Large Cranial Defects Research Articles

444 Quantitative Mapping of Cerebral Blood Flow and Blood-Brain Barrier Water Exchange Rate (Kw) Reveals the Mechanobiological Impact of Cranioplasty: A Magnetic Resonance Imaging Study of Patients With Cranial Defects

INTRODUCTION: Large cranial defects may cause neurological decline due to brain shift, while cranioplasty may improve cognitive function, although the underlying mechanisms remain poorly understood. Blood-brain barrier (BBB) water exchange rate (Kw) is a novel magnetic resonance imaging (MRI) method which provides insights into the processes underlying the effects of cranioplasty. METHODS: Adult patients with cranial defects who were candidates for elective cranioplasty were consented and enrolled. Using a 3T MRI, we conducted baseline imaging on all patients, and repeated the imaging during the early post-cranioplasty period. The Kw and CBF were quantified, and asymmetry was calculated as the difference between the values on the ipsilateral and contralateral hemispheres relative to the cranial defect, divided by the sum of those values. Pairwise comparisons of the changes from baseline to post-cranioplasty period were performed using Wilcoxon signed-rank test. RESULTS: A total of 10 patients were enrolled (mean age: 35.4 ± 9.49, 9/10 men). The global CBF showed significant improvements after cranioplasty. There was a remarkable Kw asymmetry in the caudate area at baseline (low on defect side), which significantly improved post-operatively (median: -0.077 vs. 0.021, p = 0.049), while the changes in CBF in this area were not significant (median: -0.002 vs. 0.014, p = 0.160). Other brain regions yielded no significant changes in Kw asymmetry. CONCLUSIONS: Reduced Kw has been reported in cognitive decline and cerebral small vessel diseases, and may be related to impaired water circulation in the brain. We observed increased global CBF and Kw asymmetry in caudate which may reflect improved brain physiology and water circulation following cranioplasty. Kw is a non-invasive and non-contrast method that offers an opportunity to understand the intricate changes in brain homeostasis following reconstruction surgery.

Polyetheretherketone Implant Cranioplasty for Large Cranial Defects: A Seven-Year Follow-Up.

Goals of a cranioplasty include protection of the brain, restoration of normal appearance, and neurological function improvement. Although choice of materials for cranial remodeling has changed through the years, computer-designed polyetheretherketone (PEEK) implant has gained traction as a preferred material used for cranioplasty. However, long-term outcomes and complications of PEEK implants remain limited. The goal of this study was to report long-term clinical outcomes after PEEK implant cranioplasty. A retrospective chart review was performed on patients undergoing PEEK cranioplasty between January 2007 and February 2023. Preoperative, intraoperative, and postoperative data were collected and analyzed. Twenty-two patients were included in this study. Mean postoperative follow-up time was 83.45 months (range: 35.47-173.87). Before PEEK implant cranioplasty, patients with multiple cranial procedures had undergone a mean of 2.95 procedures. PEEK implant cranioplasty indications were prior implant infection (14) and secondary reconstruction of cranial defect (8). The mean implant size was 180.43cm2 (range: 68.00-333.06). Four patients received a 2-piece implant. Postoperative complications included: perioperative subgaleal self-resolving fluid collection in 1 patient, hematoma in another, and 3 infections resulting in explantations with successful reinsertion in 2 patients. Four of 5 patients with preoperative history of seizures reported improved seizures and all 4 patients with preoperative syndrome of the trephined reported improved symptoms and neurological function. At a mean follow-up of 7 years, most PEEK implants continued to provide protection to the brain and consistent symptom relief in patients suffering from prior postcraniectomy/craniotomy sequelae of seizures and syndrome of the trephined.

