Sustained Release Drug Delivery Research Articles

Place of intravitreal dexamethasone implant in the treatment armamentarium of diabetic macular edema.

Diabetic macular edema (DME) is a very important and well-known cause of visual loss in diabetics. Blood–retina barrier disruption and consequent intraretinal fluid accumulation may lead to retinal thickening at the posterior pole namely DME. Even though it is not clearly understood, current evidence suggests that chronic low-grade inflammation characterized with various cytokines has a major role in the occurrence of DME. Clinical trials are continuously shaping our treatment approaches for the eyes with DME. Today, vascular endothelial growth factor (VEGF) inhibitor and steroid administrations are the main alternatives in DME treatment. Dexamethasone (DEX) implant (Ozurdex®; Allergan, Inc., Irvine, CA, United States) was approved by the United States Food & Drug Administration in 2014 for DME treatment. The implant is made up of a biodegradable solid copolymer that is broken down by releasing its active ingredient into the vitreous cavity over time. Biphasic release feature of this sustained-release drug delivery system ensures its efficacy for up to 6 mo with an acceptable and manageable safety profile. DEX implant provides a favorable anatomical and functional outcome in DME as shown in several randomized-controlled studies but has a relatively higher ocular side-effect profile such as increased risk of cataract formation and raised intraocular pressure when compared to the gold standard anti-VEGF agents. Thus, DEX implant becomes the second-line treatment option demonstrating inadequate clinical response to anti-VEGF therapy. However, it can be preferred as the first-line treatment in vitrectomized and pseudophakic eyes. Even in some selected conditions DEX implant is favored over anti-VEGF agents where the use of VEGF-inhibitors is either inappropriate or contraindicated such as the patients with a recent history of a major cardiovascular or cerebrovascular event, pregnancy and noncompliant to frequent visits. This mini-review briefly overviews the efficacy, safety profile and complications of DEX implant and summarizes the outcome of DEX implant administration in major clinical studies on DME treatment.

Electrospun Nanofibers of Polycaprolactone/Collagen as a Sustained-Release Drug Delivery System for Artemisinin.

The application of artemisinin (ART) in the treatment of malaria has been restricted to a certain degree due to its inherent limitations, such as short half-life, poor solubility, limited bioavailability, and re-crystallization. Electrospun nanofibers loaded with ART provide an excellent solution to these limitations and yield sustained drug release as well as inhibition of drug re-crystallization. In this study, ART-loaded polycaprolactone (PCL)/collagen (Col) nanofibers with different proportions of polymers were prepared. ART-loaded PCL/Col nanofibers were characterized, and further ART anti-crystallization and release behaviors were studied. SEM was used to observe the morphology of PCL/Col nanofibers. X-ray diffraction (XRD) was used to characterize the physical state of ART in ART-loaded PCL/Col nanofibers. Fourier transform infrared spectroscopy (FTIR), water contact angle measurement, weight loss, degree of swelling, and drug release experiments can verify the differences in performance of ART-loaded PCL/Col nanofibers due to different polymer ratios. The release curve was analyzed by kinetics, showing sustained release for up to 48 h, and followed the Fickian release mechanism, which was shown by the diffusion index value obtained from the Korsmeyer-Peppas equation.

Metronidazole- and Amoxicillin-Loaded PLGA and PCL Nanofibers as Potential Drug Delivery Systems for the Treatment of Periodontitis: In Vitro and In Vivo Evaluations.

The purpose of this study was to prepare poly (D-L) lactide-co-glycolide (PLGA) and poly ε-caprolactone (PCL) nanofibers containing metronidazole and amoxicillin using an electrospinning process as intrapocket sustained-release drug delivery systems for the treatment of periodontal diseases. Scanning electron microscopy showed that the drug containing PLGA and PCL nanofibers produced from the electrospinning process was uniform and bead-free in morphology. The obtained nanofibers had a strong structure and resisted external tension according to the tensiometry results. The cytotoxicity results indicated acceptable cell viability (>80%). Quantification by high-performance liquid chromatography showed almost complete in vitro drug release between 7 and 9 days, whereas 14 days were required for complete drug release in vivo. No significant signs of irritation or inflammatory reaction were detected after three weeks of subcutaneous implantation of nanofibers in the animal models, thus indicating suitable compatibility. The results therefore suggest that the designed nanofibers can be used as potential commercial formulations in the treatment of periodontitis as controlled-release intrapocket drug delivery systems that can increase patient compliance. This is due to their ability to reduce the frequency of administration from three times daily in a systemic manner to once weekly as local delivery.

