection given inaccessible tumor location or poor health status. Furthermore, despite being first line treatment, temozolomide has only limited efficacy.MethodsThe development of injectable hydrogel-based carrier systems allows for the delivery of a wide range of chemotherapeutics that can achieve high local concentrations, thus potentially avoiding systemic side effects and wide-spread neurotoxicity. To test this modality in a realistic environment, we developed a diblock copolypeptide hydrogel (DCH) capable of carrying and releasing paclitaxel, a compound that we found to be highly potent against primary gliomasphere cells.ResultsThe DCH produced minimal tissue reactivity and was well tolerated in the immune-competent mouse brain. Paclitaxel-loaded hydrogel induced less tissue damage, cellular inflammation and reactive astrocytes than cremaphor-taxol (typical taxol-carrier) or hydrogel alone. In a deep subcortical xenograft model of glioblastoma in immunodeficient mice, injection of paclitaxel-loaded hydrogel led to local tumor control and improved survival. However, the tumor cells were highly migratory and were able to eventually escape the area of treatment.ConclusionsThese findings suggest this technology may be ultimately applicable to patients with deep-seated inoperable tumors, but as currently formulated, complete tumor eradication would be highly unlikely. Future studies should focus on targeting the migratory potential of surviving cells.

One-pot fabrication of uniform half-moon-shaped biodegradable microparticles via microfluidic approach

Engineering of physical parameters such as shape and texture of microparticle can provide solutions to overcome limitations of conventional microparticles. We demonstrate the fabrication of uniform half-moon-shaped microparticles using synthesized poly(d,l-lactide) via a tube-type microfluidic approach. A true half-moon appearance, which comprises of dimple patterns on a round surface and a plain flat surface, is obtained by the optimization of fabrication conditions and a new self-rupturing mechanism. A new pop out mechanism allows for the one-pot synthesis of microparticles with complicated structures. The microparticles can have promising applications such as suspension cell culture, injectable cell carrier, and inhalable particulate drug delivery system because of their excellent cell adhesion, low weight resulting from an internal porous structure, and biodegradable character.

A Novel Fabrication of Dose-Dependent Injectable Curcumin Biocomposite Hydrogel System Anesthetic Delivery Method for Care and Management of Musculoskeletal Pain.

Chronic musculoskeletal pain has biological, psychological, and social components. In this article, we have demonstrated the easily injectable nanocomposite carrier for the treatment of chronic musculoskeletal pain. Briefly, the curcumin (Cur) loaded with lipid nanocapsules (LNCs; Cur@LNCs) using the phase invasion method. The synthesized Cur@LNCs were characterized by using scanning electron microscopy, transmittance electron microscopy, and the size of the fabricated nanoparticles confirmed by dynamic light scattering analysis. The synthesized Cur@LNC injectable hydrogel shows excellent results in vivo in the rat model. We have examined the efficiency of the chronic constriction injury in the rat model and induced the pain using thermal paw withdrawal latency. The injectable hydrogels Cur@LNCs display a remarkable reduction in pain 7 days post administrations compared to the untreated group animals. This work could establish the preclinical candidate of the neuropathic pain response in the future.

Fluorescent Magnetic Iron Oxide NanoparticleEncapsulated Protein Hydrogel Against Doxorubicin-Associated Cardiotoxicity and for Enhanced Cardiomyocyte Survival

Doxorubicin (DOX) is a widely used and effective anticancer drug. However, it shows high cardiotoxicity in several patients. The exact biological mechanisms of DOX-induced cardiotoxicity remain unclear. In the present study, we developed and assessed novel injectable hydrogel matrices combined with nanoparticles and secretome biomolecules to reduce DOXinduced cytotoxicity in human stem cell-derived cardiomyocytes. A Fe₂O₃ nanoparticle-loaded biocompatible silk sericin nanocomposite form was fabricated and used as an injectable carrier for secretome for in vivo cardiomyocyte metabolism. The formulated hydrogels carrying secretome were analyzed in vitro for proliferation, migration, and tube formation of human stem cell-derived cardiomyocytes. Biological analyses revealed that the secretome-encapsulated florescent Fe₃O₂ Silk sericin (Sec@MSS) hydrogel markedly reduced calcein-PI dual staining in cardiomyocytes, revealing significantly induced apoptosis. Furthermore, we evaluated the mitochondrial membrane potential for DOX and Sec@MSS hydrogel, and demonstrated apoptosis of the cardiomyocytes in the DOX-alone and Sec@MSS groups. However, the cardiotoxicity of Sec@MSS sericin was much lower than that in the DOX group, and was further evaluated via VEGFR and TUNEL analyses. The results indicate that Sec@MSS hydrogel might serve as an effective treatment agent in cardiac diseases in the future.