Calcium crosslinked macroporous bacterial cellulose scaffolds with enhanced in situ mineralization and osteoinductivity for cranial bone regeneration

The inherent biological inertness and lack of three-dimensional (3D) macroporous structures greatly hinder the use of pristine bacterial cellulose (BC) as a tissue engineering scaffold for bone regeneration. To address this issue, we developed a simple and effective strategy to fabricate a BC-based scaffold with excellent bioactivity and macroporous structure by crosslinking short-cut BC nanofibers using Ca2+. The Ca2+ crosslinked macroporous BC scaffold (MPBC@Ca) presents better structural stability due to the enhanced cellulose hydration. Importantly, the Ca2+ on the surface of BC nanofibers can serve as an active nucleation site to accelerate the deposition of hydroxyapatite (HAp), which is beneficial for the construction of biomimetic bone tissue extracellular matrix (ECM) microenvironment. The HAp-deposited MPBC@Ca scaffolds (HAp-MPBC@Ca) with biomimetic ECM microenvironment have excellent cytocompatibility and enhanced osteogenic differentiation of stem cells in vitro. Furthermore, the results of in vivo tests revealed that the HAp-MPBC@Ca scaffold has favorable osteoinductivity and accelerates cranial bone tissue regeneration. This study proposes a novel strategy to improve the bioactivity of BC and presents the great potential of biomimetic ECM microenvironment BC-based scaffold for repairing large cranial bone defects.

Exploring complications following cranioplasty after decompressive hemicraniectomy: A retrospective bicenter assessment of autologous, PMMA and CAD implants

Cranioplasty (CP) after decompressive hemicraniectomy (DHC) is a common neurosurgical procedure with a high complication rate. The best material for the repair of large cranial defects is unclear. The aim of this study was to evaluate different implant materials regarding surgery related complications after CP. Type of materials include the autologous bone flap (ABF), polymethylmethacrylate (PMMA), calcium phosphate reinforced with titanium mesh (CaP-Ti), polyetheretherketone (PEEK) and hydroxyapatite (HA). A retrospective, descriptive, observational bicenter study was performed, medical data of all patients who underwent CP after DHC between January 1st, 2016 and December 31st, 2022 were analyzed. Follow-up was until December 31st, 2023. 139 consecutive patients with a median age of 54 years who received either PMMA (56/139; 40.3%), PEEK (35/139; 25.2%), CaP-Ti (21/139; 15.1%), ABF (25/139; 18.0%) or HA (2/139; 1.4%) cranial implant after DHC were included in the study. Median time from DHC to CP was 117 days and median follow-up period was 43 months. Surgical site infection was the most frequent surgery-related complication (13.7%; 19/139). PEEK implants were mostly affected (28.6%; 10/35), followed by ABF (20%; 5/25), CaP-Ti implants (9.5%; 2/21) and PMMA implants (1.7%, 1/56). Explantation was necessary for 9 PEEK implants (25.7%; 9/35), 6 ABFs (24.0%; 6/25), 3 CaP-Ti implants (14.3%; 3/21) and 4 PMMA implants (7.1%; 4/56). Besides infection, a postoperative hematoma was the most common cause. Median surgical time was 106 min, neither longer surgical time nor use of anticoagulation were significantly related to higher infection rates (p = 0.547; p = 0.152 respectively). Ventriculoperitoneal shunt implantation prior to CP was noted in 33.8% (47/139) and not significantly associated with surgical related complications. Perioperative lumbar drainage, due to bulging brain, inserted in 38 patients (27.3%; 38/139) before surgery was protective when it comes to explantation of the implant (p = 0.035). Based on our results, CP is still related to a relatively high number of infections and further complications. Implant material seems to have a high effect on postoperative infections, since surgical time, anticoagulation therapy and hydrocephalus did not show a statistically significant effect on postoperative complications in this study. PEEK implants and ABFs seem to possess higher risk of postoperative infection. More biocompatible implants such as CaP-Ti might be beneficial. Further, prospective studies are necessary to answer this question.

Novel Calcium Phosphate Promotes Interbody Bony Fusion in a Porcine Anterior Cervical Discectomy and Fusion Model.

