Harnessing macrophage-mediated degradation of gelatin microspheres for spatiotemporal control of BMP2 release

Ramkumar T. Annamalai; Paul A. Turner; William F. Carson; Benjamin Levi; Steven Kunkel; Jan P. Stegemann

doi:10.1016/j.biomaterials.2018.01.040

Harnessing macrophage-mediated degradation of gelatin microspheres for spatiotemporal control of BMP2 release

Ramkumar T. Annamalai
, Paul A. Turner
, William F. Carson
, Benjamin Levi
, Steven Kunkel
, Jan P. Stegemann

Biomedical Engineering

Research output: Contribution to journal › Article › peer-review

140 Scopus citations

Abstract

Biomaterials-based approaches to harnessing the immune and inflammatory responses to potentiate wound healing hold important promise. Bone fracture healing is characterized by an acute inflammatory phase, followed by a transition to a regenerative and repair phase. In this study, we developed genipin-crosslinked gelatin microspheres designed to be preferentially degraded by inflammatory (M1) macrophages. Highly crosslinked (>90%) microspheres allowed efficient incorporation of bioactive bone morphogenetic protein 2 (BMP2), a potent stimulator of osteogenesis in progenitor cells, via electrostatic interactions. Release of BMP2 was directly correlated with degradation of the gelatin matrix. Exposure of microspheres to polarized murine macrophages showed that degradation was significantly higher in the presence of M1 macrophages, relative to alternatively activated (M2) macrophages and unpolarized controls. Microsphere degradation in the presence of non-inflammatory cells resulted in very low degradation rates. The expression of matrix metalloproteinases (MMPs) and tissue inhibitors of MMP (TIMPs) by macrophages were consistent with the observed phenotype-dependent degradation rates. Indirect co-culture of BMP2-loaded microspheres and macrophages with isolated adipose-derived mesenchymal stem cells (MSC) showed that M1 macrophages produced the strongest osteogenic response, comparable to direct supplementation of the culture medium with BMP2. Controlled release systems that are synchronized with the inflammatory response have the potential to provide better spatiotemporal control of growth factor delivery and therefore may improve the outcomes of recalcitrant wounds.

Original language	English
Pages (from-to)	216-227
Number of pages	12
Journal	Biomaterials
Volume	161
DOIs	https://doi.org/10.1016/j.biomaterials.2018.01.040
State	Published - Apr 2018

Bibliographical note

Publisher Copyright:
© 2018 Elsevier Ltd

Funding

We acknowledge Melissa Scola of Dr. Kunkel's lab for her assistance with the MMP and TIMP gene expression analysis. Research reported in this publication was supported in part by the National Institute of Arthritis and Musculoskeletal and Skin Diseases (R01AR062636, to JPS), the National Institute of Dental and Craniofacial Research (R01DE026630, to JPS), and the National Science Foundation (DMR 1641065, to JPS and PAT). BL is supported by funding from NIH/National Institute of General Medical Sciences Grant K08GM109105-0, NIH/National Institutes of Health R01 GM123069 and R01 AR071379, American College of Surgeons Clowes Award and the International FOP Association. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. We acknowledge Melissa Scola of Dr. Kunkel's lab for her assistance with the MMP and TIMP gene expression analysis. Research reported in this publication was supported in part by the National Institute of Arthritis and Musculoskeletal and Skin Diseases ( R01AR062636 , to JPS), the National Institute of Dental and Craniofacial Research ( R01DE026630 , to JPS), and the National Science Foundation (DMR 1641065 , to JPS and PAT). BL is supported by funding from NIH/ National Institute of General Medical Sciences Grant K08GM109105-0 , NIH/ National Institutes of Health R01 GM123069 and R01 AR071379 , American College of Surgeons Clowes Award and the International FOP Association . The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Funders	Funder number
National Science Foundation Arctic Social Science Program	DMR 1641065, 1641065
National Institutes of Health (NIH)	R01 GM123069
National Institute of General Medical Sciences DP2GM119177 Sophie Dumont National Institute of General Medical Sciences	K08GM109105-0
National Institute of Arthritis and Musculoskeletal and Skin Diseases	R01AR062636, R01AR071379
National Institute of Dental and Craniofacial Research	R01DE026630
American College of Surgeons
International Fibrodysplasia Ossificans Progressiva Association

