Multi-component polymer hydrogels present complex physiochemical interactions that make accurate compositional analysis challenging. This study evaluates three analytical techniques: Nuclear Magnetic Resonance (NMR), Advanced Polymer Chromatography (APC), and Thermogravimetric Analysis (TGA) to quantify polyvinyl alcohol (PVA) and polyethylene glycol (PEG) content in hybrid freeze-thaw derived PVA/PEG/PVP hydrogels. Hydrogels were synthesized using an adapted freeze-thaw method across a wide range of PVA:PEG ratios, with PVP included at 1 wt% to assess potential intermolecular effects. NMR and APC reliably quantified polymer content with low average errors of 2.77% and 2.01%, respectively, and were unaffected by phase separation or hydrogen bonding within the composite matrix. TGA enabled accurate quantification at PVA contents ≤ 62.5%, where PEG and PVA maintained distinct thermal decomposition behaviors. At higher PVA concentrations, increased hydrogen bonding and crystalline restructuring, confirmed by FTIR through shifts near 1140 cm-1 and significant changes in the -OH region, altered thermal profiles and reduced TGA accuracy. Together, these findings establish APC as a high-throughput alternative to NMR for multi-component polymer analysis and outline critical thermal and structural thresholds that influence TGA-based quantification. This work provides a framework for characterizing complex polymer networks in biomedical hydrogel systems.

