OBJECTIVES:To evaluate the effect of the width of the buccal gap on the alveolar process reduction after immediate implant placement (IIP) at maxillary central incisor sites, compared to contralateral pristine tooth sites. MATERIAL AND METHODS:Twenty-eight subjects who were treated with IIP to replace a maxillary central incisor and presented a pristine contralateral tooth site were included in this retrospective cohort study. The width of the gap between the implant and the inner walls of the socket was measured and grafted with deproteinized bovine bone mineral (DBBM). Subjects were divided into 2 groups: wide gap: > 2 mm (n = 14); Narrow gap: ≤ 2 mm (n = 14). CBCT scans were obtained after a mean follow-up of 6 (± 4) years and evaluated by a calibrated examiner. Dimensional measurements of the healed alveolar ridge (implant site) and alveolar process (tooth site) were compared between the two groups. RESULTS:The Narrow gap group showed significantly greater ridge resorption (41.1% ± 20.2%) in relation to the corresponding pristine tooth sites than the wide gap group (8.5% ± 11%). The width of the alveolar ridge at 3 and 5 mm below the crest and the height of the buccal wall were also significantly reduced in the narrow gap group. CONCLUSIONS:A buccal gap > 2-mm wide grafted with DBBM after IIP may preserve more than 90% of the dimensions of the alveolar process. Conversely, a grafted narrow gap frequently results in significantly reduced ridge preservation.

OBJECTIVE:To examine the effect of vaginal oestrogen cream on pessary continuation rates in pelvic organ prolapse. DESIGN:Multicentre, randomised, double blind, placebo controlled trial. SETTING:12 academic medical centres in China (May 2020-June 2023). PARTICIPANTS:Postmenopausal women with symptomatic pelvic organ prolapse ≥stage 2 and successfully fitted with ring pessaries were randomly assigned in a 1:1 ratio to receive oestrogen cream or placebo cream. INTERVENTIONS:One gram of conjugated oestrogen cream (0.625 mg/g) or placebo cream was inserted vaginally every night for the first two weeks after successful pessary fitting followed by twice weekly for 12 months. MAIN OUTCOME MEASURES:The primary outcome was the pessary continuation rate with satisfaction, which was defined as the proportion of participants who continued using the pessary and reported a response of very much better or much better on the Patient Global Impression of Improvement questionnaire at 12 months. Secondary outcomes included self-reported pelvic floor symptoms and adverse events. All analyses were based on a modified intention-to-treat approach, including participants who had at least one visit. RESULTS:Of 420 postmenopausal women randomised, 411 had at least one visit and were included in the modified intention-to-treat analysis (208 in the vaginal oestrogen group and 203 in the placebo group). The mean age of participants was 66 years. Pessary continuation rate with satisfaction did not differ significantly between the oestrogen group and the placebo group (181/208 (87.0%) v 176/203 (86.7%); risk difference 0.3%, 95% confidence interval -6.2% to 6.9%; P=0.92). Excessive discharge (34/208 (16.3%) v 52/203 (25.6%); -9.3%, -17.1% to -1.4%), vaginal erosion or ulcer (4/208 (1.9%) v 14/203 (6.9%); -5.0%, -8.9% to -1.0%), and vaginal bleeding (3/208 (1.4%) v 13/203 (6.4%); -5.0%, -8.7% to -1.2%) were less common in the vaginal oestrogen group. CONCLUSIONS:Oestrogen cream did not improve the continuation rate of ring pessary use with satisfaction. Use of oestrogen cream might be associated with a lower risk of common adverse events. The clinical decision to use vaginal oestrogen should take into account its benefits and risks and the patient's personal preferences. TRIAL REGISTRATION:ClinicalTrials.gov NCT04393194.