Experimental porcine anterior cervical discectomy and fusion (ACDF) model: a proof-of-concept study. The effect of monetite synthetic bone graft (SBG) containing calcium pyrophosphate and β-tricalcium phosphate on cervical spinal fusion in a noninstrumented two-level large animal model. ACDF is the gold standard surgical technique for the treatment of degenerative cervical spinal diseases. However, pseudarthrosis associated with increased patient morbidity occurs in ∼2.6% of the surgeries. SBG may enhance bony fusion and subsequently decrease the risk of pseudarthrosis. Recent studies on monetite-based SBGs for use in large cranial defects in humans have shown promising bone healing results, necessitating further investigation of their use in cervical spinal fusion. Four adult female Danish Göttingen minipigs received partial cervical anterior discectomy and intervertebral defects at an upper and lower level. One defect was filled with SBG, and the other was left empty. Bony fusion was evaluated using computed tomography (CT) at three-month intervals for 12 months. Fifteen months postsurgery, the animals were euthanized for further ex vivo qualitative histopathologic and micro-CT evaluations. Fusion rates were compared using the Fisher exact test at each time point. Increased interbody bony fusion rates were observed at SBG levels (4/4) compared with control levels (0/4) evaluated by CT at 6 and 9 months postsurgery ( P =0.029). Fusion was observed at all SBG levels 12 months postsurgery and at only one control level. Histopathologic evaluation confirmed high-quality interbody bony fusion at all SBG levels and fusion by spondylosis at one control level. This proof-of-concept study provides preliminary evidence of a novel, calcium pyrophosphate-containing, and β-tricalcium phosphate-containing monetite SBG that promotes bony fusion compared with a negative control in a clinically relevant porcine model of ACDF.

Effectiveness of Additive Manufactured Titanium Implants in the Reconstruction of Large Cranial Defects: Case Series and Review of Literature

Abstract Introduction Replacement of lost soft and hard tissues of the human body has always been a daunting task across all surgical specialties. Reconstruction of a cranial deformity is challenging due to the functional and cosmetic requirements. A major constraint with large cranial bony deformity reconstruction is the nonavailability of graft of a specific shape and size. Materials and Method A total of four cases of large cranial defects which included three cases of unilateral and one case of midline residual deformity were reconstructed at our center using customized titanium implants. These implants were fabricated using additive manufacturing/3D printing technology utilizing computerized tomographic data. Conclusion The additively manufactured titanium implants appear to be a viable option in the reconstruction of large cranial defects.

Cranioplasty Using Three-Dimensional-Printed Polycaprolactone Implant and Free Latissimus Dorsi Musculocutaneous Flap in a Patient with Repeated Wound Problem following Titanium Cranioplasty.

Titanium mesh is an alloplastic material widely used for the reconstruction of moderate-to-large skull defects. Repeated wound problems or infection following these reconstructions inevitably lead to the replacement of the cranioplasty material. Among the various alloplastic materials, polycaprolactone implants are usually used for the coverage of small defects such as burr holes. 1 Herein, we present a case of a large cranial defect successfully reconstructed with three-dimensional-printed polycaprolactone implant and a free latissimus dorsi musculocutaneous flap. Until 1-year follow-up, the patient showed a favorable esthetic outcome with no complications or wound relapse.

Current Concepts in Cranial Reconstruction: Review of Alloplastic Materials.

Background:Cranioplasty for acquired cranial defects can be complex and challenging. Benefits include improved cosmesis, protection of intracranial structures, and restoration of neurocognitive function. These defects can be reconstructed with preserved craniectomy bone flaps, split autografts, or alloplastic materials. When alloplastic cranioplasty is planned, the material should be carefully selected. There is confusion on which material should be used in certain scenarios, particularly in composite defects.Methods:The PubMed database was used to conduct a nonsystematic review of literature related to these materials and the following factors: time required in preoperative planning and fabrication, intraoperative time, feasibility of intraoperative modification, fixation method (direct or indirect), implant cost, overall complication rate, and surgical revision rates.Results:Surgical revision rates for alloplastic materials range from 10% to 23%. Retention of titanium mesh at 4 years is 85% in composite reconstruction with free fasciocutaneous and free myocutaneous flaps. In composite reconstruction with locoregional and free muscle flaps, the retention of titanium mesh at 4 years is 47%. The retention of nontitanium and nonpreserved autogenous reconstruction is 72% and 82%, respectively.Conclusions:Alloplastic materials should be considered for reconstruction of large (>100 cm2) cranial defects, especially for adult patients younger than 30 years, and all patients with bone flaps that are fragmented or have been cryopreserved for an extended period. Preformed titanium mesh provides a favorable primary reconstructive option when a staged reconstruction is not possible or indicated but should be avoided in composite defects reconstructed with locoregional scalp and free muscle flaps.