Alan Cowan: Buprenorphine from the bench to the bedside-Personal notes.

In 2005, Bob Adams, the Chief Veterinarian at Johns Hopkins, wondered if sustained release technology could be used to improve postsurgical analgesia for animal medicine. Henry Brem, Director of the Hunterian Laboratories, had organized an international consortium to advance therapy for brain tumors and stroke. The Hunterian had over 20 years of experience with the safety and effectiveness of neutral lipids, phospholipids, carbohydrates, gels, polymers, and assorted devices for sustained-release drug delivery. We had the technology. What was the best pharmacology? Buprenorphine was the obvious analgesic. Reports of adverse events in the veterinary literature were rare.

3D Printed Intragastric Floating and Sustained-Release Tablets with Air Chambers

This work aimed to use hot-melt extrusion (HME) and dual fused deposition modeling (FDM) 3D printing technology to develop a novel intragastric floating and sustained-release drug delivery system. The intragastric floating and sustained-release tablet was engineered by employing hydroxypropyl methylcellulose (AffinisolTM HPMC HME 15LV) for a drug-loaded core and polylactic acid (PLA) for an insoluble shell with an air chamber. Filaments for the drug-loaded core were compounded using a single-screw hot melt extruder. 3DMAX software was utilized to design a core with a complementary shell which consisted of a hollow chamber at the top and a drug-release window with different sizes (radius in 1.5, 2.5, 3, 3.5, 4.5 mm) at the bottom. Pharmaceutical characterization, solid dispersion evaluation, and drug release behavior were studied. The model drug in all formulations kept stable, and part of the drug in the extruded filaments and 3D printed tablets became amorphous. The introduction of an air chamber reduced the tablet density to below 0.9 g/cm3 and the 3D printed tablets floated immediately and continuously during the drug release process. The presence of the insoluble shell greatly prolonged the drug release time, and the drug release rate was positively correlated with the area of the release window. In addition, compared with shellless tablets, the 3D printed tablets with air chambers (radius in 4.5 mm) showed closer zero-order drug release for 24 h and released drug by diffusion-erosion combined mechanism. The developed intragastric floating and sustained-release tablets with air chambers could be applied to various drugs and provided a new way for the development of personalized drug delivery systems.

Hitchhiking on Controlled-Release Drug Delivery Systems: Opportunities and Challenges for Cancer Vaccines.

Cancer vaccines represent among the most promising strategies in the battle against cancers. However, the clinical efficacy of current cancer vaccines is largely limited by the lack of optimized delivery systems to generate strong and persistent antitumor immune responses. Moreover, most cancer vaccines require multiple injections to boost the immune responses, leading to poor patient compliance. Controlled-release drug delivery systems are able to address these issues by presenting drugs in a controlled spatiotemporal manner, which allows co-delivery of multiple drugs, reduction of dosing frequency and avoidance of significant systemic toxicities. In this review, we outline the recent progress in cancer vaccines including subunit vaccines, genetic vaccines, dendritic cell-based vaccines, tumor cell-based vaccines and in situ vaccines. Furthermore, we highlight the efforts and challenges of controlled or sustained release drug delivery systems (e.g., microparticles, scaffolds, injectable gels, and microneedles) in ameliorating the safety, effectiveness and operability of cancer vaccines. Finally, we briefly discuss the correlations of vaccine release kinetics and the immune responses to enlighten the rational design of the next-generation platforms for cancer therapy.

Mucoadhesive microspheres of glutaraldehyde crosslinked mucilage of Isabgol husk for sustained release of gliclazide

Mucoadhesive microspheres have their own significant amongst the various sustained release drug delivery systems. The prolonged residence time of these delivery devices at drug absorption site results in steep concentration gradient and enhanced bioavailability. In this study, the mucilage of Isabgol husk was applied as polymeric backbone to develop gliclazide loaded microspheres by crosslinking with glutaraldehyde. The formulations were studied for surface morphology, swelling behavior, particle size, in vitro release, release kinetics, in vitro mucoadhesion and gamma scintigraphy in rabbits. The release of gliclazide from microspheres was controlled by swelling of crosslinked microspheres followed by diffusion. Gamma scintigraphic images acquired for microspheres retention in (GIT) of rabbits indicated the residence of formulation upto 24 h after oral administration. Gliclazide retained its integrity in polymeric matrix of microspheres as observed by Fourier transform infrared spectroscopy, differential scanning calorimetry and powder X-ray diffractometry. The sustained release of gliclazide and prolonged retention of microspheres in gastrointestinal track disclosed the rationality of mucoadhesive Isabgol husk microspheres in controlling the hyperglycemia in diabetes.