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Over the long history of evolution, nature has developed a variety of biological systems with switchable recognition functions, such as the ion transmissibility of biological membranes, which can switch their ion selectivities in response to diverse stimuli. However, developing a method in an artificial host-guest system for switchable recognition of specific guests upon the change of external stimuli is a fundamental challenge in chemistry because the order in the host-guest affinity of a given system hardly varies along with environmental conditions. Herein, we report temperature-responsive recognition of two similar gaseous guests, CO 2 and C 2 H 2 , with selectivities switched by temperature change by a diffusion-regulatory mechanism, which is realized by a dynamic porous crystal featuring ultrasmall pore apertures with flip-flop locally-motive organic moiety. The dynamic local motion regulates the diffusion process of CO 2 and C 2 H 2 and amplifies their rate differences, allowing the crystal to selectively adsorb CO 2 at low temperatures and C 2 H 2 at high temperatures with separation factors of 498 (CO 2 /C 2 H 2 ) and 181 (C 2 H 2 /CO 2 ), respectively.

The aim of this cohort study was to assess the effect of connective tissue graft (CTG) following immediate implant placement (IIP) at maxillary central incisors on esthetic outcomes, buccal bone thickness, soft tissue dimensional alterations, and patient-centered outcomes. Twenty-eight patients treated with IIP at maxillary central incisor sites with approximately 6 ± 4 years in function were divided according to the use of CTG (n = 17) or no CTG (n = 11). The primary variable of the study was the Pink and White Esthetic Score (PES/WES), evaluated in photographs taken before and after implant placement. The thickness of the buccal bone, midbuccal mucosal level (MBML) changes, and patient satisfaction were assessed and compared between the two groups. The results showed similar PES/WES before IIP between the CTG and no-CTG groups (13.5 ± 3.7 and 12.6 ± 3.2, respectively). After IIP, the PES/WES value in the CTG group was significantly higher (15 ± 2.5) than in the no-CTG group (12.1 ± 3.1) (P = .012). No significant differences in the buccal bone thickness, MBML, or patient satisfaction were observed in CTG and no-CTG groups. This study found that CTG following IIP and socket grafting promoted better esthetic outcomes.

BACKGROUND:The effect of the buccal gap width on the clinical outcome of socket graft and immediate implant placement (IIP) at maxillary central incisor sites has not been investigated. Thus, the aim of the present study was to evaluate the effect of the width of the buccal gap on the thickness of the newly formed buccal wall. METHODS:Forty-two patients and 51 maxillary central incisor sites treated with IIP and ridge preservation by means of graft of the buccal gap at the maxillary central incisor region were included in the study. The width of the buccal gap was measured and filled with deproteinized bovine bone mineral. Implant sites were divided into two groups: wide gap (WG, >2 mm; n = 34) and narrow gap (NG, ≤2 mm; n = 17). After at least 1 year in function (5 ± 4), CBCT scans were obtained and assessed by a calibrated examiner. The thickness of the buccal and palatal bone walls, the percentage of the implant height covered by bone in the buccal and palatal aspects and the position of the buccal and palatal crests were compared between the two groups. A linear regression model was performed to assess predictors of the thickness of the buccal bone. RESULTS:The buccal bone was significantly thicker in the WG group than the NG group at all levels observed (overall 1.9 ± 0.9 mm and 0.5 ± 0.6 mm, respectively). The thickness of the palatal bone was similar between both groups (>2 mm). The percentage of the implant height covered by bone at the buccal aspect was significantly higher in the WG group (95 ± 16.6%) than in the NG group (59.4 ± 42.3%). The position of the buccal crest in relation to the implant shoulder was significantly more coronal (0.3 ± 2.2 mm) in the WG group than in the NG group (-4.7 ± 5.6 mm). The regression analysis model indicated that the width of the buccal gap was the only predictor of the thickness of the newly formed buccal bone wall (p < 0.001). CONCLUSION:Grafting of >2 mm-wide buccal gaps following IIP promoted a thicker buccal bone wall.

