Biomaterials Science Blog

Protein-based biologics are gaining tremendous interests in the biomedical field after several successful translations into commercialized products. To this end, key hurdles in the development of protein-based therapeutics need to be properly addressed first. One of the most prominent issues is the instability of protein therapeutics in vivo, which requires higher and more frequent doses. As a result, protein-based therapy can become prohibitive in cost and may pose potential safety risks. Engineering protein therapeutics using biomaterials offer unique strategies to solve this problem by prolonging the half-life and enhancing the efficacy of these. In this blog, we feature three articles published in Biomaterials Science recently on the topic of Engineering Advanced Biologics as therapeutic agents.

1. Multivalent conjugates of basic fibroblast growth factor enhance in vitro proliferation and migration of endothelial cells
Aline Zbinden, Shane Browne, Eda I. Altiok, Felicia L. Svedlund, Wesley M. Jackson and Kevin E. Healy
Biomater. Sci., 2018, Advance Article, DOI: 10.1039/C7BM01052D

The authors reported the chemical conjugation of basic fibroblast growth factor (bFGF) onto hyaluronic acid (HA). Such multivalent conjugates were envisioned to increase residence time in vivo, protect bFGF from enzymatic degradation, and enhance protein bioactivity. Using a small molecule linker (N-(ε-Maleimidocaproic acid) hydrazide), bFGF was successfully conjugated at two different protein-to-polymer ratios and their structures were confirmed by extensive physico-chemical characterization. Compared to bFGF alone, HA conjugated bFGF displayed enhanced activity to promote the proliferation and more interestingly, the scratch closure of human umbilical cord vein endothelial cells. It’s noteworthy that the protein-to-polymer ratio and the conjugate size are two key parameters that could be easily tuned to modulate the bioactivity of the conjugate.

2. Synergistic effects of hyaluronate – epidermal growth factor conjugate patch on chronic wound healing
Yun Seop Kim, Dong Kyung Sung, Won Ho Kong, Hyemin Kim and Sei Kwang Hahn
Biomater. Sci., 2018, Advance Article, DOI: 10.1039/C8BM00079D

Similar to the strategy discussed above, the authors also utilized the biocompatible HA as carrier to conjugate epidermal growth factor (EGF) which is otherwise labile in vivo. The enzymatic degradation and stability studies revealed the superior stability of EGF when conjugated with HA. In vitro, HA–EGF conjugate increased keratinocyte proliferation, VEGF secretion, and migration towards scratch closure when compared to EGF alone. In vivo, HA–EGF conjugates loaded HA patch closed the wound in a rat model by enhancing de novo ECM secretion and mitigating inflammatory response. Overall, those comprehensive studies demonstrated the significance of protein-HA conjugates in improving the therapeutic effects of protein biologics.

3. Intra-articular TSG-6 delivery from heparin-based microparticles reduces cartilage damage in a rat model of osteoarthritis
Liane E. Tellier, Elda A. Treviño, Alexandra L. Brimeyer, David S. Reece, Nick J. Willett, Robert E. Guldbergde and Johnna S. Temenoff
Biomater. Sci., 2018, Advance Article, DOI: 10.1039/C8BM00010G

Here, the authors aimed to improve the delivery of TNF-α-stimulated gene-6 (TSG-6) for treating osteoarthritis. Specifically, they focused on heparin, another glycosaminoglycan, as a carrier biomaterial for TSG-6 delivery. It was first discovered that N-desulfated heparin maintained the beneficial role in promoting the bioactivity of TSG-6. Microparticles were thus made from N-desulfated heparin followed by TSG-6 encapsulation. TSG-6 was able to be released and demonstrated significantly higher anti-plasmin activity compared to soluble TSG-6. In a rat medial meniscal transection model, treatment of TSG-6 delivered by N-desulfated heparin but not in soluble form resulted in similar cartilage thickness, volume and GAG level compared to uninjured cartilage. These results showcased the advantages of heparin based microparticle in preserving and enhancing the bioactivity of therapeutic TSG-6 protein.