The Role of Matrix Tablet in Oral Drug Delivery System

Matrix tablet is an important tool for controlled and sustained release dosage forms. The important route of drug administered by oral route. The oral dosage forms developed and improvedthe patient compliance. The oral controlled release system has been developed by change to formulation scientist, due to the inability to restrain and localized of a system at target area of the gastrointestinal tract. The hydrophilic polymers are becomes product of choice for important ingredients formulation of sustained release dosage forms.The benefit of sustained release dosage forms are compared to the conventional dosage forms and uniform therapeutic effects and drug plasma concentration. The matrices used of various class of hydrophilic, hydrophobic, mineral or biodegradabletypes of polymers and their degradation product have been focused. The drug have less half-life and eliminated from the body with in short period of time. The formulation of drug matrix types have been avoided by difficult sustained release drug delivery system. The mechanism of matrix tablets include the both dissolution and diffusion controlled. It produce the therapeutic efficacy. The goal of this review article is to discuss the release mechanism of the drug dosage form of various polymers and a matrix system used in preparation of matrix tablets.

A Novel Approach on Role of Polymers Used In Sustained Release Drug Delivery System- A Review

A Novel Approach on Role of Polymers Used In Sustained Release Drug Delivery System- A Review

English

BACKGROUND Osteoarthritis is a common, age-related, chronic and slowly progressive joint disorder which ultimately leads to joint failure. To achieve sustained release drug delivery and ease of administration, the present study was carried out to formulate a glucosamine solid lipid microparticle-based hydrogel. METHODS 20 batches of glucosamine solid lipid microparticle were prepared by melt dispersion technique. They were then evaluated with regard to various parameters such as physical appearance, pH analysis, spreadability, viscosity, drug content, in vitro drug release and accelerated stability studies. Then the glucosamine solid lipid microparticle-based hydrogel was compared with the glucosamine loaded hydrogel. RESULTS Of these batches, batches 18, 19 and 20 of increasing homogenizing speed of 1000, 1500 and 2000 rpm were found be efficient but the batch 18 showed better encapsulation efficiency. Batch 18 showed particle size of 86 ± 5 µm, encapsulation efficiency of 81.74 ± 4.5 and the zeta potential value of - 29 ± 1. So, batch 18 was found to be the optimised formulation which was further taken for incorporating the Carbopol. The efficient encapsulated glucosamine solid lipid microparticle-based hydrogel was formulated. There were no significant changes in physicochemical properties on stability studies. CONCLUSIONS Glucosamine solid lipid microparticle-based hydrogel had good particle size, high encapsulation efficiency and high zeta potential value and showed high percentage drug release which was better than the glucosamine loaded hydrogel. KEY WORDS Glucosamine Solid Lipid Microparticle Based Hydrogel, Osteoarthritis, Encapsulation Efficiency, Zeta Potential, Melt Dispersion Technique

Light-Activated Local Drug Delivery From Hydrogels: Potential for GBM Treatment

Following post-operative treatment, the vast majority of GBMs recur, usually within 2 cm of the tumor resection margin. Since these tumors seldom metastasize outside the CNS, improved localized therapies should prove beneficial. Drug delivery systems (DDS) that allow control over drug release by an externally applied energy, such as light, have the potential of improving the results of chemotherapy. Light-activated hydrogel DDS, implanted in the operative cavity formed by tumor resection, bypasses the blood brain barrier and allows for a precise spatio-temporal control of drug release or drug activation. Localized, on-demand release of anticancer drugs to normal brain infiltrated by tumor cells should therefore improve therapeutic efficacy and minimize systemic, drug-related side effects. Various forms of light-activated hydrogels have utilized near infrared, visible or ultraviolet wavelength irradiation. One form of hydrogel, fibrin glue (FG), composed of a combination of fibrinogen and thrombin, has several characteristics that make it well-suited for this form of sustained release drug delivery. Unlike most synthetic hydrogels, FG is a natural product and has been used clinically in surgery for decades, so its biocompatibility and lack of toxicity has been clearly proven. The light-driven drug activation technology, photochemical internalization (PCI) has been shown to enhance the intracellular efficacy of chemotherapeutic agents released from fibrin glue. A summary of the light-activated hydrogel techniques developed for the site and temporal-specific delivery of chemotherapy for the treatment of GBM will be discussed in this review.