Keywords

BMP
Bone tissue engineering
Controlled drug release
Immunomodulation
Inflammation
Macrophages

ASJC Scopus subject areas

Biophysics
Bioengineering
Ceramics and Composites
Biomaterials
Mechanics of Materials

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10.1016/j.biomaterials.2018.01.040

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title = "Harnessing macrophage-mediated degradation of gelatin microspheres for spatiotemporal control of BMP2 release",

abstract = "Biomaterials-based approaches to harnessing the immune and inflammatory responses to potentiate wound healing hold important promise. Bone fracture healing is characterized by an acute inflammatory phase, followed by a transition to a regenerative and repair phase. In this study, we developed genipin-crosslinked gelatin microspheres designed to be preferentially degraded by inflammatory (M1) macrophages. Highly crosslinked (>90\%) microspheres allowed efficient incorporation of bioactive bone morphogenetic protein 2 (BMP2), a potent stimulator of osteogenesis in progenitor cells, via electrostatic interactions. Release of BMP2 was directly correlated with degradation of the gelatin matrix. Exposure of microspheres to polarized murine macrophages showed that degradation was significantly higher in the presence of M1 macrophages, relative to alternatively activated (M2) macrophages and unpolarized controls. Microsphere degradation in the presence of non-inflammatory cells resulted in very low degradation rates. The expression of matrix metalloproteinases (MMPs) and tissue inhibitors of MMP (TIMPs) by macrophages were consistent with the observed phenotype-dependent degradation rates. Indirect co-culture of BMP2-loaded microspheres and macrophages with isolated adipose-derived mesenchymal stem cells (MSC) showed that M1 macrophages produced the strongest osteogenic response, comparable to direct supplementation of the culture medium with BMP2. Controlled release systems that are synchronized with the inflammatory response have the potential to provide better spatiotemporal control of growth factor delivery and therefore may improve the outcomes of recalcitrant wounds.",

keywords = "BMP, Bone tissue engineering, Controlled drug release, Immunomodulation, Inflammation, Macrophages",

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doi = "10.1016/j.biomaterials.2018.01.040",

language = "English",

volume = "161",

pages = "216--227",

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AU - Levi, Benjamin

AU - Kunkel, Steven

AU - Stegemann, Jan P.

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AB - Biomaterials-based approaches to harnessing the immune and inflammatory responses to potentiate wound healing hold important promise. Bone fracture healing is characterized by an acute inflammatory phase, followed by a transition to a regenerative and repair phase. In this study, we developed genipin-crosslinked gelatin microspheres designed to be preferentially degraded by inflammatory (M1) macrophages. Highly crosslinked (>90%) microspheres allowed efficient incorporation of bioactive bone morphogenetic protein 2 (BMP2), a potent stimulator of osteogenesis in progenitor cells, via electrostatic interactions. Release of BMP2 was directly correlated with degradation of the gelatin matrix. Exposure of microspheres to polarized murine macrophages showed that degradation was significantly higher in the presence of M1 macrophages, relative to alternatively activated (M2) macrophages and unpolarized controls. Microsphere degradation in the presence of non-inflammatory cells resulted in very low degradation rates. The expression of matrix metalloproteinases (MMPs) and tissue inhibitors of MMP (TIMPs) by macrophages were consistent with the observed phenotype-dependent degradation rates. Indirect co-culture of BMP2-loaded microspheres and macrophages with isolated adipose-derived mesenchymal stem cells (MSC) showed that M1 macrophages produced the strongest osteogenic response, comparable to direct supplementation of the culture medium with BMP2. Controlled release systems that are synchronized with the inflammatory response have the potential to provide better spatiotemporal control of growth factor delivery and therefore may improve the outcomes of recalcitrant wounds.

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Harnessing macrophage-mediated degradation of gelatin microspheres for spatiotemporal control of BMP2 release

Abstract

Bibliographical note

Funding

Keywords

ASJC Scopus subject areas

Access to Document

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