Bifunctional bone substitute materials for bone defect treatment after bone tumor resection.

Aggressive benign, malignant and metastatic bone tumors can greatly decrease the quality of patients' lives and even lead to substantial mortality. Several clinical therapeutic strategies have been developed to treat bone tumors, including preoperative chemotherapy, surgical resection of the tumor tissue, and subsequent systemic chemo- or radiotherapy. However, those strategies are associated with inevitable drawbacks, such as severe side effects, substantial local tumor recurrence, and difficult-to-treat bone defects after tumor resection. To overcome these shortcomings and achieve satisfactory clinical outcomes, advanced bifunctional biomaterials which simultaneously promote bone regeneration and combat bone tumor growth are increasingly advocated. These bifunctional bone substitute materials fill bone defects following bone tumor resection and subsequently exert local anticancer effects. Here we describe various types of the most prevalent bone tumors and provide an overview of common treatment options. Subsequently, we review current progress regarding the development of bifunctional bone substitute materials combining osteogenic and anticancer efficacy. To this end, we categorize these biomaterials based on their anticancer mechanism deriving from i) intrinsic biomaterial properties, ii) local drug release of anticancer agents, and iii) oxidative stress-inducing and iv) hyperthermia-inducing biomaterials. Consequently, this review offers researchers, surgeons and oncologists an up-to-date overview of our current knowledge on bone tumors, their treatment options, and design of advanced bifunctional biomaterials with strong potential for clinical application in oncological orthopedics.

Enzymatic post-crosslinking of printed hydrogels of methacrylated gelatin and tyramine-conjugated 8-arm poly(ethylene glycol) to prepare interpenetrating 3D network structures.

Methacrylated gelatin (GelMA) has been intensively studied as a 3D printable scaffold material in tissue regeneration fields, which can be attributed to its well-known biological functions. However, the long-term stability of photo-crosslinked GelMA scaffolds is hampered by a combination of its fast degradation in the presence of collagenase and the loss of physical crosslinks at higher temperatures. To increase the longer-term shape stability of printed scaffolds, a mixture of GelMA and tyramine-conjugated 8-arm PEG (8PEGTA) was used to create filaments composed of an interpenetrating network (IPN). Photo-crosslinking during filament deposition of the GelMA and subsequent enzymatic crosslinking of the 8PEGTA were applied to the printed 3D scaffolds. Although both crosslinking mechanisms are radical based, they operate without interference of each other. Rheological data of bulk hydrogels showed that the IPN was an elastic hydrogel, having a storage modulus of 6 kPa, independent of temperature in the range of 10 - 40°C. Tensile and compression moduli were 110 kPa and 80 kPa, respectively. On enzymatic degradation in the presence of collagenase, the gelatin content of the IPN fully degraded in 7 days, leaving a stable secondary crosslinked 8PEGTA network. Using a BioMaker bioprinter, hydrogels without and with human osteosarcoma cells (hMG-63) were printed. On culturing for 21 days, hMG-63 in the GelMA/8PEGTA IPN showed a high cell viability (>90%). Thus, the presence of the photoinitiator, incubation with H2O2, and mechanical forces during printing did not hamper cell viability. This study shows that the GelMA/8PEGTA ink is a good candidate to generate cell-laden bioinks for extrusion-based printing of constructs for tissue engineering applications.

Bioactive ECM-Loaded SIS Generated by the Optimized Decellularization Process Exhibits Skin Wound Healing Ability in Type I Diabetic Rats.

Patients with diabetes have 15-25% chance for developing diabetic ulcers as a severe complication and formidable challenge for clinicians. Conventional treatment for diabetic ulcers is to surgically remove the necrotic skin, clean the wound, and cover it with skin flaps. However, skin flap often has a limited efficacy, and its acquisition requires a second surgery, which may bring additional risk for the patient. Skin tissue engineering has brought a new solution for diabetic ulcers. Herein, we have developed a bioactive patch through a compound culture and the optimized decellularization strategy. The patch was prepared from porcine small intestinal submucosa (SIS) and modified by an extracellular matrix (ECM) derived from urine-derived stem cells (USCs), which have low immunogenicity while retaining cytokines for angiogenesis and tissue regeneration. The protocol included the optimization of the decellularization time and the establishment of the methods. Furthermore, the in vitro mechanism of wound healing ability of the patch was investigated, and its feasibility for skin wound healing was assessed through an antishrinkage full-thickness skin defect model in type I diabetic rats. As shown, the patch displayed comparable effectiveness to the USCs-loaded SIS. Our findings suggested that this optimized decellularization protocol may provide a strategy for cell-loaded scaffolds that require the removal of cellular material while retaining sufficient bioactive components in the ECM for further applications.

Human adipose-derived stem cell-loaded small intestinal submucosa as a bioactive wound dressing for the treatment of diabetic wounds in rats.

Chronic nonhealing wounds are one of the most common and serious complications of diabetes, which can lead to disability of patients. Adipose-derived stem cells (ADSCs) have emerged as a promising tool for skin wound healing, but the therapeutic potential depends considerably on the cell delivery system. Small intestinal submucosa (SIS) is an extracellular matrix-based membranous scaffold with outstanding repair potential for skin wounds. In this study, we first fabricated a bioactive wound dressing, termed the SIS+ADSCs composite, by using human ADSCs as the seed cell and porcine SIS as the cell delivery vehicle. Then, we systematically investigated, for the first time, the healing potential of this wound dressing in a rat model of type 2 diabetes. In vitro studies revealed that SIS provided a favorable microenvironment for ADSCs and significantly promoted the expression of growth factors critical for chronic wound healing. After implantation in the full-thickness skin wounds of diabetic rats, the SIS+ADSCs composite showed a higher wound healing rate and wound healing quality than those in the PBS, ADSCs, and SIS groups. Along with the ability to modulate the polarization of macrophages in vivo, the SIS+ADSCs composite was potent at promoting wound angiogenesis, reepithelialization, and skin appendage regeneration. Taken together, these results indicate that the SIS+ADSCs composite has good therapeutic potential and high translational value for diabetic wound treatment.