ImportanceTransvaginal mesh (TVM) can increase the durability of vaginal surgical procedures for pelvic organ prolapse (POP) and may be indicated in certain situations despite concerns about mesh-related complications. In addition, the expense of commercial mesh kits has limited their use. The effectiveness, safety, and cost of a self-cut mesh procedure compared with a commercial mesh-kit procedure for the surgical treatment of women with POP is unclear.ObjectiveTo assess the 1-year effectiveness and safety of self-cut titanium-coated polypropylene mesh compared with a precut commercial mesh kit for the transvaginal surgical treatment of women with severe symptomatic POP.Design, Setting, and ParticipantsThis multicenter randomized noninferiority clinical trial was conducted at 11 hospitals in 8 provinces of China. A total of 336 women with symptomatic stage 3 to 4 POP were enrolled between January 22, 2018, and November 11, 2019, with follow-up through December 11, 2020.InterventionsParticipants were randomized to receive a TVM procedure using either self-cut mesh (self-cut mesh group) or a precut commercial mesh kit (mesh-kit group), both of which used the same titanium-coated polypropylene mesh.Main Outcomes and MeasuresThe primary outcome measure was composite surgical success at 1 year, which was defined as the absence of vaginal bulge symptoms, no additional retreatment for POP, and no vaginal prolapse at or beyond the hymen. Secondary outcomes included symptom-specific pelvic floor function and quality-of-life measures as well as perioperative complications, including mesh-related complications and hospitalization costs. Complications were categorized using the Clavien-Dindo system (with grade 1 indicating any deviation from the normal postoperative course but not requiring grade 2-4 interventions; grade 2, need for pharmacological treatment, blood transfusion, and/or total parenteral nutrition; grade 3, the need for surgical, endoscopic, and/or interventional radiological procedures; and grade 4, life threatening).ResultsAmong 336 female participants (mean [SD] age, 63.3 [5.9] years; all of Chinese ethnicity), 169 patients were randomized to the self-cut mesh group, and 167 were randomized to the mesh-kit group. Three patients were unavailable for follow-up after 1 year. In the intention-to-treat analysis, 162 women (95.9%) in the self-cut mesh group had outcomes that met the definition of surgical success; this result was noninferior to the surgical success rate observed in the mesh-kit group (146 women [87.4%]; risk difference, 8.5%; 95% CI, 2.2%-14.3%; P = .006). The frequency of Clavien-Dindo grade 1 to 3 perioperative complications was not significant between groups (12 of 166 women [7.2%] in the self-cut mesh group vs 20 of 161 women [12.4%] in the mesh-kit group; P = .14). Vaginal mesh exposure rates in women examined at 1 year were similar (4 women [2.4%] in the self-cut mesh group vs 8 women [4.8%] in the mesh-kit group; P = .23). Median (IQR) total hospitalization costs were $3663.00 ($3258.90-$4495.10) in the self-cut mesh group vs $6144.00 ($5434.90-$7160.20) in the mesh-kit group (P < .01), representing savings of $2481.00 (40.4%) with the use of self-cut mesh.Conclusions and RelevanceIn this clinical trial, the composite surgical success rate of a self-cut mesh procedure was noninferior to that of a commercial mesh-kit procedure using the same titanium-coated polypropylene mesh and reduced hospitalization expenses by 40.4%. These findings suggest that the use of self-cut mesh procedures may be advantageous for the surgical treatment of some women with severe POP, particularly those in countries with low and middle income.Trial RegistrationClinicalTrials.gov identifier: NCT03283124

