Yang Lab in the department of Orthopaedic Surgery

Research Program

Our research interests are in the areas of biomaterials, implant devices, drug delivery, and musculoskeletal tissue engineering. In particular, we are interested in developing bio-inspired biomaterials and platform technologies to engineer tissues and organs. We aim to improve understanding of tissue-like chemistry and structure approaches of implant device design and fabrication, how these lead to tissue-like properties and functions, and the extent to which they can enhance clinical outcomes. Our research methodology includes concept design and development, characterization and evaluation, in vitro and in vivo validation of novel biomaterials and implant devices. Our current program comprises the following themes: Enabling technology for musculoskeletal tissue engineering, surface nanotechnology for osseointegrated implant devices, and naturally derived novel biomaterials for cancer treatment.

  1. Enabling technology for musculoskeletal tissue engineering
  2. Surface nanotechnology for osseointegrated implant devices
  3. Naturally based novel biomaterials for cancer treatment

1. Enabling technology for musculoskeletal tissue engineering

Tissue engineering tradionally consists of three components: scaffolds, cells and signals. In our lab, we are interested in developing clinically-applicable platform technologies to manipulate scaffolds, cells and signals to create a condition or microenvironment in vitro or in vivo to promote tissue regeneration and self-healing. More specifically, our research aims (1) to integrate microfabrication (bottom-up) with scaffolding (top-down) approaches to re-vascularize engineered cortical and cancellous bones at a large scale, and (2) to achieve temporally and spatially controlled signals that regulate tissue regeneration, leading to a functional tissue regeneration with biomimetic complexity and enhanced functionality. Currently, we are interested in applying the tissue engineering principles to repair and treat musculoskeletal diseases and trauma such as large segmental bone defects, osteonecrosis, rotator cuff injury, and bony birth defects ,along with dental and orthopaedic infections.

One of our major endeavors is to develop bio-inspired biomaterials and medical devices to recapitulate in vivo bony microenvironment. In our lab, we are particularly interested in the concepts of functionally graded biomaterials and various means to realize them by enabling gradual and spatial variation in biomaterial chemistry, structure, property, and signals from nano-, micro- and to macro-level. The goals of our research are to seamlessly integrate different interfacial propertiesand signals and achieve multiple functions. Recently, we have invented a novel bioprinting technology, called Hybprinter, which can seamlessly integrate soft and rigid material components using different printing techniques in a sequential fashion under a single platform. We also developed novel soft and rigid biomaterals that can be used in this hybprinter for acellular and cell-laden medical devices. The technologies we developed in our lab allow us to builid the foundation for vascularized composite tissue constructs, which is potentially a solution for the shortage of organ transplantation and various grafts for disease treatments. Figure 1 shows the schematic of a vascularized composite tissue, the Hybprinter and various representative medical devices and tissue engineering constructs using different modules of the Hybprinter.

Figure 1 Schematic of vascularized composite tissue constructs, image and features of Hybprinter and representative tissue constructs and medical devices fabricated by Hybprinter.

Rotator cuff injury or tear is the most common injury in shoulder. Re-tear rate for rotator cuff injury even after surgery treatment could be as high as 91%. Some large tear is considered irreparable. Also, the suture anchor technique has been used for more than 100 years for graft fixation to bone, which is though widerly used, but also possesses potential risk for failture due to multiple interfaces. Our lab has recently invented a novel photocrosslinkable polymer, in which we manipulate light exposure to regulate mechanical properties of the polymer to achieve bone-like and tendon-like properties using the same formulation in chemistry. This broad range of mechanical properties in order difference allow us to engineer a functionally graded biomaterial to significantly reduce the interfacial stress concentration to overcome the mechanical mismatch challenge (Figure 2). Furthermore, this unprecedented capability of new biomaterials enables engineering a hybrid suture anchor-tendon graft. This could further reduce the risk of failure by eliminating the suture anchors and graft interfaces by revolutionizing the one century old technique.

Figure 2 Schematic of repair of large rotator cuff tear using graft, and the bone-tendon interface. (a) A functionally graded biomaterial with bone-like ane tendon-like properties. During loading, the tendon-like side streched, but the bone-like side remained intact. (b) Schematic and rrepresentative images of a hybrid suture anchor-tendon graft and its features.

In addition to hydrogels and polymers, we invented a method to regulate porosity and pore arrangement across a calcium phosphate-based scaffold. Figure 3 shows biodegradable porous bone mineral scaffolds with different pore sizes and spatial arrangements. The porous structure of a calcium phosphate scaffold is critical to facilitate bone regeneration as a template.

biodegradable porous bone mineral scaffolds

Figure 3 Representative digital images of biodegradable porous calcium phosphate scaffolds with different pore sizes and spatial arrangements. A is a scaffold with uniform big pores; B is a scaffold with uniform small pores; C is a scaffold with central small pores and peripheral big pores; D is a scaffold with central big pores and peripheral small pores.

Besides porous structure, the chemistry and signals on the bone mineral scaffold are also very important for bone cells and mesenchymal stem cells. Our recent study was to re-create bony microenvironment with cell-derived extracellular matrix (ECM) and biodegradable β-tricalcium phosphate (β-TCP). More specifically, we investigated whether the ECM produced by bone marrow-derived mesenchymal stem cells (hBMSC) on a β-TCP scaffold can bind bone morphogenetic protein-2 (BMP-2) and control its release in a sustained manner. We further examined the effect of ECM and the BMP-2 released from ECM on cell behavior. The loading and release kinetics of the BMP-2 on the β-TCP/ECM were significantly slower than those on the β-TCP. Furthermore, the BMP-2-loaded β-TCP/ECM stimulated reorganization of the actin cytoskeleton (shown in Figure 4), and increased cell expression of alkaline phosphatase and calcium deposition compared to those without BMP-2 loading and the β-TCP with BMP-2 loading.