BACKGROUND CONTEXT Intervertebral disc (IVD) degeneration (IVDD) is implicated as a cause of low back pain. The earliest degenerative changes typically occur in the central nucleus pulposus (NP), where progressive loss of proteoglycans and associated hydration compromise tissue mechanical function. PURPOSE We developed a noncrosslinked injectable hydrogel for NP replacement and augmentation together with its percutaneous delivery method and instrument assembly. We then evaluated the short- and long-term performance of this hydrogel in a goat model of moderate IVDD. Methods Six goats underwent two percutaneous procedures: one to induce degeneration in 3 lumbar IVDs via injection of 1U C-ABC and, 2 weeks later, a second procedure for the delivery of hydrogel at 2 levels with the third remaining untreated. Animals were euthanized at 6 weeks (n=2) and 12 weeks (n=1); three animals are currently enrolled for long-term survival. Disc height index (DHI) was measured from monthly lateral radiographs in the standing animal. Postmortem, motion segments were imaged using microcomputed tomography (µCT) to assess hydrogel distribution and bone volume fraction values (BV/TV) for cranial and caudal endplates. Volumetric analysis and compression testing were performed on explanted gels. Samples were dried to determine polymer and water content. Explant characteristics were compared to nonimplanted gels. Histology was performed to assess glycosaminoglycans and collagen content, cellularity, and disc morphology. Significant changes in DHI were established using Wilcoxon matched-pairs signed ranks tests and differences in histological grades were established using Kruskal-Wallis test with post-hoc Dunn's tests (p<0.05). Results Animals recovered uneventfully from surgical procedures. Extrusion of hydrogel into the spinal canal during delivery occurred in two animals without major clinical repercussions. At 2 weeks after C-ABC injection, DHI was ∼80% of pre-C-ABC levels. For IVDs treated with hydrogel, DHI improved while untreated IVDs continued to degenerate. The hydrogel presents radiographically unremarkable for up to 2 years post nucleoplasty. µCT imaging demonstrated that the majority of hydrogel was localized to the central NP. BV/TV ratio of treated levels at 6-week and 12-week endpoint were similar to controls. Explant analyses showed higher elastic moduli and polymer content compared to nonimplanted gels. Treated IVDs exhibited an overall improved histological grade compared to positive controls. Conclusions The results of this work illustrate the practical utility of an injectable hydrogel being effective in normalizing the mechanical function of the degenerating IVD in a clinically relevant animal model. The implant showed successful retention without extrusion following delivery. A critical benchmark for the success of any injectable implant to treat IVDD is the normalization of mechanical properties. We demonstrate through long-term in vivo follow up studies that hydrogel injected into degenerating goat discs can preserve the spine motion segment. There is a critical need for new therapies for patients with symptomatic disc degeneration that preserve joint mobility. A minimally invasive injectable therapy mitigates anulus fibrosus trauma during nucleoplasty and may restore the biomechanics of the motion segment. Moreover, successful biomechanical restoration of the affected motion segment may slow or prevent further IVDD. Motion preservation therapies may also help mitigate adjacent level IVDD in these patient cohorts. FDA DEVICE/DRUG STATUS This abstract does not discuss or include any applicable devices or drugs. Intervertebral disc (IVD) degeneration (IVDD) is implicated as a cause of low back pain. The earliest degenerative changes typically occur in the central nucleus pulposus (NP), where progressive loss of proteoglycans and associated hydration compromise tissue mechanical function. We developed a noncrosslinked injectable hydrogel for NP replacement and augmentation together with its percutaneous delivery method and instrument assembly. We then evaluated the short- and long-term performance of this hydrogel in a goat model of moderate IVDD. Six goats underwent two percutaneous procedures: one to induce degeneration in 3 lumbar IVDs via injection of 1U C-ABC and, 2 weeks later, a second procedure for the delivery of hydrogel at 2 levels with the third remaining untreated. Animals were euthanized at 6 weeks (n=2) and 12 weeks (n=1); three animals are currently enrolled for long-term survival. Disc height index (DHI) was measured from monthly lateral radiographs in the standing animal. Postmortem, motion segments were imaged using microcomputed tomography (µCT) to assess hydrogel distribution and bone volume fraction values (BV/TV) for cranial and caudal endplates. Volumetric analysis and compression testing were performed on explanted gels. Samples were dried to determine polymer and water content. Explant characteristics were compared to nonimplanted gels. Histology was performed to assess glycosaminoglycans and collagen content, cellularity, and disc morphology. Significant changes in DHI were established using Wilcoxon matched-pairs signed ranks tests and differences in histological grades were established using Kruskal-Wallis test with post-hoc Dunn's tests (p<0.05). Animals recovered uneventfully from surgical procedures. Extrusion of hydrogel into the spinal canal during delivery occurred in two animals without major clinical repercussions. At 2 weeks after C-ABC injection, DHI was ∼80% of pre-C-ABC levels. For IVDs treated with hydrogel, DHI improved while untreated IVDs continued to degenerate. The hydrogel presents radiographically unremarkable for up to 2 years post nucleoplasty. µCT imaging demonstrated that the majority of hydrogel was localized to the central NP. BV/TV ratio of treated levels at 6-week and 12-week endpoint were similar to controls. Explant analyses showed higher elastic moduli and polymer content compared to nonimplanted gels. Treated IVDs exhibited an overall improved histological grade compared to positive controls. The results of this work illustrate the practical utility of an injectable hydrogel being effective in normalizing the mechanical function of the degenerating IVD in a clinically relevant animal model. The implant showed successful retention without extrusion following delivery. A critical benchmark for the success of any injectable implant to treat IVDD is the normalization of mechanical properties. We demonstrate through long-term in vivo follow up studies that hydrogel injected into degenerating goat discs can preserve the spine motion segment. There is a critical need for new therapies for patients with symptomatic disc degeneration that preserve joint mobility. A minimally invasive injectable therapy mitigates anulus fibrosus trauma during nucleoplasty and may restore the biomechanics of the motion segment. Moreover, successful biomechanical restoration of the affected motion segment may slow or prevent further IVDD. Motion preservation therapies may also help mitigate adjacent level IVDD in these patient cohorts.

ABSTRACTCrystallite regions within a hydrogel network contribute to its mechanical strength, which is crucial for use in load‐bearing applications. However, high amounts of crystallinity can negatively impact the ability for hydrogels to be injected, an attractive property that could replace the need for highly invasive surgical procedures. The reversibility of crystallinity and its lasting impact on the injectability of poly(vinyl alcohol) and poly(ethylene glycol) hydrogels was evaluated in this paper. The relative percent crystallinity in hydrogels was evaluated after storage and autoclaving in syringes in weekly intervals using X‐ray diffraction. Results indicate that crystallinity increased over time and significantly decreased after autoclaving for all samples, where postautoclaved samples contained comparable crystallinity percentages to freshly made gels (p > 0.05). Injectability was evaluated using calculated viscosity. Aged samples were able to be injected after autoclaving, yet there was no determination established between viscosity and storage times based on the data. © 2019 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2020, 137, 48706.