Biomimetic glycopeptide hydrogel coated PCL/nHA scaffold for enhanced cranial bone regeneration via macrophage M2 polarization-induced osteo-immunomodulation

The reconstruction of large cranial bone defects by bioactive materials without exogenous cells or growth factors remains a substantial clinical challenge. Here, synthetic fibrous glycopeptide hydrogel (GRgel) self-assembled by β-sheet RADA16-grafted glucomannan was designed to mimic the glycoprotein composition and the fibrillar architecture of natural extracellular matrix (ECM), which was non-covalently composited with 3D-printed polycaprolactone/nano hydroxyapatite (PCL/nHA) scaffold for cranial bone regeneration. The glycopeptide hydrogel significantly promoted the proliferation, osteogenic differentiation of bone mesenchymal stem cells (BMSCs), which was further augmented by GRgel-induced macrophage M2-phonotype polarization and the effective M2 macrophage-BMSC crosstalk. The repair of critical-size skull bone defect in rat indicated a superior efficacy of PCL/nHA@GRgel implant on bone regeneration and osseointegration, with an average bone area of 83.3% throughout the defect location at 12 weeks post treatment. Furthermore, the osteo-immunomodulatory GRgel induced a reparative microenvironment similar with that in normal cranium, as characterized by an increased percentage of anti-inflammatory M2 macrophages and osteoblasts, and high-level vascularization. Collectively, the composite scaffold developed here with macrophage polarization-mediated osteo-immunomodulation may represent a promising implant for expediting in situ bone regeneration by providing biochemical and osteoinductive cues at the injured tissue.

Design of 3D Additively Manufactured Hybrid Structures for Cranioplasty.

A wide range of materials has been considered to repair cranial defects. In the field of cranioplasty, poly(methyl methacrylate) (PMMA)-based bone cements and modifications through the inclusion of copper doped tricalcium phosphate (Cu-TCP) particles have been already investigated. On the other hand, aliphatic polyesters such as poly(ε-caprolactone) (PCL) and polylactic acid (PLA) have been frequently investigated to make scaffolds for cranial bone regeneration. Accordingly, the aim of the current research was to design and fabricate customized hybrid devices for the repair of large cranial defects integrating the reverse engineering approach with additive manufacturing, The hybrid device consisted of a 3D additive manufactured polyester porous structures infiltrated with PMMA/Cu-TCP (97.5/2.5 w/w) bone cement. Temperature profiles were first evaluated for 3D hybrid devices (PCL/PMMA, PLA/PMMA, PCL/PMMA/Cu-TCP and PLA/PMMA/Cu-TCP). Peak temperatures recorded for hybrid PCL/PMMA and PCL/PMMA/Cu-TCP were significantly lower than those found for the PLA-based ones. Virtual and physical models of customized devices for large cranial defect were developed to assess the feasibility of the proposed technical solutions. A theoretical analysis was preliminarily performed on the entire head model trying to simulate severe impact conditions for people with the customized hybrid device (PCL/PMMA/Cu-TCP) (i.e., a rigid sphere impacting the implant region of the head). Results from finite element analysis (FEA) provided information on the different components of the model.

Aplasia Cutis Congenita of the Scalp with a Large Cranial Bone Defect：A Case Report

Aplasia Cutis Congenita of the Scalp with a Large Cranial Bone Defect：A Case Report

An innovative approach to salvage a case of extensive iatrogenic growing skull fracture resulting from failed craniosynostosis surgeries

