PMID- 29421557
OWN - NLM
STAT- MEDLINE
DCOM- 20181119
LR  - 20240313
IS  - 1878-5905 (Electronic)
IS  - 0142-9612 (Print)
IS  - 0142-9612 (Linking)
VI  - 161
DP  - 2018 Apr
TI  - Harnessing macrophage-mediated degradation of gelatin microspheres for 
      spatiotemporal control of BMP2 release.
PG  - 216-227
LID - S0142-9612(18)30060-7 [pii]
LID - 10.1016/j.biomaterials.2018.01.040 [doi]
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.
CI  - Copyright (c) 2018 Elsevier Ltd. All rights reserved.
FAU - Annamalai, Ramkumar T
AU  - Annamalai RT
AD  - Department of Biomedical Engineering, University of Michigan, Ann Arbor, USA. 
      Electronic address: ramta@umich.edu.
FAU - Turner, Paul A
AU  - Turner PA
AD  - Department of Biomedical Engineering, University of Michigan, Ann Arbor, USA.
FAU - Carson, William F 4th
AU  - Carson WF 4th
AD  - Department of Pathology, University of Michigan, Ann Arbor, USA.
FAU - Levi, Benjamin
AU  - Levi B
AD  - Department of Surgery, University of Michigan, Ann Arbor, USA.
FAU - Kunkel, Steven
AU  - Kunkel S
AD  - Department of Pathology, University of Michigan, Ann Arbor, USA.
FAU - Stegemann, Jan P
AU  - Stegemann JP
AD  - Department of Biomedical Engineering, University of Michigan, Ann Arbor, USA. 
      Electronic address: jpsteg@umich.edu.
LA  - eng
GR  - R01 GM123069/GM/NIGMS NIH HHS/United States
GR  - R01 AR062636/AR/NIAMS NIH HHS/United States
GR  - R01 AR071379/AR/NIAMS NIH HHS/United States
GR  - K08 GM109105/GM/NIGMS NIH HHS/United States
GR  - R01 DE026630/DE/NIDCR NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20180203
PL  - Netherlands
TA  - Biomaterials
JT  - Biomaterials
JID - 8100316
RN  - 0 (Bone Morphogenetic Protein 2)
RN  - 9000-70-8 (Gelatin)
SB  - IM
MH  - Animals
MH  - Bone Morphogenetic Protein 2/*chemistry
MH  - *Bone and Bones
MH  - Drug Liberation
MH  - Gelatin/*chemistry
MH  - Macrophages/metabolism
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - *Microspheres
MH  - Tissue Engineering/methods
PMC - PMC5831261
MID - NIHMS943309
OTO - NOTNLM
OT  - BMP
OT  - Bone tissue engineering
OT  - Controlled drug release
OT  - Immunomodulation
OT  - Inflammation
OT  - Macrophages
EDAT- 2018/02/09 06:00
MHDA- 2018/11/20 06:00
PMCR- 2019/04/01
CRDT- 2018/02/09 06:00
PHST- 2017/10/24 00:00 [received]
PHST- 2018/01/24 00:00 [revised]
PHST- 2018/01/25 00:00 [accepted]
PHST- 2018/02/09 06:00 [pubmed]
PHST- 2018/11/20 06:00 [medline]
PHST- 2018/02/09 06:00 [entrez]
PHST- 2019/04/01 00:00 [pmc-release]
AID - S0142-9612(18)30060-7 [pii]
AID - 10.1016/j.biomaterials.2018.01.040 [doi]
PST - ppublish
SO  - Biomaterials. 2018 Apr;161:216-227. doi: 10.1016/j.biomaterials.2018.01.040. Epub 
      2018 Feb 3.