Oral administration of monoclonal antibodies (mAbs) may enable the localized treatment of infections or other conditions in the gastrointestinal tract (GI) as well as systemic diseases. As with the development of oral protein biotherapeutics, one of the most challenging tasks in antibody therapies is the loss of biological activity due to physical and chemical instabilities. New families of complexation hydrogels with pH-responsive properties have demonstrated to be excellent transmucosal delivery vehicles. This contribution focuses on the design and evaluation of hydrogel carriers that will minimize the degradation and maximize the in vivo activity of anti-TNF-α, a mAb used for the treatment of inflammatory bowel disease (IBD) in the GI tract and systemically for the treatment of rheumatoid arthritis. P(MAA-g-EG) and P(MAA-co-NVP) hydrogels systems were optimized to achieve adequate swelling behavior, which translated into improved protein loading and release at neutral pH simulating the small intestine conditions. Additionally, these hydrogel systems preserve antibody bioactivity upon release resulting in the systemic circulation of an antibody capable of effectively performing its biological function. The compatibility if these hydrogels for mAb bioactivity preservation and release makes them candidates for use as oral delivery systems for therapeutic antibodies.

Meniscal tears are the most common orthopedic injuries to the human body, yet the current treatment of choice is a partial meniscectomy, which is known to lead to joint degeneration and osteoarthritis. As a result, there is a significant clinical need to develop materials capable of restoring function to the meniscus following an injury. Fiber-reinforced hydrogel composites are particularly suited for replicating the mechanical function of native fibrous tissues due to their ability to mimic the native anisotropic property distribution present. A critical issue with these materials, however, is the potential for the fiber-matrix interfacial properties to severely limit composite performance. In this work, the interfacial properties of an ultra-high-molecular-weight polyethylene (UHMWPE) fiber-reinforced poly(vinyl alcohol) (PVA) hydrogel are studied. A novel chemical grafting technique, confirmed using X-ray photoelectron spectroscopy, is used to improve UHMWPE-PVA interfacial adhesion. Interfacial shear strength is quantified using fiber pull-out tests. Results indicate significantly improved fiber-hydrogel interfacial adhesion after chemical grafting, where chemically grafted samples have an interfacial shear strength of 256.4±64.3kPa compared to 11.5±2.9kPa for untreated samples. Additionally, scanning electron microscopy of fiber surfaces after fiber pull-out reveal cohesive failure within the hydrogel matrix for treated fiber samples, indicating that the UHMWPE-PVA interface has been successfully optimized. Lastly, inter-fiber spacing is observed to have a significant effect on interfacial adhesion. Fibers spaced further apart have significantly higher interfacial shear strengths, which is critical to consider when optimizing composite design. The results in this study are applicable in developing similar chemical grafting techniques and optimizing fiber-matrix interfacial properties for other hydrogel-based composite systems.

OBJECT In a follow-up study to their prior work, the authors evaluated a novel delivery system for a previously established treatment for spinal cord injury (SCI), based on a poly(N-isopropylacrylamide) (PNIPAAm), lightly cross-linked with a polyethylene glycol (PEG) injectable scaffold. The primary aim of this work was to assess the recovery of both spontaneous and skilled forelimb function following a cervical dorsolateral funiculotomy in the rat. This injury ablates the rubrospinal tract (RST) but spares the dorsal and ventral corticospinal tract and can severely impair reaching and grasping abilities. METHODS Animals received an implant of either PNIPAAm-g-PEG or PNIPAAm-g-PEG + brain-derived neurotrophic factor (BDNF). The single-pellet reach-to-grasp task and the staircase-reaching task were used to assess skilled motor function associated with reaching and grasping abilities, and the cylinder task was used to assess spontaneous motor function, both before and after injury. RESULTS Because BDNF can stimulate regenerating RST axons, the authors showed that animals receiving an implant of PNIPAAm-g-PEG with codissolved BDNF had an increased recovery rate of fine motor function when compared with a control group (PNIPAAm-g-PEG only) on both a staircase-reaching task at 4 and 8 weeks post-SCI and on a single-pellet reach-to-grasp task at 5 weeks post-SCI. In addition, spontaneous motor function, as measured in the cylinder test, recovered to preinjury values in animals receiving PNIPAAm-g-PEG + BDNF. Fluorescence immunochemistry indicated the presence of both regenerating axons and BDA-labeled fibers growing up to or within the host-graft interface in animals receiving PNIPAAm-g-PEG + BDNF. CONCLUSIONS Based on their results, the authors suggest that BDNF delivered by the scaffold promoted the growth of RST axons into the lesion, which may have contributed in part to the increased recovery rate.