Selective Motion Control of a Novel Magnetic-Driven Minirobot With Targeted Drug Sustained-Release Function

In this article, we propose a novel magnetic-actuated multimodule drug sustained-release minirobot (DSM) manipulated by an external rotating electromagnetic field. The structure of the DSM is mainly divided into three parts: 1) a shell; 2) an internal propeller; and 3) a drug chamber. The shell can effectively protect the intestinal tract and reduce the various resistances during the work; the built-in propeller not only realizes active locomotion but also saves internal space, which provides the feasibility for the development of functional modules of the robot. The drug chamber pushes the carried drugs out of the chamber similar to a syringe. With structural optimization, we have realized the sustained-release and quantitative drug delivery based on the characteristics of minimagnets’ individual starting frequency- and pitch-related calculations. The main challenge to achieve these functions is to manipulate two magnets in the same magnetic field to drive different functional modules, without mutual interference between the two magnets. In this article, a series of simulations and experiments are conducted to evaluate DSM's motion performance, drug delivery function, and dose control during drug delivery. In the experiment, two different drug delivery points were set up to make DSM spray the drug on the fester areas twice respectively. Finally, an <italic xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">in vitro</i> experiment using the DSM prototype was executed with fresh pig large intestine in a curved shape pipe mold.

Potential of Exosomes for Diagnosis and Treatment of Joint Disease: Towards a Point-of-Care Therapy for Osteoarthritis of the Knee.

In the knee joint, articular cartilage injury can often lead to osteoarthritis of the knee (OAK). Currently, no point-of-care treatment can completely address OAK symptoms and regenerate articular cartilage to restore original functions. While various cell-based therapies are being developed to address OAK, exosomes containing various components derived from their cells of origin have attracted attention as a cell-free alternative. The potential for exosomes as a novel point-of-care treatment for OAK has been studied extensively, especially in the context of intra-articular treatments. Specific exosomal microRNAs have been identified as possibly effective in treating cartilage defects. Additionally, exosomes have been studied as biomarkers through their differences in body fluid composition between joint disease patients and healthy subjects. Exosomes themselves can be utilized as a drug delivery system through their manipulation and encapsulation of specific contents to be delivered to specific cells. Through the combination of exosomes with tissue engineering, novel sustained release drug delivery systems are being developed. On the other hand, many of the functions and activities of exosomes are unknown and challenges remain for clinical applications. In this review, the possibilities of intra-articular treatments utilizing exosomes and the challenges in using exosomes in therapy are discussed.

A carboxymethyl lentinan layer by layer self-assembly system as a promising drug chemotherapeutic platform

Surface functionalization of mesoporous silica nanoparticles (MSNs) has been proposed as an efficient strategy for enhancing the biocompatibility and efficiency of an MSN-based carrier platform. Herein, natural polyelectrolyte multilayers composed of poly-l-ornithine (PLO) and carboxymethyl lentinan (LC) were coated on the surface of MSNs through a layer-by-layer (LbL) self-assembly technique, and were characterized by ζ-potential, FTIR, 13C NMR, SEM, TEM, XRD, and TG. The prepared carrier presented alternating positive and negative potentials when coated with the polyelectrolytes, and the surface of MSN-PLO/LC was rougher compared to the naked MSNs. The biocompatibility tests, including cytocompatibility, hemocompatibility, and histocompatibility, showed that MSNs biocompatibility could be improved by modifying LC. A high loading and sustained release drug delivery system was constructed after loading doxorubicin (DOX) into the prepared MSN-PLO/LC, which exhibited significant anti-proliferative efficiency in human cervical cancer cell lines (Hela). Therefore, the PLO/LC LbL NPs (layer-by-layer self-assembled nanoparticles coated with PLO/LC layers) based on MSNs, which is easily prepared by electrostatic interactions, can be considered a promising drug chemotherapeutic platform and delivery technique for future human cervical cancer therapy.

