Hyaluronan-based Hydrogel Research Articles

Hyaluronan hydrogels with a low degree of modification as scaffolds for cartilage engineering

In the field of cartilage engineering, continuing efforts have focused on fabricating scaffolds that favor maintenance of the chondrocytic phenotype and matrix formation, in addition to providing a permeable, hydrated, microporous structure and mechanical support. The potential of hyaluronan-based hydrogels has been well established, but the ideal matrix remains to be developed.This study describes the development of hyaluronan sponges-based scaffolds obtained by lysine methyl-ester crosslinking. The reaction conditions are optimized with minimal chemical modifications to obtain materials that closely resemble elements in physiological cellular environments. Three hydrogels with different amounts of crosslinkers were produced that show morphological, water-uptake, mechanical, and stability properties comparable or superior to those of currently available hyaluronan-scaffolds, but with significantly fewer hyaluronan modifications. Primary human chondrocytes cultured with the most promising hydrogel were viable and maintained lineage identity for 3 weeks. They also secreted cartilage-specific matrix proteins. These scaffolds represent promising candidates for cartilage engineering.

Macrophage Response to Allogeneic Adipose Tissue-Derived Stromal Cells in Hyaluronan-Based Hydrogel in a Porcine Vocal Fold Injury Model.

Adipose tissue-derived stromal cells (ASC) embedded in hyaluronan scaffold is a beneficial prophylactic treatment for vocal fold (VF) surgical scar. Here, we investigated the macrophage inflammatory response to allogeneic ASC-constructs and identified changes in lamina propria extracellular matrix. Pig ASC were characterized and transfected with GFP+ lentivirus. Thirty-three pigs underwent VF biopsies, and after 3 days, gel alone, gel+pASC, placebo, or pASC alone was injected into wound bed. Animals were sacrificed 3, 7, or 26 days post-injection. Flow cytometry; qPCR for NF-α, TGFβ, IL-10, IL-4, IFNγ, IL-12, FGF2, Col1A1, and HGF; and immunohistochemistry for collagen, elastin, HA, and fibronectin were performed to characterize macrophage phenotype, quantify cytokine transcription, analyze extracellular matrix remodeling, and track GFP+ cells. No significant differences were found in SWC3+/SWC9+ phenotype or mRNA expression between cells+gel, gel, or placebo. The ASC alone exhibited significantly greater collagen, gel alone resulted in significantly less hyaluronan, and gel+pASC significantly more fibronectin (all P < .05). The pASC-GFP+ were detected 26 days post-injection. The ASC-constructs were biocompatible; they did not influence the macrophage inflammatory response or provoke increases in collagen expression. Long-term engraftment was confirmed.

Charged Triazole Cross-Linkers for Hyaluronan-Based Hybrid Hydrogels.

Polyelectrolyte hydrogels play an important role in tissue engineering and can be produced from natural polymers, such as the glycosaminoglycan hyaluronan. In order to control charge density and mechanical properties of hyaluronan-based hydrogels, we developed cross-linkers with a neutral or positively charged triazole core with different lengths of spacer arms and two terminal maleimide groups. These cross-linkers react with thiolated hyaluronan in a fast, stoichiometric thio-Michael addition. Introducing a positive charge on the core of the cross-linker enabled us to compare hydrogels with the same interconnectivity, but a different charge density. Positively charged cross-linkers form stiffer hydrogels relatively independent of the size of the cross-linker, whereas neutral cross-linkers only form stable hydrogels at small spacer lengths. These novel cross-linkers provide a platform to tune the hydrogel network charge and thus the mechanical properties of the network. In addition, they might offer a wide range of applications especially in bioprinting for precise design of hydrogels.