Objectives: 1) Develop a novel construct of human periodontal ligament stem cells (hPDLSCs) encapsulated in degradable alginate microbeads (DAMB) with human platelet lysate (hPL) and injectable calcium phosphate cement (ICPC); 2) Investigate the proliferation and osteogenic differentiation of hPDLSCs in ICPC with hPL as a xeno-free supplement and animal serum replacement for bone tissue engineering applications. Methods: hPDLSCs were encapsulated in alginate-fibrin microbeads (DAMB + fibrin), alginate-hPL degradable microbeads (DAMB + hPL), or alginate-fibrin-hPL microbeads (DAMB + fibrin + hPL). The proliferation and osteogenic differentiation of hPDLSCs were investigated in culturing with the ICPC scaffold. Results: Flexural strength of ICPC was 8.4 ± 0.91 MPa, and elastic modulus was 1.56 ± 0.1 GPa, exceeding those of cancellous bone. hPDLSCs had higher viability in DAMB + fibrin + hPL group than in DAMB + fibrin. ALP was 69.97 ± 16.96 mU/mg for ICPC + DAMB + fibrin + hPL group, higher than 30.68 ± 2.86 mU/mg of ICPC + DAMB + fibrin ( p < 0.05) and 4.12 ± 1.65 mU/mg of control ( p < 0.01). At 7 days, osteogenic gene expressions ( ALP , RUNX2 , COL1 , and OPN ) in ICPC + DAMB + fibrin + hPL and ICPC + DAMB + fibrin were 4–11 folds that of control. At 21 days, the hPDLSC-synthesized bone mineral amounts in ICPC + DAMB + fibrin + hPL and ICPC + DAMB + fibrin were 13.2 folds and 11.1 folds that of control group, respectively. Conclusion: The novel injectable CPC scaffold encapsulating hPDLSCs and hPL is promising to protect and deliver hPDLSCs. The hPL-based medium significantly enhanced the osteogenic differentiation of hPDLSCs in ICPC + DAMB + fibrin + hPL construct, suggesting a promising xeno-free approach for bone tissue regeneration applications.

Background : Pelvic organ prolapse is a common benign condition in women, defined as the descent of one or more of the following: anterior vaginal wall; posterior vaginal wall; uterus (cervix); and apex of the vagina (vaginal vault or cuff scar after hysterectomy). Vulvar cancer is uncommon, accounting for 2-5% of gynecologic malignancies. Vulvar cancer and pelvic organ prolapse tend to occur in elderly individuals with other complications, such as heart disease, hypertension and diabetes. Risk during the perioperative period is very high; therefore, gynecologists should provide the most appropriate and comprehensive treatment plan to achieve a good prognosis. Case presentation : The patient’s main concerns is vulva pruritus and vulva mass prolapse. Important clinical examinations include vulvar biopsy suggesting vulvar carcinoma, and the POP Quantification (POP-Q) scores showing Aa:+2, Ba:+2, C:0, D:0, Ap:+1, Bp:+1. The primary diagnoses is highly differentiated squamous cell carcinoma of the vulva, pelvic organ prolapse. The patient underwent extensive vulvotomy, vulvoplasty, partial urethrotomy, external urethroplasty, partial cervicectomy, anterior and posterior vaginal wall repair, sacrospinous ligament suspension, and laparoscopic bilateral inguinal lymph node dissection. The patient recovered well and was discharged from hospital. But unfortunately, the patient was followed-up via telephone and died 1 year after surgery. Conclusions : Vulvar cancer and pelvic organ prolapse tend to occur in elderly individuals with other complications, such as heart disease, hypertension and diabetes. Risk during the perioperative period is very high; therefore, gynecologists should provide the most appropriate and comprehensive treatment plan to achieve a good prognosis.