PH-responsive nanocarriers for combined chemotherapies: a new approach with old materials

Ethyl cellulose (EC) is widely used in the pharmaceutical field as a polymeric excipient to fabricate sustained-release drug delivery systems. To develop a controlled release carrier exploiting the unique characteristic acidic environment of the target tumor site, this study examined the use of EC and lecithin (LC) as a nanoparticulated system. Paclitaxel and dihydroartemisinin were used as model drug combinations. The optimized formulated nanoparticles (NPs) of EC (EC NPs) and EC/LC (EC/LC NPs) were spherical and approximately 130 nm in diameter as determined by dynamic light scattering and electron microscopy analyses. The in vitro drug release from EC/LC NPs exhibited a pH-dependent pattern. In in vitro cell studies, the NPs were taken up by cells, and cell growth was inhibited by drugs released from the formulations. Most importantly, the in vivo anti-tumor study in mice showed a significant reduction in tumor volume after the intravenous administration of EC/LC NPs, suggesting the potential of using EC and LC as controlled and pH-sensitive drug delivery carriers.

Development and Characterization of LBG-PVA Interpenetrating Networks Incorporating Gliclazide for Sustained Release

Background: Controlled oral dosage forms have always been preferred for drugs with variable absorption, and short biological half life and frequent dosing. The prime goal with sustained release systems is to maintain uniform therapeutic blood levels for more extended periods of time. Interpenetrating networks (IPNs) have been evidenced as uniform sustained release systems. In the current study, polyvinyl alcohol (PVA) and locust bean gum (LBG) based IPNs were developed for the oral sustained release drug delivery of gliclazide (shows variable absorption). Methods: The IPNs were synthesized by emulsion cross-linking method using glutaraldehyde (GA) as a cross linking agent. Gliclazide is a potential second generation, and short-acting sulfonylurea oral hypoglycemic agent having a short biological half-life (2-4 h), variable absorption and poor oral bioavailability. Various batches of IPNs were formulated by varying LBG: PVA ratio and evaluated for percentage yield, drug entrapment efficiency (DEE), swelling properties and in vitro drug release studies. Further characterizations were done by Fourier Transform Infrared Spectroscopy (FTIR), C13 Solid state NMR, X-Ray diffraction study (XRD), Scanning electron microscopy (SEM), and Differential scanning microscopy (DSC) studies. Results: The percentage yield, drug entrapment and equilibrium swelling were observed to be dependent on PVA-LBG ratio and GA amount. Sustained release of drug was observed in all IPN formulations (approx 59 - 86% in 8 h in various batches) with variable release kinetics. SEM studies revealed the regular structures of IPNs. FTIR, XRD, C13 Solid state NMR and DSC studies proposed that drug was successfully incorporated into the formed IPNs. Conclusion: IPNs of LBG and PVA can be used as a promising carrier with uniform sustained release characteristics.

Sustained-release drug delivery systems for the treatment of glaucoma.

Glaucoma, a leading cause of irreversible blindness, affects more than 64 million people worldwide and is expected to grow in number due to the aging global population and enhanced methods of detection. Although topical therapies are often effective when used as prescribed, the drawbacks of current medical management methods include poor patient adherence, local and systemic side effects, and in some cases, limited therapeutic efficacy. Novel ocular drug delivery platforms promise to deliver differentiated drug formulations with targeted delivery leveraging patient-independent administration. Several platforms are in various stages of development with promising pre-clinical and clinical data. The Bimatoprost Sustained Release (SR) intracameral implant was approved in the United States in March of 2020, making it the first long-term injectable therapy available for the treatment of glaucoma. This review aims to provide an update on novel sustained release drug delivery systems that are available today as well as those that might be commercialized in coming years.

A pH-sensitive and sustained-release oral drug delivery system: the synthesis, characterization, adsorption and release of the xanthan gum-graft-poly(acrylic acid)/GO-DCFP composite hydrogel.