All articles free to read until 24 May

About the webwriter

Yingfei Xue is a web writer for Biomaterials Science. Currently, he is a PhD candidate and graduate student researcher in Dr. Shilpa Sant lab at the University of Pittsburgh, USA. His research focus on nano-/micro-technology in novel heart valve therapy. Find him on Twitter: @Phil_Xue or connect him on ResearchGate

Hydrogels represent one of the most important classes of biomaterials and have been widely used for drug/cell delivery, tissue engineering, and disease models due to their biocompatibility and biodegradability properties. Traditional bulk hydrogels often suffer from drawbacks such as limited injectability, lack of control over morphology, and low cell adherence. Therefore, hydrogels engineered via innovative biomaterial chemistry and biofabrication technologies aim to overcome these obstacles and hold the promise to translate hydrogel based therapy into clinical setting.

This month we focus on three articles published in Biomaterials Science reporting the recent advances in engineered hydrogels as therapeutics, 3D printing platforms, and cell culture systems.

1. Protein-engineered hydrogels enhance the survival of induced pluripotent stem cell-derived endothelial cells for treatment of peripheral arterial disease
Abbygail A. Foster, Ruby E. Dewi, Lei Cai, Luqia Hou, Zachary Strassberg, Cynthia A. Alcazar, Sarah C. Heilshorn and Ngan F. Huang
Biomater. Sci., 2018, Advance Article
DOI: 10.1039/C7BM00883J

Cell therapies via direct cell transplantation often resulted in limited therapeutic effects due to low cell viability and retention. Therefore, the authors utilized the platform technology of injectable shear-thinning hydrogel (termed as SHIELD) to mitigate such problems. SHIELD consists of engineered recombinant protein and polyethylene glycol modified proline-rich peptide domains, and it promoted cell-matrix interaction to improve cell viability and retention. Additionally, SHIELD was further strengthened by thermoresponsive poly(N-isopropylacrylamide). The encapsulation of human induced pluripotent stem cell-derived endothelial cells in SHIELD protected cells from membrane damage caused by injection and augmented cell proliferation under hypoxia. In a rodent model of peripheral arterial disease, cell injection with SHIELD had significantly higher cell retention in vivo and further promoted microvessel formation to relieve ischemic insult when compared to saline control.

2. Applying macromolecular crowding to 3D bioprinting: fabrication of 3D hierarchical porous collagen-based hydrogel constructs
Wei Long Ng, Min Hao Goh, Wai Yee Yeong, May Win Naing
Biomater. Sci., 2018, Advance Article
DOI: 10.1039/C7BM01015J

It has been well recognized that scaffold architecture plays a critical role in determining the cellular behavior. Tradition hydrogels fabricated by freeze drying, solvent casting, and phase separation were often confined to less controllable architectures. Utilizing 3D bioprinting via drop-on-demand (DOD) technique, the authors printed 3D hierarchical porous collagen scaffolds with finely controlled  pore size and porosity . In this process, droplets of polyvinylpyrrolidone (PVP) were uniformly printed to facilitate the rapid and homogeneous cross-linking, enhance collagen fibrillogenesis, and tune the collagen architecture in a controlled manner. This printing strategy yielded a cytocompatible construct as demonstrated by a primary human dermal fibroblasts model.

3. Evaluation of RGD functionalization in hybrid hydrogels as 3D neural stem cell culture systems
Emanuele Mauri, Alessandro Sacchetti, Nunzio Vicario, Luca Peruzzotti-Jametti, Filippo Rossi and Stefano Pluchino
Biomater. Sci., 2018, Advance Article
DOI: 10.1039/C7BM01056G

To improve the stem cell based therapy for the repair and regeneration of central nervous system, the authors engineered hydrogels which composed of polyethylene glycol, agarose, and polyacrylic acid with cell-adhesive and cell-recognition Arg-Gly-Asp (RGD) motif. When interfacing with neural stem cells, the RGD modified hydrogels enabled a higher ratio of active proliferating cell population compared to a 2D laminin surface or non-RGD hydrogel throughout the 21 day in vitro culture. Additionally, the examination of conditioned media obtained from the in vitro culture revealed the higher level of nutrients contained in the RGD modified hydrogels group, indicating the superior biocompatibility of RGD modified hydrogel construct.