The osmotic pressure of the medium used for in vitro swelling evaluation has been shown to have a significant effect on the swelling behavior of a material. In this study, the effect of osmotic pressure during swelling on poly(vinyl alcohol) hydrogel material properties was evaluated in vitro. Osmotic pressure solutions are necessary in order to mimic the swelling pressure observed in vivo for soft tissues present in load-bearing joints. Hydrogels were characterized after swelling by mechanical testing, X-ray diffraction and optical microscopy in the hydrated state. Results indicated that hydrogel mechanical properties remained tailorable with respect to initial processing parameters; however, significant aging occurred in osmotic solution. This was observed when evaluating the mechanical properties of the hydrogels, which, before swelling, ranged from 0.04 to 0.78 MPa but, after swelling in vitro using osmotic pressure solution, ranged from 0.32 to 0.93 MPa. Significant aging was also noted when evaluating crystallinity, with the relative crystallinity ranging between 0.4 and 5.0% before swelling and between 6.5 nd 8.0% after swelling. When compared to swelling in a non-osmotic pressure solution or in phosphate-buffered saline solution, the mechanical properties were more dependent upon the final swelling content. Furthermore, increases in crystallinity were not as significant after swelling. These results highlight the importance of choosing the appropriate swelling medium for in vitro characterization based on the desired application.

Receptor-mediated endocytosis (RME) has been extensively studied as a method for augmenting the transport of therapeutic devices across monolayers. These devices range from simple ligand-therapeutic conjugates to complex ligand-nanocarrier systems. However, characterizing the uptake of these carriers typically relies on their comparisons to the native therapeutic, which provides no understanding of the ligand or cellular performance. To better understand the potential of the RME pathway, a model for monolayer transport was designed based on the endocytosis cycle of transferrin, a ligand often used in RME drug-delivery devices. This model established the correlation between apical receptor concentration and transport capability. Experimental studies confirmed this relationship, demonstrating an upper transport limit independent of the applied dose. This contrasts with the dose-proportional pathways that native therapeutics rely on for transport. Thus, the direct comparison of these two transport mechanisms can produce misleading results that change with arbitrarily chosen doses. Furthermore, transport potential was hindered by repeated use of the RME cycle. Future studies should base the success of this technology not on the performance of the therapeutic itself, but on the capabilities of the cell. Using receptor-binding studies, we were able to demonstrate how these capabilities can be predicted and potentially adopted for high-throughput screening methods.

Fiber-reinforced hydrogel composites offer a unique advantage for soft fibrous tissue applications due to their ability to reproduce the anisotropic property distribution present within these tissues. As for many composite materials, the fiber–matrix interface of hydrogel composites can severely limit composite performance. In particular, the fiber–hydrogel interface for poly(vinyl alcohol) (PVA) hydrogel composites reinforced with ultra high molecular weight polyethylene (UHMWPE) fibers was extremely poor due to the innate hydrophobicity of UHMWPE. To improve interfacial adhesion, a novel biocompatible PVA grafting technique utilizing oxygen plasma treatments to activate fiber surfaces was developed to form a direct covalent linkage at the fiber–matrix interface. Grafting was confirmed via scanning electron microscopy (SEM) and X-ray photoelectron spectroscopy (XPS). Chemical grafting was tailored as a function of the number of sites available for covalent bonding and the percentage of sites reacted. Interfacial adhesion was determined for a range of grafting conditions using a single fiber pull-out test. PVA grafting resulted in significant improvements to interfacial shear strength from 11 kPa without any treatment to above 220 kPa following grafting. In some cases after grafting, failure was observed in tension within the fibers indicating the UHMWPE–PVA interface was successfully optimized. The results of this study can be used as a model for developing similar grafting techniques for other hydrogel-based composite systems.

Receptor-mediated pathways offer the ability to transport therapeutics across cellular monolayers that would otherwise block them. However, current characterization methods have been found to be inadequate in their ability to adequately describe the full benefit of these drug delivery systems. In this report, we describe a novel way to define their transport using receptor-ligand kinetic models.