In this study, graphene oxide (GO) was successfully prepared using the improved Hummers method, and the prepared GO powder was dissolved in distilled water and subjected to ultrasonic stripping. Diclofenac potassium (DCFP) was selected as a model drug to systematically evaluate the adsorption mechanism of DCFP by GO. Different reaction models were constructed to fit the adsorption kinetics and adsorption isotherms of DCFP on GO, in order to further explore the underlying adsorption mechanism. The results demonstrated that the pseudo-second-order kinetic model and Freundlich model could better delineate the adsorption process of DCFP by GO. Both π–π stacking and hydrophobic interaction were mainly involved in the adsorption process, and there were electrostatic interaction and hydrogen bonding at the same time. Then, the xanthan gum-graft-poly(acrylic acid)/GO (XG-g-PAA/GO) composite hydrogel was synthesized by in situ polymerization as a slow-release drug carrier. For this reason, a XG-g-PAA/GO–DCFP composite hydrogel was synthesized, and its in vitro drug release and pharmacokinetic data were assessed. The results showed that the synthesized XG-g-PAA/GO composite hydrogel had a certain mechanical strength and uniform color, indicating that GO is evenly distributed in this composite hydrogel. Moreover, the results of a swelling ratio test demonstrated that the swelling ratios of the XG-g-PAA/GO composite hydrogel were significantly increased with increasing pH values, implying that this material is sensitive to pH. The in vitro drug release experiment showed that the cumulative release of DCFP after 96 h was significantly higher in artificial intestinal fluid than in artificial gastric fluid. These findings indicate that the XG-g-PAA/GO–DCFP composite hydrogel exhibits pH sensitivity under physiological conditions. Besides, the results of in vivo pharmacokinetic analysis revealed that the t1/2 of DCFP group was 2.03 ± 0.35 h, while that of the XG-g-PAA/GO–DCFP composite hydrogel group was 10.71 ± 2.04 h, indicating that the synthesized hydrogel could effectively prolong the drug action time. Furthermore, the AUC(0–t) of the DCFP group was 53.99 ± 3.18 mg L−1 h−1, while that of the XG-g-PAA/GO–DCFP composite hydrogel group was 116.79 ± 14.72 mg L−1 h−1, suggesting that the bioavailability of DCFP is greatly enhanced by this composite hydrogel. In conclusion, this study highlights that the XG-g-PAA/GO–DCFP composite hydrogel can be applied as a sustained-release drug carrier.

In-vitro studies of Curcumin-β-cyclodextrin inclusion complex as sustained release system

Curcumin has always gained attention due to its diverse medicinal properties; concerns are related to its metabolism and aqueous solubility. Researchers are putting forth persistent attempts to improve its water solubility. Out of various methodologies tested, complex formation with β-cyclodextrin has been effective enough to enhance its solubility. A number of reports are available in literature which shows increased aqueous solubility of curcumin-cyclodextrin inclusion complex. In addition to its enhanced aqueous solubility as β-cyclodextrin-inclusion complex by 206 folds, we here studied curcumin-cyclodextrin inclusion complex as a sustained release drug delivery system. Initially synthesized inclusion complex has been characterized using FT-IR, SEM, XRD, UV-Vis, and particle size analysis. Interactions of curcumin, as a guest in cyclodextrin host moiety in context with biological molecules were monitored by anti-oxidant, serum protein protecting, anti-trypsin, anti-amylase, and anti-cathepsin activities. And, for the first time, the sustained release character of curcumin over a period of 5h from the β-cyclodextrin inclusion complex has been reported.

Characterization of Zinc Oxide Nanoparticle Cross-Linked Collagen Hydrogels.

Collagen is the most abundant protein in mammals and possesses high biocompatibility and low antigenicity. These biological properties render it one of the most useful biomaterials for medical applications. This study investigated the mechanical and physical characteristics of collagen hydrogels cross-linked with different ratios of polyvinylpyrrolidone capped zinc oxide nanoparticles (ZPVP). Fourier transform infrared spectroscopy indicated molecular interactions between collagen fibers and ZPVP. Texture analysis revealed a significant increase in gel hardness, adhesiveness, and viscosity after cross-linking with ZPVP. Rheological measurements showed that as the ratio of ZPVP increased, stronger hydrogels were formed which in turn resulted in more sustained release of the model drug, dexamethasone sodium phosphate. We can therefore conclude that the mechanical properties of collagen hydrogels can be modified by controlling the ratio of ZPVP used for cross-linking, offering the potential to develop biocompatible sustained release drug delivery systems.