Read these articles for free until 19 March

About the webwriter

Yingfei Xue is a web writer for Biomaterials Science. Currently, he is a PhD candidate and graduate student researcher in Dr. Shilpa Sant lab at the University of Pittsburgh, USA.  His research focus on nano-/micro-technology in novel heart valve therapy. Find him on Twitter: @Phil_Xue  or connect with him on ResearchGate.

The geometry of micro- or nano-materials determine their physico-chemical properties and play crucial roles in directing an array of in vivo biological activities. Historically, the significance of micro-/nano-geometry for biomaterials has not been adequately appreciated due to the limitations in manufacturing techniques. Recent years have witnessed the exponential growth of micro-/nano-fabrication technologies which allow closer scrutiny of the relationship between the micro-/nano-geometry and the biological effects of materials. This month the focus is on three articles published in Biomaterials Science reporting the recent advances to achieve controlled micro-/nano-geometry of biomedical devices including microdisks, nanosheets, and microcapsules.

1. Advanced manufacturing of microdisk vaccines for uniform control of material properties and immune cell function

Qin Zeng, Peipei Zhang, Xiangbin Zeng, Lisa H. Tostanoski and Christopher M. Jewell
Biomater. Sci., DOI: 10.1039/c7bm00520b

The heterogeneity in the geometry and loading level represents one major drawback of synthetic vaccine constructs. Therefore, taking advantage of the facile and flexible technique of soft lithography, the authors designed and fabricated PLGA microdisks with controllable dimension and payload loading. Compared to the conventional PLGA microparticles made by emulsion, microdisks possessed highly uniform diameter with less variation. Importantly, microdisks could safely co-deliver vaccine antigen and molecular adjuvants to primary dendritic cells. As a result, dendritic cells could be activated according to the composition of antigen and adjuvants. This controllable and programmable microdisk system will serve as platform to probe the relationship between the vaccine design parameters and immune responses in vivo.

2. The biodistribution, excretion and potential toxicity of different-sized Pd nanosheets in mice following oral and intraperitoneal administration

Xiaolan Chen, Jingchao Li, Yizhuan Huang, Jingping Wei, Duo Sun and Nanfeng Zheng
Biomater. Sci., 2017, 5, 2448. DOI: 10.1039/c7bm00769h

To elucidate the in vivo behaviors of Pd nanosheets (NSs), the authors synthesized size-specific Pd NSs (with 5 nm, 30 nm, or 80 nm in diameter) by controlling the chemical reaction conditions. Those NSs were then administrated via oral feeding or intraperitoneal injection to reveal different biodistribution, excretion, and toxicity profiles of those size-specific NSs. Interestingly, when intraperitoneally delivered, larger sized Pd NSs (80 nm) had higher accumulation in liver and spleen than the smaller sized Pd NSs (5 nm), which had higher accumulation in tumor tissue. In addition, the smaller sized NSs (5 nm) exhibited more excretion through urine than larger sized Pd NSs (30 and 80 nm). Overall, this study indicated that the size of nanomaterials could have significant influence on their biodistribution and bioavailability in vivo.

3. Development of drug-loaded polymer microcapsules for treatment of epilepsy

Yu Chen, Qi Gu, Zhilian Yue, Jeremy M. Crook, Simon E. Moulton, Mark J. Cook and Gordon G. Wallace
Biomater. Sci., 2017, 5, 2159. DOI: 10.1039/c7bm00623c

To achieve the goal of developing controllable local delivery system for treating epilepsy, the authors developed drug-loaded PLGA based microspheroids, microspheres, and microfibers by tuning the solution concentration during electrojetting (electrospinning and/or electrospraying) process. All the resultant microcapsules had excellent shape and size uniformity with high controllability and low variance. Different microcapsule geometry led to various sustained drug release profiles in vitro without compromising their cytocompatibility. This study highlighted the potential of programmable and controllable delivery system and suggested the potential role of geometry in controlling the drug release profile of micron-sized biomedical device.

Read these articles for free until 3 February

About the webwriter

Yingfei Xue is a web writer for Biomaterials Science. Currently, he is a PhD candidate and graduate student researcher in Dr. Shilpa Sant lab at the University of Pittsburgh, USA.  His research focus on nano-/micro-technology in novel heart valve therapy. Find him on Twitter: @Phil_Xue  or connect with him on ResearchGate.