Infectious bone defects remain a significant challenge in orthopedics and dentistry. Calcium phosphate cement (CPC) have attracted significant interest in use as local drug delivery system, which with great potential to control release of antibiotics for the treatment of infectious bone defects. Within the current study, a novel antibacterial scaffold of chitosan-reinforced calcium phosphate cement delivering doxycycline hyclate (CPCC + DOX) was developed. Furthermore, the capacity of CPCC + DOX scaffolds for bone regeneration was enhanced by the human periodontal ligament stem cells (hPDLSCs) encapsulated in alginate beads. CPCC + DOX scaffolds were fabricated to contain different concentrations of DOX. Flexural strength of CPCC + DOX ranged from 5.56 ± 0.70 to 6.2 ± 0.72 MPa, which exceeded the reported strength of cancellous bone. Scaffolds exhibited continual DOX release, reaching 80% at 21 days. Scaffold with 5 mg/ml DOX (CPCC + DOX5mg) had a strong antibacterial effect, with a 4-log colony forming unit reduction against S. aureus and P. gingivalis. The proliferation and osteogenic differentiation of hPDLSCs encapsulated in alginate hydrogel microbeads were investigated in culture with CPCC + DOX scaffolds. CPCC + DOX5mg had no negative effect on proliferation of hPDLSCs. Alkaline phosphatase activity, mineral synthesis, and osteogenic gene expressions for CPCC + DOX5mg group were much higher than control group. DOX did not compromise the osteogenic induction. In summary, the novel CPCC + DOX scaffold exhibited excellent mechanical properties and strong antibacterial activity, while supporting the proliferation and osteogenic differentiation of hPDLSCs. The CPCC + DOX + hPDLSCs construct is promising to enhance bone regeneration and combat bone infections in dental, craniofacial, and orthopedic applications.

Ten keys for successful esthetic-zone single immediate implants encapsulate in an evidence-based manner the treatment planning and replacement of single hopeless teeth in the maxillary anterior sextant. These include two treatment-planning, five surgical, and three prosthetic keys, which, collectively, aim to minimize soft- and hard-tissue complications for an optimal esthetic implant restoration. The Straightforward, Advanced, and Complex (SAC) classification is designed to aid clinicians in the treatment planning of dental implant cases. As per this classification, cases are stratified by the degree of surgical and restorative risk and complexity for both the surgical and prosthetic phases of treatment. A technique-sensitive and skill-demanding task, the replacement of multiple adjacent teeth in the esthetic zone poses significant challenges for clinicians and is considered a complex SAC procedure surgically and restoratively. This article presents a case report on the replacement of multiple adjacent teeth in the esthetic zone, demonstrating the use of 10 key principles to achieve an optimal esthetic outcome.

Calcium phosphate cements (CPCs) have excellent biocompatibility and osteoconductivity for dental, craniofacial, and orthopedic applications. This article reviews recent developments in stem cell delivery via CPC for bone regeneration. This includes: (1) biofunctionalization of the CPC scaffold, (2) co-culturing of osteoblasts/endothelial cells and prevascularization of CPC, (3) seeding of CPC with different stem cell species, (4) human umbilical cord mesenchymal stem cell (hUCMSC) and bone marrow MSC (hBMSC) seeding on CPC for bone regeneration, and (5) human embryonic stem cell (hESC) and induced pluripotent stem cell (hiPSC) seeding with CPC for bone regeneration. Cells exhibited good attachment/proliferation in CPC scaffolds. Stem-cell-CPC constructs generated more new bone and blood vessels in vivo than did the CPC control without cells. hUCMSCs, hESC-MSCs, and hiPSC-MSCs in CPC generated new bone and blood vessels similar to those of hBMSCs; hence, they were viable cell sources for bone engineering. CPC with hESC-MSCs and hiPSC-MSCs generated new bone two- to three-fold that of the CPC control. Therefore, this article demonstrates that: (1) CPC scaffolds are suitable for delivering cells; (2) hUCMSCs, hESCs, and hiPSCs are promising alternatives to hBMSCs, which require invasive procedures to harvest with limited cell quantity; and (3) stem-cell-CPC constructs are highly promising for bone regeneration in dental, craniofacial, and orthopedic applications.