Abstract B30: Ex vivo culture of breast cancer patient-derived xenografts in modified 3-D hyaluronan hydrogels

Abstract The high attrition rate of potential anti-cancer drugs entering clinical trials indicates the need for more predictive pre-clinical model systems. Standard compound screening is high-throughput and relatively inexpensive, but conducted with non-representative cells in a non-physiological environment. Three-dimensional (3D) culture systems provide cells a more physiological microenvironment including relevant extracellular matrix (ECM) cues and cell-cell interactions. Patient-derived xenograft (PDX) culture preserves tumor heterogeneity while mitigating harsh selective pressures induced by traditional 2D culture methods. However, in vivo mouse models are slow and expensive, often with low “take” rates that limit the numbers of drugs and drug combinations that can be tested. Within the present study, we established the direct culture of breast cancer PDX cells in a hyaluronan-based hydrogel matrix that is amenable to automated dispensing. Washington University Human in Mouse (WHIM) breast cancer PDX tumors were dissociated and PDX cell were encapsulated in 3D hydrogels for in vitro culture. In vitro cultured PDX cells showed high viability over 7 days, as assessed by standard live/dead assay. Cell morphology and marker retention were also examined using immunofluorescence staining for markers including ER, EpCAM, and vimentin, and were found to be subtype-consistent. Ongoing studies seek to expand the PDX tumors in hydrogel matrices such that they may be useful for a variety of applications including drug screening, proteome and kinome activation analysis, and other applications that will enable the development of personalized therapies suited to individual breast cancer patients presenting with various disease subtypes. Citation Format: Lindsey K. Sablatura, MeghaShyam Kavuri, Priya Richards, Daniel A. Harrington, Matthew J. Ellis, Mary C. Farach-Carson. Ex vivo culture of breast cancer patient-derived xenografts in modified 3-D hyaluronan hydrogels. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Breast Cancer Research; Oct 17-20, 2015; Bellevue, WA. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(2_Suppl):Abstract nr B30.

Therapeutic hyaluronan-based hydrogel enables local drug delivery for recovery after stroke

Event Abstract Back to Event Therapeutic hyaluronan-based hydrogel enables local drug delivery for recovery after stroke Anup Tuladhar1, 2, Cindi M. Morshead1, 2, 3 and Molly S. Shoichet1, 2, 4, 5 1 University of Toronto, Institute of Biomaterials and Biomedical Engineering, Canada 2 University of Toronto, Donnelly Centre for Cellular and Biomolecular Research, Canada 3 University of Toronto, Department of Surgery, Canada 4 University of Toronto, Department of Chemical Engineering and Applied Chemistry, Canada 5 University of Toronto, Department of Chemistry, Canada Introduction: Local drug delivery to the brain circumvents the blood-brain barrier preventing the use of many drugs to treat brain injury[1]. Unfortunately, the current clinical method causes further tissue damage due to cannula insertion into brain tissue and has an increased infection risk[2]. Our