BMP-2-loaded β-TCP/ECM stimulated reorganization of the actin cytoskeleton

Figure 4 Representative immunofluorescent images for F-actin distribution in hBMSCs taken by a confocal laser scanning microscope after 3 days incubation. (A) Cells in the β-TCP scaffolds group; (B) Cells in the BMP-2-loaded β-TCP scaffolds; (C) Cells in the β-TCP/ECM-7 scaffolds; (D) Cells in the BMP-2-loaded β-TCP/ECM-7 scaffolds; (E) Cells in the β-TCP/ECM-14 scaffolds; and (F) Cells in the BMP-2-loaded β-TCP/ECM-7 scaffolds. (from Biomaterials 2011; 32:6119)

In another study, we evaluated bone formation efficacy aided by biodegradable calcium phosphate scaffolds in the absence of growth factors and stem cells using a rat cranial critical size bone defect (Figure 5). Newly-formed bone can be clearly observed by micro CT images and histological stains. We are engineering scaffolds, growth factor delivery, and stem cells for accelerating bone formation.

rat cranial critical size bone defect

Figure 5 CaP scaffolds aided bone healing in the absence of BMP-2 and cells using a rat cranial critical size bone defect (8 mm in diameter) after one-month implantation. Images of μCT (top) show the newly-formed bone in a scaffold. Histological data (bottom) show that the newly-formed bone by H&E stain filled the gap in the bone defect. PB = pre-existing bone

 

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2. Surface nanotechnology for osseointegrated implant devices

Surface engineering in our lab focuses on implant surface chemistry, texture and mechanical properties to improve performance of osseointegrated implant devices. In clinics, osseointegration, which is defined as the direct bone-implant contact, is critical for initial fixation and long-term success of endosseous dental and orthopedic implants. The initial host response after implantation is similar to a common bone wound healing modified by the presence of the implant. The new bone formation in the gap between the implant surface and host bone consists of three categories: osteogenesis at the implant surface (contact osteogenesis), within the surgical microgap at sites of neovasculization, and the surgical host bone margin (distance osteogenesis). As such, surface features that may influence any or all of these rates of bone formation will have the potential to enhance osseointegration. In our lab, the implant surface chemistry, texture and mechanical properties have been modified via plasma spraying, sputtering, ion implantation and chemical treatment. The chemistry includes titanium, hydroxyapatite, zirconia, titania, and biomolecule and growth factor. The enhancement of osseointegration has been evidenced by in vitro cell culture and in vivo animal study. Some examples in the implant surface modification, characterization, and biological evaluation are presented below.

Plasma sprayed hydroxyapatite and titanium coated cobalt hip implant devices

Figure 6 Plasma sprayed hydroxyapatite and titanium coated cobalt hip implant devices. (a) Digital photos. The left shows a cobalt metallic hip stem implant. The center shows a white hydroxyapatite coating on the proximal stem. The right shows a grey titanium coating on the proximal stem. (b) Scanning electron micrographs of plasma sprayed hydroxyapatite coating. (c) Scanning electron micrographs of plasma sprayed titanium coating. The plasma sprayed coatings roughened the surface textures that facilitate and promote osseointegration.

natro grains, pores and rods

Figure 7 Scanning electron micrographs of nanoscale implant surfaces. Using different techniques, we can fabricate different nanoscale morphologies. For example, we can use vapor based deposition to make dense surfaces with different nanosize grains. We can use solution based deposition to produce porous surfaces with different nanosize pores. Also, we can use solid based deposition to prepare nano rods with different nanosize diameters. The amazing fact that different nano patterns have different effects on cell responses may enable us to guide cells towards our desired response.

osseointegration osseointegration - 8 weeks after

Figure 8 Biological evaluation of plasmas sprayed titanium implants in vitro and in vivo. The left panel shows in vitro osteoblast cells’ adhering, migrating and ingrowth on the plasma sprayed titanium porous coating under a scanning electron microscope. The right panel shows osseointegration of new bone–titanium interface under a fluorescent microscope. The plasma sprayed functionally porous graded titanium coated samples were placed into a dog femur. At eight weeks after implantation, the new bone was not only directly in contact with the implant, but also grew into the interconnected pores and formed mechanical interlocking, thereby enhancing the fixation of implants with bone. Yellow indicates new bone; black indicates titanium.

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3. Naturally based novel biomaterials for cancer treatment

We are interested in developing naturally based novel biomaterials for improving the efficacy of cancer treatment and reducing side effects. Glioblastoma is the most common malignant tumor of the nervous system in adult humans. The survival rates of patients have not changed in the past 30 years because high grade gliomas mostly recur locally. Therefore, local therapies combined with surgical intervention are an ideal approach to improve the efficacy of treatments. These methods administer drugs directly into the brain, bypass the blood brain barrier (BBB), and deliver the drugs in a concentration-dependent manner. Some clinical studies have demonstrated that local chemotherapy delivered by polymer carrier significantly prolongs the survival time of patients. Currently we are developing a novel naturally based ellagic acid-chitosan composite that is safe and highly efficacious for an improved local chemotherapy.

Fluorescence images of GFP tagged rat C6 glioma

Figure 9 Fluorescence images of GFP (green fluorescent protein) tagged rat C6 glioma in nude mouse right flanks on the 5th and 21st days after tumor inoculation. The chitosan-ellagic acid composite significantly inhibited the tumor growth in a mouse flank model. (A) tumor-bearing control group; (B) chitosan carrier control group; (C) chitosan-ellagic acid experimental group. The arrows indicate the tumors.

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