Background: Transvaginal mesh can increase the durability of surgery for pelvic organ prolapse. However, commercial mesh kits can be expensive. We assessed the efficacy of a much cheaper self-cut titanium-coated polypropylene mesh with a mesh-kit for treating symptomatic pelvic organ prolapse. Methods: We conducted a multicenter, randomized, non-inferiority trial. Patients were randomized to either self-cut mesh or commercial mesh-kit. Patients with symptomatic stage III-IV pelvic organ prolapse were enrolled at 11 centers between January 2018 and November 2019. The primary outcome measure was composite success at one year defined by absence of vaginal bulge symptoms, and no additional re-treatment for POP, and no vaginal prolapse at or beyond the hymen. Secondary outcomes included symptom-specific pelvic floor function and quality of life measures, complications and costs. Findings: A total of 336 participants were randomized. In the intention-to-treat analysis, 95∙9% (162/169) met the definition of surgical success in the self-cut group, which was noninferior to the 87∙4% (146/167) surgical success in the mesh-kit group (risk difference, 8∙5 [95%CI 2∙2 to 14∙3]). The frequency of Clavien-Dindo grade I-III complications were not significant between groups (12 [7∙2%] vs 20 [12∙4%], P=0∙14). Vaginal mesh exposure rates in women examined within 1 year [self-cut group 4/169 (2∙4%) vs mesh-kit group 8/167 (4∙8%)] were similar (P=0∙23). Interpretation: This trial demonstrated that composite surgical success of a self-cut mesh procedure was non-inferior to a commercial mesh-kit procedure using the same mesh. The use of self-cut mesh was effective and safe, while reducing the hospitalization expense by approximately 40%. Clinical Trial Registration Details: Clinicaltrials.gov, NCT03283124. Funding Information: Chinese Academy of Medical Science Initiative for Innovative Medicine(CAMS-2017-12M-1-002). Medstron Medical(shanghai) Co. Ltd, the agent of Tiloop® products in China, provided monetary support for this research including interim meeting and third party (LinkDoc Beijing company) EDC system. Declaration of Interests: We declare no competing interests. Ethics Approval Statement: The study was approved by the Institutional Review Board of Peking Union Medical College Hospital (JS-1278).

BACKGROUND:Doxorubicin (DOX) is a leading chemotherapeutic in cancer treatment because of its high potency and broad spectrum. Liposomal doxorubicin (Doxil®) is the first FDA-approved PEG-liposomes of DOX for the treatment of over 600,000 cancer patients, and it can overcome doxorubicin-induced cardiomyopathy and other side effects and prolong life span. The addition of MPEG2000-DSPE could elevate the total cost of cancer treatment.OBJECTIVE:We intended to prepare a novel DOX liposome that was prepared with inexpensive materials egg yolk lecithin and Kolliphor HS15, thus allowing it to be much cheaper for clinical application.METHODS:DOX liposomes were prepared using the combination of thin-film dispersion ultrasonic method and ammonium sulfate gradient method and the factors that influenced formulation quality were optimized. After formulation, particle size, entrapment efficiency, drug loading, stability, and pharmacokinetics were determined.RESULTS:DOX liposomes were near-spherical morphology with the average size of 90 nm and polydispersity index (PDI) of less than 0.30. The drug loading was up to 7.5%, and the entrapment efficiency was over 80%. The pharmacokinetic studies showed that free DOX could be easily removed and the blood concentration of free DOX group was significantly lower than that of DOX liposomes, which indicated that the novel DOX liposome had a certain sustainedrelease effect.CONCLUSION:In summary, DOX liposome is economical and easy-prepared with prolonged circulation time. Lay Summary: Doxorubicin (DOX) is a leading chemotherapeutic in cancer treatment because of its high potency and broad spectrum. Liposomal doxorubicin (Doxil®) is the first FDAapproved PEG-liposomes of DOX to treat over 600.000 cancer patients, overcoming doxorubicin- induced cardiomyopathy and other side effects and prolonging life span. The addition of MPEG2000-DSPE could elevate the total cost of cancer treatment. We intend to prepare a novel DOX liposome prepared with inexpensive materials egg yolk lecithin and Kolliphor HS15, thus allowing it to be much cheaper for clinical use. The novel DOX liposome is economical and easy-prepared with prolonged circulation time.