AbstractAimThe challenges encountered in management of severe cranial deformity and a large iatrogenic ‘growing skull fracture’ in a 10‐year‐old child, developing as the result of two previous unsuccessful craniosynostosis surgeries, are described.Material and MethodsA novel surgical approach was employed with two goals in mind. The first was to relieve the raised intracranial pressure resulting from restenosis of the cranial sutures. This was achieved by fronto‐orbital advancement, which also created adequate space to allow for subsequent unhindered growth of the brain. The second goal was to bridge and reconstruct the large cranial defect that had formed as a result of the ‘growing skull fracture’ effect, resulting from the failed earlier surgeries, and to restore the herniating dura and brain parenchyma back within the cranial vault. This was achieved by raising a wide bifrontal calvarial bone flap, followed by its rotation, kerfing and recontouring before replacement, thus reducing the size of the extensive defect. This was accompanied by osteotomizing and repositioning smaller segments of the flap, to bridge the remaining gaps and restore the integrity and contour of the calvarial shield.Results and ConclusionThis innovative and versatile combination surgery, comprising of advancement of the fronto‐orbital bandeau, and anterior crania vault reshaping by osteotomization and reassembly of the bifrontal bone flap, yielded excellent aesthetic and functional outcomes.

In situ bone regeneration of large cranial defects using synthetic ceramic implants with a tailored composition and design.

The repair of large cranial defects with bone is a major clinical challenge that necessitates novel materials and engineering solutions. Three-dimensionally (3D) printed bioceramic (BioCer) implants consisting of additively manufactured titanium frames enveloped with CaP BioCer or titanium control implants with similar designs were implanted in the ovine skull and at s.c. sites and retrieved after 12 and 3 mo, respectively. Samples were collected for morphological, ultrastructural, and compositional analyses using histology, electron microscopy, and Raman spectroscopy. Here, we show that BioCer implants provide osteoinductive and microarchitectural cues that promote in situ bone regeneration at locations distant from existing host bone, whereas bone regeneration with inert titanium implants was confined to ingrowth from the defect boundaries. The BioCer implant promoted bone regeneration at nonosseous sites, and bone bonding to the implant was demonstrated at the ultrastructural level. BioCer transformed to carbonated apatite in vivo, and the regenerated bone displayed a molecular composition indistinguishable from that of native bone. Proof-of-principle that this approach may represent a shift from mere reconstruction to in situ regeneration was provided by a retrieved human specimen, showing that the BioCer was transformed into well-vascularized osteonal bone, with a morphology, ultrastructure, and composition similar to those of native human skull bone.

Clinical evaluation of rapid 3D print-formed implants for surgical reconstruction of large cranial defects.

To clinically evaluate 3D print-formed implant process, using cranioplasty as a proof of concept, to examine its effectiveness and utility as a method of intraoperative implant fabrication. Twelve patients had a 3D print-formed template created for patient-specific implant manufacture. Of these patients, 10 received intraoperatively formed polymethylmethacrylate cranioplasty implants between 2013 and 2019. The 3D print-formed implant templates produced to manufacture these patient-specific implants were generated using patient computed tomography scans and 3D printed using fused deposition modelling technology. Cosmetic and functional results were determined by participating surgeons, in conjunction with a patient questionnaire. The functional results and stability of the implants were deemed to be favourable by participating surgeons. Three of the 10 patients completed a post-cranioplasty survey, all of whom judged their cosmetic results as good or excellent. At time of writing, the rate of surgical revision was zero and without clinically adverse outcomes. 3D print-formed implants are an effective method of patient-specific implant formation.

Inferior Meatus Mucosal Flap for Septal Reconstruction and Resurfacing After Nasoseptal Flap Harvest.

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Quantitative determination of the optimal temporoparietal fascia flap necessary to repair skull-base defects.

The ability to reconstruct large cranial base defects has greatly improved with the development of pedicled vascularized flaps. The temporoparietal fascia flap (TPFF) is a viable alternative to the Hadad-Bassagasteguy nasoseptal flap for large ventral skull-base defects. This study aims to characterize the size of the TPFF necessary for optimal ventral skull-base reconstruction. Eleven formaldehyde-fixed cadaveric heads were used to harvest TPFF of varying heights on each side (total = 22). TPFF was passed through the pterygomaxillary fissure (PMF) to the ventral skull base to assess its coverage. For a subgroup of 12 sides, the TPFF was trimmed to determine the minimum height necessary for coverage. The TPFF height was (mean ± standard deviation [SD]) 14.72 ± 1.02 cm (range, 12.5 to 16.5 cm) and width was 8.43 ± 1.05 cm (range, 6 to 10.5 cm). The distance from the TPFF pedicle through the PMF was 5.8 ± 0.5 cm (range, 5 to 6.5 cm). All TPFF flaps provided complete ipsilateral coverage of clival defects, and all but 1 covered the entire clivus. All TPFF flaps, when rotated anteriorly, provided coverage up to the cribriform plate. The minimum TPFF height necessary for complete coverage of cribriform defects and ventral defects up to the planum sphenoidale was 12 cm. TPFF height for specimens with and without complete ventral skull-base coverage was significantly different (p < 0.0001). The TPFF is a versatile alternative to the nasoseptal flap and a height of at least 12 cm can provide enough coverage for all ventral skull base defects.