lab has developed a bioactive hydrogel for local drug delivery[3]. The gel, HAMC, is a physical blend of hyaluronan and methylcellulose. HAMC can be implanted onto the brain’s surface without damaging tissue. By mixing drug-loaded polymeric particles into the gel we can locally deliver drugs for several weeks[4]. Herein we investigate local delivery of two neuroactive drugs, cyclosporine (CsA) and erythropoietin (EPO), to stimulate motor recovery and tissue regeneration in stroke-injured rats. Materials and Methods: HAMC hydrogel (1.4wt% hyaluronan, 3wt% methylcellulose) was mixed with CsA-loaded poly(lactic-co-glycolic acid) (PLGA) microparticles and injected it onto the ispilateral brain surface of rats with an endothelin-1 stroke. We measured CsA diffusion over time in dorsoventral brain sections using mass spectrometry. Next, we measured the effects of local CsA delivery from HAMC in the stroke-injured brain after 7 days. Tissue sections from untreated, CsA+HAMC treated and HAMC treated rats were stained for NeuN to determine stroke infarct size, Ki67 to determine cell proliferation in the neural stem/progenitor cell (NSPC) niche and DCX to count migratory neuronal progenitors[5]. Results and Discussion: Local delivery with HAMC successfully provided sustained CsA release to the brain for 14 days, with drug accumulation in the subcortical NSPC niche lining the lateral ventricles. Interestingly, the stroke infarct volume was reduced by HAMC alone compared to untreated controls (p<0.05), revealing a protective effect of the hydrogel (Fig.1). This is likely due to the anti-inflammatory effects of hyaluronan. CsA locally released from HAMC significantly increased the amount of proliferating cells in the NSPC niche relative to untreated controls (p<0.01) (Fig.2). While CsA-treated animals had a 1.6-fold increase in the number of neuronal progenitors relative to untreated and HAMC-only treated animals, no statistically significant differences were found due to large variability. Figure 1. Stroke infarct volume is reduced by hyaluronan-based hydrogel (n=4-5, *p<0.05) Figure 2. Local CsA delivery from HAMC increased the amount of Ki67+ proliferating cells in the lateral ventricles of stroke-injured rats (n=5-7, **p<0.01) To promote motor recovery in stroke-injured rats, the co-delivery of CsA with EPO will be studied. CsA has been shown to stimulate endogenous NSPCs and EPO has been shown to promote neurogenesis in a stroke injury model. In ongoing studies, we are studying the drug release and motor function of stroke-injured rats treated with our local delivery strategy. Conclusions: Local drug delivery to the brain can be achieved using HAMC hydrogel. The gel alone was sufficient to significantly reduce injury after stroke. We showed that sustained CsA delivery to subcortical regions of the brain, in particular the NSPC niche, was possible. Drug accumulation in this niche was sufficient to stimulate endogenous NSPCs in the injured brain. Ongoing work combines local CsA and EPO delivery to promote motor recovery and tissue regeneration in stroke-injured animals. Canadian Institute for Health Research; Ontario Graduate Scholarship; CIHR Training Program in Regenerative Medicine; Heart and Stroke Foundation