Aim: This systematic review and meta-analysis were conducted to assess and compare the accuracy of conventional and digital implant impressions. The review was registered on the PROSPERO register (registration number: CRD42016050730). Material and Methods: A systematic literature search was conducted adhering to PRISMA guidelines to identify studies on implant impressions published between 2012 and 2017. Experimental and clinical studies at all levels of evidence published in peer-reviewed journals were included, excluding expert opinions. Data extraction was performed along defined parameters for studied specimens, digital and conventional impression specifications and outcome assessment. Results: Seventy-nine studies were included for the systematic review, thereof 77 experimental studies, one RCT and one retrospective study. The study setting was in vitro for most of the included studies (75 studies) and in vivo for four studies. Accuracy of conventional impressions was examined in 59 studies, whereas digital impressions were examined in 11 studies. Nine studies compared the accuracy of conventional and digital implant impressions. Reported measurements for the accuracy include the following: (a) linear and angular deviations between reference models and test models fabricated with each impression technique; (b) three-dimensional deviations between impression posts and scan bodies respectively; and (c) fit of implant-supported frameworks, assessed by measuring marginal discrepancy along implant abutments.) Meta-analysis was performed of 62 studies. The results of conventional and digital implant impressions exhibited high values for heterogeneity. Conclusions: The available data for accuracy of digital and conventional implant impressions have a low evidence level and do not include sufficient data on in vivo application to derive clinical recommendations.

T h is p ap er h as b ee n p ee rre v ie w ed a n d a cc ep te d f o r p u b li ca ti o n , b u t h as y et t o u n d er g o c o p y ed it in g a n d p ro o f co rr ec ti o n . T h e fi n al p u b li sh ed v er si o n m ay d if fe r fr o m t h is p ro o f. Co-seeding human endothelial cells with hiPSC-derived mesenchymal stem cells on calcium phosphate scaffold enhances osteogenesis and vascularization in rats

Macroporous calcium phosphate cement (CPC) with stem cell seeding is promising for bone regeneration. The objective of this study was to investigate the effects of co‐delivering autologous bone marrow mesenchymal stem cells (BMSCs) and autologous platelet‐rich plasma (PRP) in CPC scaffold for bone regeneration in minipigs for the first time. Twelve female adult Tibet minipigs (12–18 months old) were used. A cylindrical defect with 10 mm height and 8 mm diameter was prepared at the femoral condyle. Two bone defects were created in each minipig, one at each side of the femoral condyle. Three constructs were tested: (1) CPC scaffold (CPC control); (2) CPC seeded with BMSCs (CPC‐BMSC); (3) CPC seeded with BMSCs and PRP (CPC‐BMSC‐PRP). Two time points were tested: 6 and 12 weeks (n = 4). Good integration of implant with surrounding tissues was observed in all groups. At 12 weeks, the CPC‐BMSC‐PRP group had significantly less residual CPC remaining in the defect than the CPC‐BMSC group and the CPC control (p < 0.05). The residual CPC volume for the CPC‐BMSC‐PRP group was half that of the CPC control. New bone formation for CPC‐BMSC‐PRP was more than two‐fold that of the CPC control (p < 0.05). CPC‐BMSC‐PRP had new blood vessel density that was nearly two‐fold that of the CPC control (p < 0.05). In conclusion, CPC scaffold with autologous BMSC‐PRP doubled the new bone regeneration and blood vessel density in minipigs compared with the CPC control. In the present study, the new macroporous CPC system with co‐delivered BMSC‐PRP has been shown to promote scaffold resorption and bone regeneration in large defects. Copyright © 2017 John Wiley & Sons, Ltd.