The biocompatibility, processing ease, and mechanical properties of freeze-thawed poly(vinyl alcohol) (PVA)-based hydrogels have encouraged significant research toward developing this material for various biomedical applications. Crystallization that occurs during the freeze-thawing process is cited in the literature as the primary mechanism responsible for the resultant mechanical properties. Further analysis, however, shows the presence of two unique mechanisms that contribute to PVA's mechanical properties. During freeze-thaw cycling water freezes causing phase separation, which facilitates crystallization. The impact of phase separation during freeze-thaw cycling was investigated by comparing freeze-thawed and aged PVA hydrogels. Aged hydrogels were not prepared by freezing and, therefore, did not exhibit significant phase separation. The amount of phase separation was discerned using optical microscopy in the hydrated state. Crystallinity and mechanical properties were also evaluated as a function of the number of cycles (for freeze-thawed gels) and aging time (for aged gels). For freeze-thawed hydrogels, crystallinity deviated significantly from the trend observed in compressive modulus, indicating that crystallinity was not the only factor determining the hydrogel's mechanical properties. Phase separation was found to occur during freeze-thaw cycling independently of crystallization, especially at later freeze-thaw cycles (after the third). The trends observed for both crystallinity and modulus for aged hydrogels, however, were in better agreement with each other. Further evaluation of the mechanical properties of aged and freeze-thawed hydrogels with similar crystallinities indicated that freeze-thawed hydrogels have significantly higher modulus values (p < 0.05). As a result, phase separation, independently of crystallization, was determined to have a significant effect on gelation during freeze-thaw cycling. In particular, PVA-rich regions that are formed during phase separation, without additional cross-linking, are believed to have a significant effect on the resultant mechanical properties.

PLGA particles have been extensively used as a sustained drug-delivery system, but there are multiple drawbacks when delivering proteins. The focus of this work is to address the most significant disadvantages to the W/O/W double emulsion procedure and demonstrate that simple changes to this procedure can have significant changes to particle size and dispersity and considerable improvements to protein loading, activity and sustained active protein release. A systematic approach was taken to analyze the effects of the following variables: solvent miscibility (dichloromethane (DCM), ethyl acetate, acetone), homogenization speed (10 000-25 000 rpm), PLGA concentration (10-30 mg/ml) and additives in both the organic (sucrose acetate isobutyrate (SAIB)) and aqueous (bovine serum albumin (BSA)) phases. Increasing solvent miscibility decreased particle size, dispersity and protein denaturation, while maintaining adequate protein loading. Increasing solvent miscibility also lowered the impact of homogenization on particle size and dispersity and protein activity. Changes to PLGA concentration demonstrated a minimum impact on particle size and dispersity, but showed an inverse relationship between protein encapsulation efficiency and particle protein weight percent. Most particles tested provided sustained release of active protein over 60 days. Increasing solvent miscibility resulted in increases in the percent of active protein released. When subjected to synthesis conditions with DCM as the solvent, BSA as a stabilizer resulted in the maximum stabilization of protein at a concentration of 100 mg/ml. At this concentration, BSA allowed for increases in the total amount of active protein delivered for all three solvents. The benefit of SAIB was primarily increased protein loading.

Object The authors investigated the feasibility of using injectable hydrogels, based on poly(N-isopropylacrylamide) (PNIPAAm), lightly cross-linked with polyethylene glycol (PEG) or methylcellulose (MC), to serve as injectable scaffolds for local delivery of neurotrophins and cellular transplants into the injured spinal cord. The primary aims of this work were to assess the biocompatibility of the scaffolds by evaluating graft cell survival and the host tissue immune response. The scaffolds were also evaluated for their ability to promote axonal growth through the action of released brain-derived neurotrophic factor (BDNF). Methods The in vivo performance of PNIPAAm-g-PEG and PNIPAAm-g-MC was evaluated using a rodent model of spinal cord injury (SCI). The hydrogels were injected as viscous liquids into the injury site and formed space-filling hydrogels. The host immune response and biocompatibility of the scaffolds were evaluated at 2 weeks by histological and fluorescent immunohistochemical analysis. Commercially available matrices were used as a control and examined for comparison. Results Experiments showed that the scaffolds did not contribute to an injury-related inflammatory response. PNIPAAm-g-PEG was also shown to be an effective vehicle for delivery of cellular transplants and supported graft survival. Additionally, PNIPAAm-g-PEG and PNIPAAm-g-MC are permissive to axonal growth and can serve as injectable scaffolds for local delivery of BDNF. Conclusions Based on the results, the authors suggest that these copolymers are feasible injectable scaffolds for cell grafting into the injured spinal cord and for delivery of therapeutic factors.