Bioengineered hyaluronan-based hydrogels for retinal cell delivery

Bioengineered hyaluronan-based hydrogels for retinal cell delivery

Recent Advances in Delivery of Cytokines, Growth Factors, and Molecules of Therapeutic Interest from Hyaluronan-based Hydrogels

Hyaluronic acid (HA) is a long-chain biopolymer that is used for a wide variety of therapeutic purposes because of its high biocompatibility and advantageous physico-chemical properties. Typical uses include surgical preparations, adhesion prevention, viscosupplementation and drug and cytokine delivery. Storage and release of desired factors can be effectively achieved when HA-based carriers are synthesized as hydrogels, although doing so normally requires chemical modification of the native HA structure. Delivery of stored solutes from these gels can be either “simple”, that is from a gel not including separate components intended to control release, or “regulated” when specific components are included for that purpose. A diverse assortment of modified forms of HA has been developed and used in therapeutic, clinical, veterinary and laboratory research environments, and the number of such applications is likely to grow in future years. In this article, we review recent developments in this field. Keywords: Biomaterials, connective tissue, cytokines, growth factors, hyaluronan, hydrogels.

Safety and performance of Hydros and Hydros-TA for knee osteoarthritis: a prospective, multicenter, randomized, double-blind feasibility trial

BackgroundStudies have evaluated the concomitant use of hyaluronan (HA) with steroids, anti-inflammatory drugs and analgesic agents in an attempt to magnify the extent and duration of pain relief due to knee osteoarthritis. To date there has not been an intra-articular combination therapy available for relief of knee osteoarthritis symptoms – one that combines the fast acting onset of symptom relief provided by a corticosteroid with the long-lasting symptom relief provided by HA in a single injection. The objective of this study was to evaluate the safety and preliminary performance of two new HA formulations, Hydros (hyaluronan-based hydrogel suspended in hyaluronan solution) and Hydros-TA (HA plus 10 mg of triamcinolone acetonide [TA]) in subjects with knee osteoarthritis.MethodsWe conducted a Phase 2 prospective, multicenter, randomized, double-blind feasibility trial. Participants (n = 98; mean age 60 years) with knee osteoarthritis (Kellgren-Lawrence grade 2 or 3) were randomized to three treatment groups: Hydros, Hydros-TA, and Synvisc-One® (hylan G-F 20). Participants received one 6 ml intra-articular injection in the treatment knee and were evaluated at 2, 6, 13, and 26 weeks post-treatment. Safety was assessed from adverse events at all study visits. The primary efficacy outcome was the change from baseline on the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) A (Pain) score for the treatment knee.ResultsAdverse events were similar across treatment groups with the most common being arthralgia, joint swelling, back pain, and joint stiffness. Arthralgia was reported 5 times with Synvisc-One, 4 with Hydros, and 1 with Hydros-TA. Each group demonstrated a reduction in the WOMAC A (Pain) score over 26 weeks: [least-square mean (standard error)] 30.5 (5.1) mm for Hydros; 34.4 (4.7) mm for Hydros-TA; 28.0 (5.4) mm for Synvisc-One and an observed improvement of 2.5 mm (p = 0.64) and 6.4 mm (p = 0.24) over Synvisc-One for Hydros and Hydros-TA, respectively.ConclusionsA single injection of Hydros or Hydros-TA was well-tolerated and relieved pain associated with knee osteoarthritis over 26 weeks. Data indicate that Hydros-TA had a more rapid pain relief compared to Hydros alone. A Phase 3 trial is underway to confirm these preliminary results.Trial registration numberNCT01134406.

New Formulations of Polysaccharide-Based Hydrogels for Drug Release and Tissue Engineering.

Polysaccharide-based hydrogels are very promising materials for a wide range of medical applications, ranging from tissue engineering to controlled drug delivery for local therapy. The most interesting property of this class of materials is the ability to be injected without any alteration of their chemical, mechanical and biological properties, by taking advantage of their thixotropic behavior. It is possible to modulate the rheological and chemical-physical properties of polysaccharide hydrogels by varying the cross-linking agents and exploiting their thixotropic behavior. We present here an overview of our synthetic strategies and applications of innovative polysaccharide-based hydrogels: hyaluronan-based hydrogel and new derivatives of carboxymethylcellulose have been used as matrices in the field of tissue engineering; while guar gum-based hydrogel and hybrid magnetic hydrogels, have been used as promising systems for targeted controlled drug release. Moreover, a new class of materials, interpenetrating hydrogels (IPH), have been obtained by mixing various native thixotropic hydrogels.

Hydrogel-based 3D model of patient-derived prostate xenograft tumors suitable for drug screening.

The lack of effective therapies for bone metastatic prostate cancer (PCa) underscores the need for accurate models of the disease to enable the discovery of new therapeutic targets and to test drug sensitivities of individual tumors. To this end, the patient-derived xenograft (PDX) PCa model using immunocompromised mice was established to model the disease with greater fidelity than is possible with currently employed cell lines grown on tissue culture plastic. However, poorly adherent PDX tumor cells exhibit low viability in standard culture, making it difficult to manipulate these cells for subsequent controlled mechanistic studies. To overcome this challenge, we encapsulated PDX tumor cells within a three-dimensional hyaluronan-based hydrogel and demonstrated that the hydrogel maintains PDX cell viability with continued native androgen receptor expression. Furthermore, a differential sensitivity to docetaxel, a chemotherapeutic drug, was observed as compared to a traditional PCa cell line. These findings underscore the potential impact of this novel 3D PDX PCa model as a diagnostic platform for rapid drug evaluation and ultimately push personalized medicine toward clinical reality.