Comparison of two different titanium cranioplasty methods: Custom-made titanium prostheses versus precurved titanium mesh.

Background: The aim of this study was to compare the results of two different titanium cranioplasties for reconstructing skull defects: standard precurved mesh versus custom-made prostheses.Methods: Retrospective analysis of 23 patients submitted to titanium cranioplasty between January 2014 and January 2019. Ten patients underwent delayed cranioplasty using custom-made prostheses; and 13 patients were treated using precurved titanium mesh (ten delayed cranioplasties, and three single-stage resection- reconstructions). Demographic, clinical, and radiological data were recorded. Results and complications of the two methods were compared, including duration of surgery, cosmetic results (visual analog scale for cosmesis [VASC]), and costs of the implants.Results: Complications: one epidural hematoma in the custom-made group, one delayed failure in precurved group due to wound dehiscence with mesh exposure. There were no infections in either group. All custom-made prostheses perfectly fitted on the defect; eight of 13 precurved mesh prostheses incompletely covered the defect. Custom-made cranioplasty obtained better cosmetic results (average VASC 94 vs. 68), shorter surgical time (141min vs. 186min), and -fewer screws was needed to fix the prostheses in place (6 vs. 15). However, satisfactory results were obtained using precurved mesh in cases of small defects and in single-stage reconstruction. Precurved mesh was found to be cheaper (€1,500 vs. €5,500).Conclusion: Custom-made cranioplasty obtained better results and we would suggest that this should be a first choice, particularly for young patients with a large cranial defect. Precurved mesh was cheaper and useful for single-stage resection-reconstruction. Depending on the individual conditions, both prostheses have their place in cranioplasty therapies.

Syndrome of the Trephined: Quantitative Functional Improvement after Large Cranial Vault Reconstruction.

Large decompressive craniectomies may be life-saving; however, they may also result in syndrome of the trephined. This postrecovery sequela is characterized by dizziness, fatigue, depression, weakness, speech slowing, gait disturbance, and impaired mentation. Because this entity is poorly understood, the authors attempted to quantify the functional improvement in patients with syndrome of the trephined after cranial vault reconstruction. Patients with cranial vault defects (>50 cm) from trauma, meningioma, and hemorrhage were studied preoperatively and postoperatively (6 months) after cranial vault reconstruction using (1) the Cognistat Active Form and (2) the Functional Independence Measure instrument (n = 40). Cranial vault reconstructive techniques varied from split cranial bone to alloplastic implants (polyetheretherketone or titanium mesh). Of the 143 patients treated with decompressive craniectomies, 28 percent (n = 40) developed symptoms of syndrome of the trephined. A larger craniectomy defect size correlated with development of syndrome of the trephined. Time from craniectomy to presentation of symptoms was 4.5 months. Time from craniectomy to cranial vault reconstruction was 6.1 months. Time from cranial vault reconstruction to symptom improvement was 4.3 days. Complete functional recovery of syndrome of the trephined was seen in 70 percent. Type of cranial vault reconstruction included polyetheretherketone implant (57.5 percent), split calvarial graft (22.5 percent), and titanium mesh (20 percent), and was not a determinant of functional improvement. Cognistat assessment score noted improvement (from 38 to 69); likewise, the Functional Independence Measure measurement tool showed improvement (from 38 to 98). Syndrome of the trephined occurs more frequently than previously described in posttraumatic patients with large cranial vault defects. Cranial vault reconstruction leads to significant, quantifiable functional improvement in a large number of patients. Therapeutic, IV.