Graft co-polymer networks have shown promise as devices for oral delivery of proteins. By increasing adhesion of these networks at the delivery site of the upper small intestine by utilizing small covalent chemical linkages caused by the addition of an aldehyde functional group we can make them more viable. These aldehydes bind covalently by way of a condensation reaction with the amines of the amino acids found in the glycoprotein network of the mucus layer of the small intestine to form imines. To investigate the effectiveness of this linkage the co-polymers are prepared in three different percentages of poly(ethylene glycol) (PEG) and aldehyde-modified PEG, and characterized through swelling, release and adhesion testing. The percentages of aldehyde-modified PEG used are 0.06, 0.6 and 3.3%. The swelling results indicate that the formulations with the aldehyde-modified PEG maintained the same pH sensitivity and transition around a pH of 5.8 as those formulations without the aldehyde moiety. Release results indicate that the release of insulin of the most promising 3.3% aldehyde formulation was successful with a release of about 80% after 3 h, which compares favorably with the similar release of the controls done in previous work. Adhesion testing was carried out through the use of a mechanical testing apparatus. Data have been gathered and plotted to give a detachment force (N) versus displacement (m) curve, of which the work of adhesion (mu J) was found by taking the area underneath the curve. Adhesion results indicate an increase to the already present adhesion of the co-polymers due to increased percentages of the aldehyde-modified PEG tethers where the 3.3% formulation showed an increase of 10-30 mu J over both control formulations. (C) Koninklijke Brill NV, Leiden, 2011

An osmotic solution was used to evaluate poly(vinyl alcohol) (PVA) hydrogels as potential non-degradable soft tissue replacements in vitro. Osmotic solutions are necessary in order to mimic the swelling pressure observed in vivo for soft tissues present in load-bearing joints. In vitro studies indicated that PVA hydrogels experience minimal changes in swelling with a polymer concentration of 20 wt.% PVA in phosphate-buffered saline solution (0atm) and between 30 and 35 wt.% PVA in osmotic solution with a pressure of 0.95atm. Swelling in osmotic pressure solutions caused decreases in the equilibrium hydrogel hydration. An investigation of hydrogel compressive modulus indicated that PVA hydrogels are within the range of articular cartilage, meniscal tissue, and the temporomandibular joint disk. Furthermore, it is possible to tailor PVA hydrogels through careful modification of the polymer concentration and freeze–thaw cycles during hydrogel preparation to match both a desired swelling ratio and a desired compressive modulus or porosity. The microstructure of the PVA hydrogels was also evaluated as a function of freeze–thaw cycles and polymer concentration to give an insight into the processes occurring during synthesis and swelling in osmotic solutions.

Because of similar mechanical properties to native cartilage, synthetic hydrogels based on poly(vinyl alcohol) (PVA) have been proposed for replacement of damaged articular cartilage, but they suffer from a complete lack of integration with surrounding tissue. In this study, insulin-like growth factor-1 (IGF-1), an important growth factor in cartilage regeneration, was encapsulated in degradable poly(lactic-co-glycolic acid) (PLGA) microparticles embedded in the PVA hydrogels in a single step based on a double emulsion. The release of IGF-1 from these hydrogels was sustained over 6weeks in vitro. Poly(glycolic acid) (PGA) fiber scaffolds were wrapped around the hydrogels, seeded with chondrocytes, and implanted subcutaneously in athymic mice. The release of IGF-1 enhanced cartilage formation in the layers surrounding the hydrogels, in terms of the content of extracellular matrix components and mechanical properties, and increased integration between the cartilage layers and the hydrogels, according to gross observation of the cross-sections and histology. The compressive modulus of the cartilage–hydrogel constructs without IGF-1 was 0.07±0.02MPa, compared to 0.17–0.2MPa for hydrogels that contained IGF-1. The biochemical and mechanical markers of cartilage formation were not different between the low and high concentrations of IGF-1, despite an order of magnitude difference in concentration. This study shows that the sustained release of IGF-1 can enhance tissue formation and points to a possible strategy for effecting integration with surrounding tissue.