Pre-incubation of chemically crosslinked hyaluronan-based hydrogels, loaded with BMP-2 and hydroxyapatite, and its effect on ectopic bone formation

The effects of pre-incubation of hyaluronan hydrogels, for different lengths of time after the initiation of chemical crosslinking and prior to injection, were explored both by investigating the in vitro BMP-2 release kinetics from the hydrogel and by studying the ectopic bone formation in rats. From the curing profile, obtained from rheological analysis, appropriate pre-incubation times (1 min, 5 h and 3 days) were selected, to prepare slightly, moderately and fully cured hydrogels. Comparable release profiles were observed for all three test groups in vitro. Furthermore, radiography, pQCT and histology of the explanted grafts showed cancellous bone formation in all groups after 5 weeks in vivo. However, longer pre-incubation times gave rise to an increase in bone volume, but a decrease in bone density. Moreover, the 5 h and the 3 days grafts appeared to be more ordered and resistant to deformation from the surrounding tissue than the 1 min grafts. The observed variations in mechanical and biological properties could potentially be used to adapt the treatment for a specific indication.

Thiolated hyaluronan-based hydrogels crosslinked using oxidized glutathione: An injectable matrix designed for ophthalmic applications

Future ophthalmic therapeutics will require the sustained delivery of bioactive proteins and nucleic acid-based macromolecules and/or provide a suitable microenvironment for the localization and sustenance of reparative progenitor cells after transplantation into or onto the eye. Water-rich hydrogels are ideal vehicles for such cargo, but few have all the qualities desired for novel ophthalmic use, namely in situ gelation speed, cytocompatibility, biocompatibility and capacity to functionalize. We describe here the development of an ophthalmic-compatible crosslinking system using oxidized glutathione (GSSG), a physiologically relevant molecule with a history of safe use in humans. When GSSG is used in conjunction with an existing hyaluronate-based, in situ crosslinkable hydrogel platform, gels form in less than 5min using the thiol–disulfide exchange reaction. This GSSG hydrogel supports the 3-D culture of adipose-derived stem cells in vitro and shows biocompatibility in preliminary intracutaneous and subconjunctival experiments in vivo. In addition, the thiol–disulfide exchange reaction can also be used in conjunction with other thiol-compatible chemistries to covalently link peptides for more complex formulations. These data suggest that this hydrogel could be well suited for local ocular delivery, focusing initially on front of the eye therapies. Subsequent uses of the hydrogel include delivery of back of the eye treatments and eventually into other soft, hyaluronan-rich tissues such as those from the liver and brain.

Hyaluronan-Based Three-Dimensional Microenvironment Potently Induces Cardiovascular Progenitor Cell Populations.

The relationship between stem cell niches in vivo and their surrounding microenvironment is still relatively unknown. Recent advances have indicated that extrinsic factors within the cardiovascular progenitor cell niche influence maintenance of a multipotent state as well as drive cell-fate decisions. We have previously shown the direct effects of extracellular matrix (ECM) proteins and have now investigated the effects of dimension on the induction of a cardiovascular progenitor cell (CPC) population. We have shown here that the three-dimensionality of a hyaluronan-based hydrogel greatly induces a CPC population, as marked by Flk-1. We have compared the effects of a 3D microenvironment to those of conventional 2D cell culture practices and have found that the 3D microenvironment potently induces a progenitor cell state.

Thermoreversible hyaluronan-based hydrogel supports in vitro and ex vivo disc-like differentiation of human mesenchymal stem cells