Dual-functional porous and cisplatin-loaded polymethylmethacrylate cement for reconstruction of load-bearing bone defect kills bone tumor cells.

Malignant bone tumors are usually treated by resection of tumor tissue followed by filling of the bone defect with bone graft substitutes. Polymethylmethacrylate (PMMA) cement is the most commonly used bone substitute in clinical orthopedics in view of its reliability. However, the dense nature of PMMA renders this biomaterial unsuitable for local delivery of chemotherapeutic drugs to limit the recurrence of bone tumors. Here, we introduce porosity into PMMA cement by adding carboxymethylcellulose (CMC) to facilitate such local delivery of chemotherapeutic drugs, while retaining sufficient mechanical properties for bone reconstruction in load-bearing sites. Our results show that the mechanical strength of PMMA-based cements gradually decreases with increasing CMC content. Upon incorporation of ≥3% CMC, the PMMA-based cements released up to 18% of the loaded cisplatin, in contrast to cements containing lower amounts of CMC which only released less than 2% of the cisplatin over 28 days. This release of cisplatin efficiently killed osteosarcoma cells in vitro and the fraction of dead cells increased to 91.3% at day 7, which confirms the retained chemotherapeutic activity of released cisplatin from these PMMA-based cements. Additionally, tibias filled with PMMA-based cements containing up to 3% of CMC exhibit comparable compressive strengths as compared to intact tibias. In conclusion, we demonstrate that PMMA cements can be rendered therapeutically active by introducing porosity using CMC to allow for release of cisplatin without compromising mechanical properties beyond critical levels. As such, these data suggest that our dual-functional PMMA-based cements represent a viable treatment option for filling bone defects after bone tumor resection in load-bearing sites.

A Stable Large Animal Model for Dural Defect Repair with Biomaterials and Regenerative Medicine.

IMPACT STATEMENT: Using biomaterials and regenerative medicine to repair tissue defects has been a very hot research field, during which the development of stable large animal models with appropriate biotechnology is crucial. Recently, more and more researchers are paying attention to dural defect repair. However, the lack of widely recognized stable large animal models has seriously affected the related further research. In this study, a stable large animal dural defect model is developed exactly for the first time. Therefore, the article would attract considerable attention and be highly cited after publication.

Hydrogel from Acellular Porcine Adipose Tissue Accelerates Wound Healing by Inducing Intradermal Adipocyte Regeneration.

As an important component of the skin, intradermal adipocytes are closely associated with skin homeostasis and wound healing. Although studies have focused on the role of fibroblasts, keratinocytes, and inflammatory cells in wound healing, the role of adipocytes has not been fully investigated. Here, we verified whether the induction of adipocyte regeneration in a wound bed can effectively promote wound healing, finding that the hydrogel from acellular porcine adipose tissue in combination with adipose-derived stem cells can induce in situ adipogenesis in the wound microenvironment. The newly regenerated adipocytes enhanced fibroblast migration, accelerated wound closing, and enhanced wound epithelialization. More importantly, newly formed intact skin structure was observed after treating the wound with adipose-derived stem cell-loaded hydrogel from acellular porcine adipose tissue. These results show that hydrogel from acellular porcine adipose tissue might substantially improve re-epithelialization, angiogenesis, and skin-appendage regeneration, making it a promising therapeutic biomaterial for skin wound healing.

Comparison of small intestinal submucosa and polypropylene mesh for abdominal wall defect repair.

Abdominal wall defects are a common medical problem, and inadequate repair methods can lead to serious complications. Abdominal wall reconstruction using autologous tissue, or non-biological, biological, or composite patches is often performed to repair defective areas. In particular, composite patches containing both polymeric and biological materials have gained increasing attention due to their good mechanical properties and biocompatibility. However, it is still unclear whether the quality of repairs using composite patches is superior to that of a biological patch. Based on the limitations of previous studies, we compared small intestinal submucosa (SIS) patches with SIS + polypropylene mesh (PPM) patches for repairing abdominal wall defects in adult beagle dogs. Forty-five female dogs were subjected to surgical resection to produce abdominal wall defects. SIS or SIS + PPM was used as patch for the defects. Morphology, biomechanics, and histological evaluations were performed to evaluate the efficacy and safety of such therapies. Our findings demonstrated that SIS had advantages over SIS + PPM considering biological activity and histocompatibility without increasing the risk of repair failure.

Efficacy and safety of small intestinal submucosa in dural defect repair in a canine model.

Dural defects are a common problem, and inadequate dural closure can lead to complications. Several types of dural substitute materials have recently been discarded or modified owing to poor biocompatibility or mechanical properties and adverse reactions. The small intestinal submucosa (SIS) is a promising material used in a variety of applications. Based on the limitations of previous studies, we conducted an animal study to evaluate the efficacy and safety of the SIS in preclinical trials. Twenty-four male beagle dogs were subjected to surgical resection to produce dural defects. SIS or autologous dural mater was patched on the dural defect. Gross and histological evaluations were carried out to evaluate the efficacy and safety of the therapy. Our findings demonstrated that the SIS, which stimulated connective and epithelial tissue responses for dural regeneration and functional recovery without immunological rejection, could provide prolonged defect repair and prevent complications. The mechanical properties of the SIS could be adjusted by application of multiple layers, and the biocompatibility of the material was appropriate. Thus, our data suggested that this material may represent an alternative option for clinical treatment of dural defects.