Multifunctional injectable protein-based hydrogel for bone regeneration

Protein plays an important role in the maintenance of osmotic pressure and binding and transportation of nutrients to cells, which is essential for the rapid regeneration of bone tissues. Bovine serum albumin (BSA) is the most abundant plasma protein in the body. Here, theBSA-based hydrogel was first developed through the thiolated bovine serum albumin (sBSA) employing the robust and reversible -SAg coordination, which owns injectable, self-healing and antibacterial properties for the treatment of bone defect regeneration. First, the BSA was treated with Traut's reagent to replace the primary amine groups of the lysine residue in its primary structure with thiol groups. Then, the thiolated BSA (sBSA) was added with silver nitrate to be crosslinked. -SAg coordination took place immediately when sBSA and silver were mixed and a shear-thinning hydrogel was thus produced. By adjusting the proportion of BSA, the mechanical properties of the hydrogels can be adjusted. Moreover, this novel protein-based hydrogel is bio-degradable and can slowly release silver ions to generate an antibacterial effect for P. gingivalis and F. nucleatum bacterial. Moreover, the protein-based injectable hydrogel has very good biocompatibility and bioactivity on promoting bone regeneration. As shown in this study, the in vitro experiments showed that the hydrogel effectively enhanced the osteogenesis differentiation of osteogenic precursor cells. And the in vivo study showed faster and better bone repair outcomes in large cranial defect rabbit model, in comparison to the commercially used spongious bone substitutes (Bio-OSS). Therefore, protein-based hydrogel is a very good promising material for bone regeneration.

Thiolated bone and tendon tissue particles covalently bound in hydrogels for in vivo calvarial bone regeneration

Bone regeneration of large cranial defects, potentially including traumatic brain injury (TBI) treatment, presents a major problem with non-crosslinking, clinically available products due to material migration outside the defect. Commercial products such as bone cements are permanent and thus not conducive to bone regeneration, and typical commercial bioactive materials for bone regeneration do not crosslink. Our previous work demonstrated that non-crosslinking materials may be prone to material migration following surgical placement, and the current study attempted to address these problems by introducing a new hydrogel system where tissue particles are themselves the crosslinker. Specifically, a pentenoate-modified hyaluronic acid (PHA) polymer was covalently linked to thiolated tissue particles of demineralized bone matrix (TDBM) or devitalized tendon (TDVT), thereby forming an interconnected hydrogel matrix for calvarial bone regeneration. All hydrogel precursor solutions exhibited sufficient yield stress for surgical placement and an adequate compressive modulus post-crosslinking. Critical-size calvarial defects were filled with a 4% PHA hydrogel containing 10 or 20% TDBM or TDVT, with the clinical product DBXⓇ being employed as the standard of care control for the in vivo study. At 12 weeks, micro-computed tomography analysis demonstrated similar bone regeneration among the experimental groups, TDBM and TDVT, and the standard of care control DBXⓇ. The group with 10% TDBM was therefore identified as an attractive material for potential calvarial defect repair, as it additionally exhibited a sufficient initial recovery after shearing (i.e., > 80% recovery). Future studies will focus on applying a hydrogel in a rat model for treatment of TBI. Statement of SignificanceNon-crosslinking materials may be prone to material migration from a calvarial bone defect following surgical placement, which is problematic for materials intended for bone regeneration. Unfortunately, typical crosslinking materials such as bone cements are permanent and thus not conducive to bone regeneration, and typical bioactive materials for bone regeneration such as tissue matrix are not crosslinked in commercial products. The current study addressed these problems by introducing a new biomaterial where tissue particles are themselves the crosslinker in a hydrogel system. The current study successfully demonstrated a new material based on pentenoate-modified hyaluronic acid with thiolated demineralized bone matrix that is capable of rapid crosslinking, with desirable paste-like rheology of the precursor material for surgical placement, and with bone regeneration comparable to a commercially available standard-of-care product. Such a material may hold promise for a single-surgery treatment of severe traumatic brain injury (TBI) following hemicraniectomy.