Background contextThe fate of human mesenchymal stem cells (hMSCs) supplied to the degenerating intervertebral disc (IVD) is still not fully understood and can be negatively affected by low oxygen, pH, and glucose concentration of the IVD environment. The hMSC survival and yield upon injection of compromised IVD could be improved by the use of an appropriate carrier and/or by predifferentiation of hMSCs before injection. PurposeTo optimize hMSC culture conditions in thermoreversible hyaluronan-based hydrogel, hyaluronan-poly(N-isopropylacrylamide) (HA-pNIPAM), to achieve differentiation toward the disc phenotype in vitro, and evaluate whether preconditioning contributes to a better hMSC response ex vivo. Study designIn vitro and ex vivo whole-organ culture of hMSCs. MethodsIn vitro cultures of hMSCs were conducted in HA-pNIPAM and alginate for 1 week under hypoxia in chondropermissive medium alone and with the supplementation of transforming growth factor β1 or growth and differentiation factor 5 (GDF-5). Ex vivo, hMSCs were either suspended in HA-pNIPAM and directly supplied to the IVDs or predifferentiated with GDF-5 for 1 week in HA-pNIPAM and then supplied to the IVDs. Cell viability was evaluated by Live-Dead assay, and DNA, glycosaminoglycan (GAG), and gene expression profiles were used to assess hMSC differentiation toward the disc phenotype. ResultsThe HA-pNIPAM induced hMSC differentiation toward the disc phenotype more effectively than alginate: in vitro, higher GAG/DNA ratio and higher collagen type II, SOX9, cytokeratin-19, cluster of differentiation 24, and forkhead box protein F1 expressions were found for hMSCs cultured in HA-pNIPAM compared with those cultured in alginate, regardless of the addition of growth factors. Ex vivo, direct combination of HA-pNIPAM with the disc environment induced a stronger disc-like differentiation of hMSCs than predifferentiation of hMSCs followed by their delivery to the discs. ConclusionsHyaluronan-based thermoreversible hydrogel supports hMSC differentiation toward the disc phenotype without the need for growth factor supplementation in vitro and ex vivo. Further in vivo studies are required to confirm the suitability of this hydrogel as an effective stem cell carrier for the treatment of IVD degeneration.

In vitro characterization of macrophage interaction with mesenchymal stromal cell‐hyaluronan hydrogel constructs

Macrophages play a critical role in mediating not only normal tissue healing, but also the host reaction against biomaterial scaffolds. There is increasing interest in regenerative medicine to combine mesenchymal stromal/stem cells (MSCs) with biomaterial scaffolds to modulate inflammatory response while restoring tissue architecture. The objective of the current study was to investigate the interaction between MSCs (derived from bone marrow, adipose or vocal fold tissue) encapsulated in hyaluronan-based hydrogel and differentiating macrophages as measured by extracellular matrix (ECM) gene expression and cytokine, chemokine, and growth factor concentrations. Gene expression was analyzed using real-time polymerase chain reaction from MSCs embedded in Carbylan-GSX after 7 days of coculture with or without CD14+ cells. Protein concentrations were measured using a Bio-plex assay from cell culture supernatants on days 3 and 7 for all conditions. Following 7 days, we identified upregulation of collagen-I, collagen-III, procollagen, and matrix metalloproteinase-9 genes compared to control conditions. We demonstrate increased concentrations of immunoregulatory cytokines [interleukin (IL)-1β, tumor necrosis factor-α, macrophage inflammatory protein-1α, IFN-γ, IL-12, and IL-10] and remodeling growth factors (vascular endothelial growth factor, hepatocyte growth factor) in MSC-3D constructs cocultured with macrophages compared to control conditions, with some temporal variation. Our results indicate an alteration of expression of ECM proteins important to tissue regeneration and cytokines critical to the inflammatory cascade when 3D constructs were cultured with differentiating macrophages.

The retention and bioactivity of rhBMP-2 released from a bisphosphonate-linked hyaluronan-based hydrogel

Searchable abstracts of presentations at key conferences on calcified tissues ISSN 2052-1219 (online)

Cellular behavior in micropatterned hydrogels by bioprinting system depended on the cell types and cellular interaction