Amylopectin Multiple Aldehyde Crosslinked Hydrogel as an Injectable and Self‐Healing Cell Carrier for Bone Tissue Engineering

Front Cover: In article number 2000045 by Fatemeh Shokrolahi, Parvin Shokrollahi, and co-workers, a hydrogel with dynamic Schiff base linkages, so-called “dynamic hydrogel,” as an injectable cell carrier consisting of the natural biopolymers gelatin and amylopectin multiple aldehyde, is developed with all the required characteristics including biocompatibility, quick forming, injectability, self-healing, shape holding, and durability. The hydrogel is used as an injectable carrier of human bone marrow-derived mesenchymal stem cells for bone tissue engineering.

Amylopectin Multiple Aldehyde Crosslinked Hydrogel as an Injectable and Self‐Healing Cell Carrier for Bone Tissue Engineering

AbstractDespite excellent processing and biological properties of gelatin for use as a cell carrier, none of the gelatin‐based hydrogel cell carriers reported to date offer all characteristics including quick formation, injectability, self‐healing, and durability, which are simultaneously required for an ideal system. Here, a gelatin‐based hydrogel with dynamic Schiff base linkages, so‐called “dynamic hydrogel,” as an injectable cell carrier consisting of gelatin and amylopectin multiple aldehyde (AMPA), with all the required characteristics is reported. Biocompatibility and osteoinductivity of the hydrogel are verified through the culture of human bone marrow‐derived mesenchymal stem cells (hBMSCs). As live/dead results show, hBMSCs are alive and highly viable ≈85–90% within the hydrogel after 5 days. According to bromodeoxyuridine cell proliferation assay, a significant increase in the number of the cells seeded in the hydrogel confirms its clinical significance for cell therapy. Most importantly, histological visualization using Mason's Trichrome staining indicates secretion of extracellular matrix around the cells loaded in the hydrogel and also expression level evaluation of the crucial osteogenic markers, confirms that the hydrogel can provide osteoinductive support for osteocyte differentiation of hBMSCs after 14 days. Therefore, this hydrogel provides more progress on the path toward bone tissue engineering and further treatment of bone diseases.

Effect of crosslinking agents on drug distribution in chitosan hydrogel for targeted drug delivery to treat cancer

Due to in-situ gelation, an injectable hydrogel drug carrier has advantages over other delivery systems. Atomic simulations help to study the structure-performance relationship of drug delivery systems (DDS) considering the interaction between components, which is focused in this study. Chitosan hydrogel network is constructed using three different crosslinking agents, soaked with water, and thermal cycles are applied to estimate the critical temperatures. Subsequently, three different drug molecules are incorporated into the models separately and the distributions are observed by analyzing the trajectories of the drug molecules obtained from the simulations performed with canonical ensembles, as the distributions will affect the drug discharge. Afterward, a protein – associated with cancer is added to the supercell and the diffusion of the drug is observed in the presence of protein molecules. A better system consisting of the drug molecules and differently cross-linked hydrogels is recommended in this study in terms of the diffusivity of the drug molecules out of nine distinct systems.

Modulating sustained drug release from nanocellulose hydrogel by adjusting the inner geometry of implantable capsules

Nanocellulose hydrogel has been shown to be an excellent platform for drug delivery and it has been lately studied as an injectable drug carrier. 3D printing is an effective method for fast prototyping of pharmaceutical devices with unique shape and cavities enabling new types of controlled release. In this study, we combined the versatility of 3D printing capsules with controlled geometry and the drug release properties of nanocellulose hydrogel to accurately modulate its drug release properties. We first manufactured non-active capsules via 3D printing from biocompatible poly(lactic acid) (PLA) that limit the direction of drug diffusion. As a novel method, the capsules were filled with a drug dispersion composed of model compounds and anionic cellulose nanofiber (CNF) hydrogel. The main benefit of this device is that the release of any CNF-compatible drug can be modulated simply by modulating the inner geometry of the PLA capsule. In the study we optimized the size and shape of the capsules inner cavity and performed drug release tests with common beta blockers metoprolol and nadolol as the model compounds. The results demonstrate that the sustained release profiles provided by the CNF matrix can be accurately modulated via adjusting the geometry of the 3D printed PLA capsule, resulting in adjustable sustained release for the model compounds.