Vascularization of tissue-engineered bone is a critical step in maintaining cell viability and advancing cell performance in vivo. In this study, a novel tri-culture system was developed to elicit pre-vascularization of calcium phosphate cement (CPC) scaffold in which human induced pluripotent stem cell-derived mesenchymal stem cells (hiPSMSCs) were seeded together with human umbilical vein endothelial cells (HUVECs) and pericytes. In a two-step methodology design, we first performed osteoinduction of the seeded hiPSMSCs on the CPC scaffold and then incorporated HUVECs and pericytes to the hiPSMSC-colonized CPC scaffold under a favorable culturing condition, with an objective to form a stable and functional capillary-like vascular network that sustained the engineered osseous tissue. The angiogenic and osteogenic effects of various culture strategies were studied and compared in nude rat model with cranial bone defects: (1) CPC scaffold alone (CPC control); (2) Pericyte-seeded CPC (CPC-pericytes); (3) HUVEC-seeded CPC (CPC-HUVECs); (4) hiPSMSC-seeded CPC (CPC-hiPSMSCs); (5) HUVECs co-cultured with hiPSMSCs on CPC (bi-culture group) and (6) HUVECs and pericytes co-cultured with hiPSMSCs on CPC (tri-culture group). After 12weeks, tri-culture group showed the highest amount of new bone (new bone area fraction of (45.3±2.7) %, p<0.05) and vessel formation (new blood vessel density of (50.7±3.8) vessels/mm2, p<0.05) in all groups. Our results demonstrated that the tri-culture strategy was effective in promoting angiogenesis and osteogenesis for bone tissue engineering.

A major challenge in repairing large bone defects with tissue-engineered constructs is the poor vascularization in the defect. The lack of vascular networks leads to insufficient oxygen and nutrients supply, which compromises the survival of seeded cells. To achieve favorable regenerative effects, prevascularization of tissue-engineered constructs by co-culturing of endothelial cells and bone cells is a promising strategy. The aim of this study was to investigate the effects of human-induced pluripotent stem cell-derived mesenchymal stem cells (hiPSC-MSCs) co-cultured with human umbilical vein endothelial cells (HUVECs) for prevascularization of calcium phosphate cement (CPC) scaffold on bone regeneration in vivo for the first time. HUVECs co-cultured with hiPSC-MSCs formed microcapillary-like structures in vitro. HUVECs promoted mineralization of hiPSC-MSCs on CPC scaffolds. Four groups were tested in a cranial bone defect model in nude rats: (1) CPC scaffold alone (CPC control); (2) HUVEC-seeded CPC (CPC-HUVEC); (3) hiPSC-MSC-seeded CPC (CPC-hiPSC-MSC); and (4) HUVECs co-cultured with hiPSC-MSCs on CPC scaffolds (co-culture group). After 12 weeks, the co-culture group achieved the greatest new bone area percentage of 46.38%-3.8% among all groups (p < 0.05), which was more than four folds of the 10.61%-1.43% of CPC control. In conclusion, HUVECs co-cultured with hiPSC-MSCs substantially promoted bone regeneration. The novel construct of HUVECs co-cultured with hiPSC-MSCs delivered via CPC scaffolds is promising to enhance bone and vascular regeneration in orthopedic applications.

Induced pluripotent stem cells (iPSCs), reprogrammed from adult somatic cells using defined transcription factors, are regarded as a promising cell source for tissue engineering. For the purpose of bone tissue regeneration, efficient in vitro differentiation of iPSCs into downstream cells, such as mesenchymal stem cells (MSCs), osteoblasts, or osteocyte-like cells, before use is necessary to limit undesired tumorogenesis associated with the pluripotency of iPSCs. Until recently numerous techniques on the production of iPSC-derived osteogenic progenitors have been introduced. We reviewed these protocols and provided a perspective on the comparisons of osteogenic potentials of (1) iPSC-derived osteogenic cells produced by different protocols, (2) iPSCs from different somatic origins, and (3) iPSC-derived MSC-like cells and bone marrow stem cells. Finally, we discussed the potential application of the diseased iPSCs for systematic bone disorders.