The fabrication of patterned microstructures within three-dimensional (3D) matrices is a challenging subject in tissue engineering and regenerative medicine. A 3D, free-moving bioprinting system was developed and hydrogels were patterned by varying the process parameters of z-axis moving velocity and ejection velocity. The patterning of hydrogel based microfibers in a 3D matrigel was achieved with dimensions of 4.5mm length and widths from 79 to 200μm. Hyaluronan-based hydrogels mixed with fibroblasts (L929), mouse endothelial cells (MS1), or human mesenchymal stem cells (hMSCs) were patterned using a 3D moving axis bioprinter and cell behavior was monitored in culture for up to 16 days. L929 and MS1 cells and hMSCs in patterned hydrogel revealed cell-cell interactions and a morphological dependency on cell types. HMSCs formed spheres through cell aggregation, while L929 cells increased in cellular mass without cell aggregation and MS1 dispersed into the matrix instead of aggregating. The aggregation of hMSCs was attenuated by treatment with Rho kinase (ROCK) inhibitor and cadherin antibody. This reflected the close relationship between cell aggregation and migration with RhoA and cell-cell adhesion molecules. Angiogenic-specific gene expression profiles showed that expression of CD105 decreased to 22% in the ROCK inhibitor group compared to control group. These results showed that cell-based patterns in a 3D matrix are highly dependent on both cell aggregation and migration over time.

Repair of the injured spinal cord by transplantation of neural stem cells in a hyaluronan-based hydrogel

Traumatic injury to the spinal cord causes cell death, demyelination, axonal degeneration, and cavitation resulting in functional motor and sensory loss. Stem cell therapy is a promising approach for spinal cord injury (SCI); however, this strategy is currently limited by the poor survival and uncontrolled differentiation of transplanted stem cells. In an attempt to achieve greater survival and integration with the host tissue, we examined the survival and efficacy of adult brain-derived neural stem/progenitor cells (NSPCs) injected within a hydrogel blend of hyaluronan and methyl cellulose (HAMC) into a subacute, clinically relevant model of rat SCI. Prior to use, HAMC was covalently modified with recombinant rat platelet-derived growth factor-A (rPDGF-A) to promote oligodendrocytic differentiation. SCI rats transplanted with NSPCs in HAMC-rPDGF-A showed improved behavioral recovery compared to rats transplanted with NSPCs in media. Rats with NSPC/HAMC-rPDGF-A transplants had a significant reduction in cavitation, improved graft survival, increased oligodendrocytic differentiation, and sparing of perilesional host oligodendrocytes and neurons. These data suggest that HAMC-rPDGF-A is a promising vehicle for cell delivery to the injured spinal cord.

Commentary on the Differential Healing Capacity of Calvarial Bone

Commentary on the Differential Healing Capacity of Calvarial Bone

Variation in Calvarial Bone Healing Capacity

Bone morphogenetic protein-2 (BMP-2) together with a suitable carrier is an attractive option that may be used for craniofacial bone reconstruction. In this prospective randomized study, a hyaluronan-based hydrogel with BMP-2 was used to achieve bone healing in standardized critical-size cranial defects in humans after neurosurgery. Twelve patients were randomized into the treatment group (N = 6) or control group (N = 6). In the treatment group, holes made during craniotomy were treated with hydrogel with BMP-2, 250 µg/mL, or hydrogel without BMP-2. In the remaining hole/s in the same patient, Spongostan (Ethicon) alone or Tisseel (Baxter) mixed with autologous bone matrix were used as negative and positive controls, respectively. In the control group, the holes were treated with Spongostan or Tisseel mixed with bone autograft. Bone healing was assessed with CT scans after 3 and 6 months. Bone areas in treated defects were measured and statistical analysis was performed. Independent of location, bone healing in defects treated with Tisseel with autograft, hydrogel alone, or hydrogel with BMP-2 was significantly increased compared to negative control (P < 0.001, P = 0.002, and P = 0.005, respectively). In general, all defects healed significantly better in the frontal bone as compared to parietal-temporal location, except for defects treated with Tisseel and autograft, which healed well independently of location. No local or systemic side effects, including excessive bone overgrowth or inflammatory reaction, were seen in treated patients. Tissue engineering of bone with hyaluronan-based hydrogel shows good healing of cranial defects, comparable with bone autografts. The hydrogel itself may represent a novel alternative to autologous bone transplants in craniofacial bone repair. The study also reveals a general superior healing capacity in the frontal bone as compared to parietal/temporal bones.